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  • Base Sequence
  • Chemistry
  • Nature Publishing Group (NPG)  (151)
  • 2010-2014  (151)
  • 1
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    A Hox regulatory network of hindbrain segmentation is conserved to the base of vertebrates (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-09-16
    Description: A defining feature governing head patterning of jawed vertebrates is a highly conserved gene regulatory network that integrates hindbrain segmentation with segmentally restricted domains of Hox gene expression. Although non-vertebrate chordates display nested domains of axial Hox expression, they lack hindbrain segmentation. The sea lamprey, a jawless fish, can provide unique insights into vertebrate origins owing to its phylogenetic position at the base of the vertebrate tree. It has been suggested that lamprey may represent an intermediate state where nested Hox expression has not been coupled to the process of hindbrain segmentation. However, little is known about the regulatory network underlying Hox expression in lamprey or its relationship to hindbrain segmentation. Here, using a novel tool that allows cross-species comparisons of regulatory elements between jawed and jawless vertebrates, we report deep conservation of both upstream regulators and segmental activity of enhancer elements across these distant species. Regulatory regions from diverse gnathostomes drive segmental reporter expression in the lamprey hindbrain and require the same transcriptional inputs (for example, Kreisler (also known as Mafba), Krox20 (also known as Egr2a)) in both lamprey and zebrafish. We find that lamprey hox genes display dynamic segmentally restricted domains of expression; we also isolated a conserved exonic hox2 enhancer from lamprey that drives segmental expression in rhombomeres 2 and 4. Our results show that coupling of Hox gene expression to segmentation of the hindbrain is an ancient trait with origin at the base of vertebrates that probably led to the formation of rhombomeric compartments with an underlying Hox code.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209185/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209185/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Parker, Hugo J -- Bronner, Marianne E -- Krumlauf, Robb -- R01 DE017911/DE/NIDCR NIH HHS/ -- R01 NS086907/NS/NINDS NIH HHS/ -- R01DE017911/DE/NIDCR NIH HHS/ -- R01NS086907/NS/NINDS NIH HHS/ -- England -- Nature. 2014 Oct 23;514(7523):490-3. doi: 10.1038/nature13723. Epub 2014 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA. ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA. ; 1] Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA [2] Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City, Kansas 66160, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25219855" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Body Patterning/genetics ; Conserved Sequence/*genetics ; Enhancer Elements, Genetic/genetics ; *Evolution, Molecular ; Gene Expression Regulation, Developmental ; Gene Regulatory Networks/*genetics ; Genes, Homeobox/*genetics ; Lampreys/embryology/genetics ; Molecular Sequence Data ; Phylogeny ; Rhombencephalon/*embryology/*metabolism ; Vertebrates/*embryology/genetics ; Zebrafish/embryology/genetics
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  • 2
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    Conditional tolerance of temperate phages via transcription-dependent CRISPR-Cas targeting (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-09-02
    Description: A fundamental feature of immune systems is the ability to distinguish pathogenic from self and commensal elements, and to attack the former but tolerate the latter. Prokaryotic CRISPR-Cas immune systems defend against phage infection by using Cas nucleases and small RNA guides that specify one or more target sites for cleavage of the viral genome. Temperate phages include viruses that can integrate into the bacterial chromosome, and they can carry genes that provide a fitness advantage to the lysogenic host. However, CRISPR-Cas targeting that relies strictly on DNA sequence recognition provides indiscriminate immunity both to lytic and lysogenic infection by temperate phages-compromising the genetic stability of these potentially beneficial elements altogether. Here we show that the Staphylococcus epidermidis CRISPR-Cas system can prevent lytic infection but tolerate lysogenization by temperate phages. Conditional tolerance is achieved through transcription-dependent DNA targeting, and ensures that targeting is resumed upon induction of the prophage lytic cycle. Our results provide evidence for the functional divergence of CRISPR-Cas systems and highlight the importance of targeting mechanism diversity. In addition, they extend the concept of 'tolerance to non-self' to the prokaryotic branch of adaptive immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214910/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214910/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goldberg, Gregory W -- Jiang, Wenyan -- Bikard, David -- Marraffini, Luciano A -- 1DP2AI104556-01/AI/NIAID NIH HHS/ -- DP2 AI104556/AI/NIAID NIH HHS/ -- T32 AI070084/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Oct 30;514(7524):633-7. doi: 10.1038/nature13637. Epub 2014 Aug 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Bacteriology, The Rockefeller University, New York, New York 10065, USA. ; 1] Laboratory of Bacteriology, The Rockefeller University, New York, New York 10065, USA [2] Synthetic Biology Group, Institut Pasteur, 28 Rue du Dr. Roux, 75015 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25174707" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteriophages/*genetics/immunology/pathogenicity/*physiology ; Base Sequence ; CRISPR-Associated Proteins/immunology/metabolism ; CRISPR-Cas Systems/*genetics/immunology/*physiology ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics/immunology ; DNA, Viral/genetics/immunology/metabolism ; Immune Tolerance ; Lysogeny/genetics/immunology ; Molecular Sequence Data ; Proviruses/genetics/immunology/pathogenicity/physiology ; Staphylococcus epidermidis/*genetics/immunology/*virology ; *Transcription, Genetic
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  • 3
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    Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53 (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-06-12
    Description: Cutaneous melanoma is epidemiologically linked to ultraviolet radiation (UVR), but the molecular mechanisms by which UVR drives melanomagenesis remain unclear. The most common somatic mutation in melanoma is a V600E substitution in BRAF, which is an early event. To investigate how UVR accelerates oncogenic BRAF-driven melanomagenesis, we used a BRAF(V600E) mouse model. In mice expressing BRAF(V600E) in their melanocytes, a single dose of UVR that mimicked mild sunburn in humans induced clonal expansion of the melanocytes, and repeated doses of UVR increased melanoma burden. Here we show that sunscreen (UVA superior, UVB sun protection factor (SPF) 50) delayed the onset of UVR-driven melanoma, but only provided partial protection. The UVR-exposed tumours showed increased numbers of single nucleotide variants and we observed mutations (H39Y, S124F, R245C, R270C, C272G) in the Trp53 tumour suppressor in approximately 40% of cases. TP53 is an accepted UVR target in human non-melanoma skin cancer, but is not thought to have a major role in melanoma. However, we show that, in mice, mutant Trp53 accelerated BRAF(V600E)-driven melanomagenesis, and that TP53 mutations are linked to evidence of UVR-induced DNA damage in human melanoma. Thus, we provide mechanistic insight into epidemiological data linking UVR to acquired naevi in humans. Furthermore, we identify TP53/Trp53 as a UVR-target gene that cooperates with BRAF(V600E) to induce melanoma, providing molecular insight into how UVR accelerates melanomagenesis. Our study validates public health campaigns that promote sunscreen protection for individuals at risk of melanoma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112218/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112218/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Viros, Amaya -- Sanchez-Laorden, Berta -- Pedersen, Malin -- Furney, Simon J -- Rae, Joel -- Hogan, Kate -- Ejiama, Sarah -- Girotti, Maria Romina -- Cook, Martin -- Dhomen, Nathalie -- Marais, Richard -- A12738/Cancer Research UK/United Kingdom -- A13540/Cancer Research UK/United Kingdom -- A17240/Cancer Research UK/United Kingdom -- A7091/Cancer Research UK/United Kingdom -- A7192/Cancer Research UK/United Kingdom -- C107/A10433/Cancer Research UK/United Kingdom -- C5759/A12328/Cancer Research UK/United Kingdom -- England -- Nature. 2014 Jul 24;511(7510):478-82. doi: 10.1038/nature13298. Epub 2014 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK [2]. ; 1] Signal Transduction Team, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2]. ; Signal Transduction Team, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. ; Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. ; 1] Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK [2] Histopathology, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK. ; 1] Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK [2] Signal Transduction Team, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24919155" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Cell Transformation, Neoplastic/*genetics/*radiation effects ; DNA Damage/genetics ; Disease Models, Animal ; Female ; Humans ; Melanocytes/metabolism/pathology/radiation effects ; Melanoma/etiology/*genetics/metabolism/*pathology ; Mice ; Mice, Inbred C57BL ; Mutagenesis/genetics/*radiation effects ; Mutation/genetics/radiation effects ; Nevus/etiology/genetics/metabolism/pathology ; Proto-Oncogene Proteins B-raf/*genetics/metabolism ; Skin Neoplasms/etiology/genetics/metabolism/pathology ; Sunburn/complications/etiology/genetics ; Sunscreening Agents/pharmacology ; Tumor Suppressor Protein p53/*genetics/metabolism ; Ultraviolet Rays/*adverse effects
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  • 4
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    Single-cell RNA-seq reveals dynamic paracrine control of cellular variation (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-06-12
    Description: High-throughput single-cell transcriptomics offers an unbiased approach for understanding the extent, basis and function of gene expression variation between seemingly identical cells. Here we sequence single-cell RNA-seq libraries prepared from over 1,700 primary mouse bone-marrow-derived dendritic cells spanning several experimental conditions. We find substantial variation between identically stimulated dendritic cells, in both the fraction of cells detectably expressing a given messenger RNA and the transcript's level within expressing cells. Distinct gene modules are characterized by different temporal heterogeneity profiles. In particular, a 'core' module of antiviral genes is expressed very early by a few 'precocious' cells in response to uniform stimulation with a pathogenic component, but is later activated in all cells. By stimulating cells individually in sealed microfluidic chambers, analysing dendritic cells from knockout mice, and modulating secretion and extracellular signalling, we show that this response is coordinated by interferon-mediated paracrine signalling from these precocious cells. Notably, preventing cell-to-cell communication also substantially reduces variability between cells in the expression of an early-induced 'peaked' inflammatory module, suggesting that paracrine signalling additionally represses part of the inflammatory program. Our study highlights the importance of cell-to-cell communication in controlling cellular heterogeneity and reveals general strategies that multicellular populations can use to establish complex dynamic responses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4193940/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4193940/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shalek, Alex K -- Satija, Rahul -- Shuga, Joe -- Trombetta, John J -- Gennert, Dave -- Lu, Diana -- Chen, Peilin -- Gertner, Rona S -- Gaublomme, Jellert T -- Yosef, Nir -- Schwartz, Schraga -- Fowler, Brian -- Weaver, Suzanne -- Wang, Jing -- Wang, Xiaohui -- Ding, Ruihua -- Raychowdhury, Raktima -- Friedman, Nir -- Hacohen, Nir -- Park, Hongkun -- May, Andrew P -- Regev, Aviv -- 1F32HD075541-01/HD/NICHD NIH HHS/ -- 1P50HG006193-01/HG/NHGRI NIH HHS/ -- 5DP1OD003893-03/OD/NIH HHS/ -- DP1 CA174427/CA/NCI NIH HHS/ -- DP1OD003958-01/OD/NIH HHS/ -- F32 HD075541/HD/NICHD NIH HHS/ -- P50 HG006193/HG/NHGRI NIH HHS/ -- U54 AI057159/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jun 19;510(7505):363-9. doi: 10.1038/nature13437. Epub 2014 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Chemistry & Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA [2] Department of Physics, Harvard University, 17 Oxford Street, Cambridge, Massachusetts 02138, USA [3] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [4]. ; 1] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [2]. ; 1] Fluidigm Corporation, 7000 Shoreline Court, Suite 100, South San Francisco, California 94080, USA [2]. ; Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. ; Fluidigm Corporation, 7000 Shoreline Court, Suite 100, South San Francisco, California 94080, USA. ; 1] Department of Chemistry & Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA [2] Department of Physics, Harvard University, 17 Oxford Street, Cambridge, Massachusetts 02138, USA. ; School of Computer Science and Engineering, Hebrew University, 91904 Jerusalem, Israel. ; 1] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Center for Immunology and Inflammatory Diseases & Department of Medicine, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. ; 1] Department of Chemistry & Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA [2] Department of Physics, Harvard University, 17 Oxford Street, Cambridge, Massachusetts 02138, USA [3] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. ; 1] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02140, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24919153" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Viral/pharmacology ; Base Sequence ; Cell Communication ; Dendritic Cells/drug effects/*immunology ; Gene Expression Profiling ; Gene Expression Regulation/*immunology ; Immunity/*genetics ; Interferon-beta/genetics ; Mice ; Microfluidic Analytical Techniques ; *Paracrine Communication ; Principal Component Analysis ; RNA, Messenger/chemistry/genetics ; Single-Cell Analysis
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  • 5
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    C9orf72 nucleotide repeat structures initiate molecular cascades of disease (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-03-07
    Description: A hexanucleotide repeat expansion (HRE), (GGGGCC)n, in C9orf72 is the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we identify a molecular mechanism by which structural polymorphism of the HRE leads to ALS/FTD pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA*DNA hybrids (R-loops). The structural polymorphism causes a repeat-length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin, an essential nucleolar protein, preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Our results demonstrate that distinct C9orf72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046618/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046618/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Haeusler, Aaron R -- Donnelly, Christopher J -- Periz, Goran -- Simko, Eric A J -- Shaw, Patrick G -- Kim, Min-Sik -- Maragakis, Nicholas J -- Troncoso, Juan C -- Pandey, Akhilesh -- Sattler, Rita -- Rothstein, Jeffrey D -- Wang, Jiou -- 5T32CA009110-36/CA/NCI NIH HHS/ -- NS07432/NS/NINDS NIH HHS/ -- NS085207/NS/NINDS NIH HHS/ -- P30 DK089502/DK/NIDDK NIH HHS/ -- P50 AG005146/AG/NIA NIH HHS/ -- P50AG05146/AG/NIA NIH HHS/ -- R01 NS074324/NS/NINDS NIH HHS/ -- R01 NS085207/NS/NINDS NIH HHS/ -- T32 CA009110/CA/NCI NIH HHS/ -- UL1 TR001079/TR/NCATS NIH HHS/ -- England -- Nature. 2014 Mar 13;507(7491):195-200. doi: 10.1038/nature13124. Epub 2014 Mar 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry and Molecular Biology, Johns Hopkins University Baltimore, Maryland 21205, USA [2] Department of Neuroscience, Johns Hopkins University Baltimore, Maryland 21205, USA. ; 1] Department of Neurology, Johns Hopkins University Baltimore, Maryland 21205, USA [2] The Brain Science Institute, Johns Hopkins University Baltimore, Maryland 21205, USA. ; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Baltimore, Maryland 21205, USA. ; Department of Neurology, Johns Hopkins University Baltimore, Maryland 21205, USA. ; Department of Pathology, Johns Hopkins University Baltimore, Maryland, 21205, USA. ; 1] Department of Neuroscience, Johns Hopkins University Baltimore, Maryland 21205, USA [2] Department of Neurology, Johns Hopkins University Baltimore, Maryland 21205, USA [3] The Brain Science Institute, Johns Hopkins University Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24598541" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis/genetics ; B-Lymphocytes ; Base Sequence ; Cell Nucleolus/genetics/pathology ; DNA/genetics/metabolism ; DNA Repeat Expansion/*genetics ; Frontotemporal Dementia/genetics ; G-Quadruplexes ; HEK293 Cells ; Humans ; Models, Molecular ; Neurons ; Open Reading Frames/*genetics ; Phosphoproteins/metabolism ; RNA/biosynthesis/chemistry/genetics/metabolism ; RNA-Binding Proteins/metabolism ; Ribonucleoproteins/metabolism ; Stress, Physiological ; Transcription, Genetic/genetics
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  • 6
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    Giant gene banks take on disease (2014)
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    Publication Date: 2014-10-17
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Check Hayden, Erika -- England -- Nature. 2014 Oct 16;514(7522):282. doi: 10.1038/514282a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25318499" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; *Databases, Genetic ; Disease/*genetics ; Genetic Association Studies ; Genetic Variation/genetics ; Genetics, Medical ; Humans ; Information Dissemination ; Phenotype ; Sequence Analysis, DNA
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  • 7
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    The selective tRNA aminoacylation mechanism based on a single G*U pair (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-06-12
    Description: Ligation of tRNAs with their cognate amino acids, by aminoacyl-tRNA synthetases, establishes the genetic code. Throughout evolution, tRNA(Ala) selection by alanyl-tRNA synthetase (AlaRS) has depended predominantly on a single wobble base pair in the acceptor stem, G3*U70, mainly on the kcat level. Here we report the crystal structures of an archaeal AlaRS in complex with tRNA(Ala) with G3*U70 and its A3*U70 variant. AlaRS interacts with both the minor- and the major-groove sides of G3*U70, widening the major groove. The geometry difference between G3*U70 and A3*U70 is transmitted along the acceptor stem to the 3'-CCA region. Thus, the 3'-CCA region of tRNA(Ala) with G3*U70 is oriented to the reactive route that reaches the active site, whereas that of the A3*U70 variant is folded back into the non-reactive route. This novel mechanism enables the single wobble pair to dominantly determine the specificity of tRNA selection, by an approximate 100-fold difference in kcat.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323281/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323281/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Naganuma, Masahiro -- Sekine, Shun-ichi -- Chong, Yeeting Esther -- Guo, Min -- Yang, Xiang-Lei -- Gamper, Howard -- Hou, Ya-Ming -- Schimmel, Paul -- Yokoyama, Shigeyuki -- GM015539/GM/NIGMS NIH HHS/ -- GM023562/GM/NIGMS NIH HHS/ -- NS085092/NS/NINDS NIH HHS/ -- R01 GM015539/GM/NIGMS NIH HHS/ -- R01 GM023562/GM/NIGMS NIH HHS/ -- R01 GM100136/GM/NIGMS NIH HHS/ -- R01 NS085092/NS/NINDS NIH HHS/ -- England -- Nature. 2014 Jun 26;510(7506):507-11. doi: 10.1038/nature13440. Epub 2014 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Biophysics and Biochemistry and Laboratory of Structural Biology, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] RIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Biophysics and Biochemistry and Laboratory of Structural Biology, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; 1] The Skaggs Institute for Chemical Biology and the Department of Cell and Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] aTyr Pharma, 3545 John Hopkins Court, San Diego, California 92121, USA (Y.E.C.); Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, USA (M.G.). ; The Skaggs Institute for Chemical Biology and the Department of Cell and Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. ; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. ; 1] The Skaggs Institute for Chemical Biology and the Department of Cell and Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] The Scripps Florida Research Institute, 130 Scripps Way, 3B3 Jupiter, Florida 33458-5284, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24919148" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Monophosphate/analogs & derivatives/chemistry ; Alanine-tRNA Ligase/*chemistry ; Archaeoglobus fulgidus/*enzymology/*genetics ; *Base Pairing ; Base Sequence ; Catalytic Domain ; Crystallography, X-Ray ; Kinetics ; Models, Molecular ; RNA, Transfer, Ala/*chemistry/*genetics ; Substrate Specificity ; *Transfer RNA Aminoacylation
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    Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers (2014)
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    Publication Date: 2014-04-04
    Description: Cancer genome sequencing studies indicate that a single breast cancer typically harbours multiple genetically distinct subclones. As carcinogenesis involves a breakdown in the cell-cell cooperation that normally maintains epithelial tissue architecture, individual subclones within a malignant microenvironment are commonly depicted as self-interested competitors. Alternatively, breast cancer subclones might interact cooperatively to gain a selective growth advantage in some cases. Although interclonal cooperation has been shown to drive tumorigenesis in fruitfly models, definitive evidence for functional cooperation between epithelial tumour cell subclones in mammals is lacking. Here we use mouse models of breast cancer to show that interclonal cooperation can be essential for tumour maintenance. Aberrant expression of the secreted signalling molecule Wnt1 generates mixed-lineage mammary tumours composed of basal and luminal tumour cell subtypes, which purportedly derive from a bipotent malignant progenitor cell residing atop a tumour cell hierarchy. Using somatic Hras mutations as clonal markers, we show that some Wnt tumours indeed conform to a hierarchical configuration, but that others unexpectedly harbour genetically distinct basal Hras mutant and luminal Hras wild-type subclones. Both subclones are required for efficient tumour propagation, which strictly depends on luminally produced Wnt1. When biclonal tumours were challenged with Wnt withdrawal to simulate targeted therapy, analysis of tumour regression and relapse revealed that basal subclones recruit heterologous Wnt-producing cells to restore tumour growth. Alternatively, in the absence of a substitute Wnt source, the original subclones often evolve to rescue Wnt pathway activation and drive relapse, either by restoring cooperation or by switching to a defector strategy. Uncovering similar modes of interclonal cooperation in human cancers may inform efforts aimed at eradicating tumour cell communities.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050741/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050741/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cleary, Allison S -- Leonard, Travis L -- Gestl, Shelley A -- Gunther, Edward J -- R01 CA152222/CA/NCI NIH HHS/ -- England -- Nature. 2014 Apr 3;508(7494):113-7. doi: 10.1038/nature13187.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Jake Gittlen Laboratories for Cancer Research, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA [2] Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Hershey, Pennsylvania 17033, USA. ; 1] Jake Gittlen Laboratories for Cancer Research, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA [2] Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Hershey, Pennsylvania 17033, USA [3] Department of Medicine (Hematology/Oncology), Pennsylvania State University College of Medicine, Hershey, Hershey, Pennsylvania 17033, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24695311" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Breast Neoplasms/genetics/*metabolism/*pathology ; Cell Lineage ; Cell Proliferation ; Clone Cells/metabolism/pathology ; Disease Models, Animal ; Female ; Mice ; Mosaicism ; Mutation ; Neoplasm Recurrence, Local/genetics/metabolism/pathology ; Neoplastic Stem Cells/metabolism/pathology ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Wnt Signaling Pathway ; Wnt1 Protein/deficiency/*metabolism
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    Programmable RNA recognition and cleavage by CRISPR/Cas9 (2014)
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    Publication Date: 2014-10-03
    Description: The CRISPR-associated protein Cas9 is an RNA-guided DNA endonuclease that uses RNA-DNA complementarity to identify target sites for sequence-specific double-stranded DNA (dsDNA) cleavage. In its native context, Cas9 acts on DNA substrates exclusively because both binding and catalysis require recognition of a short DNA sequence, known as the protospacer adjacent motif (PAM), next to and on the strand opposite the twenty-nucleotide target site in dsDNA. Cas9 has proven to be a versatile tool for genome engineering and gene regulation in a large range of prokaryotic and eukaryotic cell types, and in whole organisms, but it has been thought to be incapable of targeting RNA. Here we show that Cas9 binds with high affinity to single-stranded RNA (ssRNA) targets matching the Cas9-associated guide RNA sequence when the PAM is presented in trans as a separate DNA oligonucleotide. Furthermore, PAM-presenting oligonucleotides (PAMmers) stimulate site-specific endonucleolytic cleavage of ssRNA targets, similar to PAM-mediated stimulation of Cas9-catalysed DNA cleavage. Using specially designed PAMmers, Cas9 can be specifically directed to bind or cut RNA targets while avoiding corresponding DNA sequences, and we demonstrate that this strategy enables the isolation of a specific endogenous messenger RNA from cells. These results reveal a fundamental connection between PAM binding and substrate selection by Cas9, and highlight the utility of Cas9 for programmable transcript recognition without the need for tags.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268322/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268322/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉O'Connell, Mitchell R -- Oakes, Benjamin L -- Sternberg, Samuel H -- East-Seletsky, Alexandra -- Kaplan, Matias -- Doudna, Jennifer A -- P50 GM102706/GM/NIGMS NIH HHS/ -- P50GM102706-03/GM/NIGMS NIH HHS/ -- T32 GM007232/GM/NIGMS NIH HHS/ -- T32 GM066698/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Dec 11;516(7530):263-6. doi: 10.1038/nature13769. Epub 2014 Sep 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA. ; Department of Chemistry, University of California, Berkeley, California 94720, USA. ; 1] Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA [2] Department of Agricultural and Biological Engineering, University of Florida, Gainesville, Florida 32611, USA. ; 1] Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA [2] Department of Chemistry, University of California, Berkeley, California 94720, USA [3] Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA [4] Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25274302" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; CRISPR-Associated Proteins/*metabolism ; CRISPR-Cas Systems/*physiology ; Cell Extracts ; Clustered Regularly Interspaced Short Palindromic Repeats/*genetics ; DNA/chemistry/genetics/metabolism ; Genetic Engineering/*methods ; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/genetics ; HeLa Cells ; Humans ; Nucleotide Motifs ; Oligonucleotides/chemistry/genetics/metabolism ; RNA/chemistry/genetics/*metabolism ; RNA, Guide/chemistry/genetics/metabolism ; RNA, Messenger/genetics/isolation & purification/metabolism ; Substrate Specificity
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    The structural basis of transfer RNA mimicry and conformational plasticity by a viral RNA (2014)
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    Publication Date: 2014-06-10
    Description: RNA is arguably the most functionally diverse biological macromolecule. In some cases a single discrete RNA sequence performs multiple roles, and this can be conferred by a complex three-dimensional structure. Such multifunctionality can also be driven or enhanced by the ability of a given RNA to assume different conformational (and therefore functional) states. Despite its biological importance, a detailed structural understanding of the paradigm of RNA structure-driven multifunctionality is lacking. To address this gap it is useful to study examples from single-stranded positive-sense RNA viruses, a prototype being the tRNA-like structure (TLS) found at the 3' end of the turnip yellow mosaic virus (TYMV). This TLS not only acts like a tRNA to drive aminoacylation of the viral genomic (g)RNA, but also interacts with other structures in the 3' untranslated region of the gRNA, contains the promoter for negative-strand synthesis, and influences several infection-critical processes. TLS RNA can provide a glimpse into the structural basis of RNA multifunctionality and plasticity, but for decades its high-resolution structure has remained elusive. Here we present the crystal structure of the complete TYMV TLS to 2.0 A resolution. Globally, the RNA adopts a shape that mimics tRNA, but it uses a very different set of intramolecular interactions to achieve this shape. These interactions also allow the TLS to readily switch conformations. In addition, the TLS structure is 'two faced': one face closely mimics tRNA and drives aminoacylation, the other face diverges from tRNA and enables additional functionality. The TLS is thus structured to perform several functions and interact with diverse binding partners, and we demonstrate its ability to specifically bind to ribosomes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136544/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136544/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Colussi, Timothy M -- Costantino, David A -- Hammond, John A -- Ruehle, Grant M -- Nix, Jay C -- Kieft, Jeffrey S -- GM081346/GM/NIGMS NIH HHS/ -- GM097333/GM/NIGMS NIH HHS/ -- P30 CA046934/CA/NCI NIH HHS/ -- P30CA046934/CA/NCI NIH HHS/ -- R01 GM081346/GM/NIGMS NIH HHS/ -- R01 GM097333/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jul 17;511(7509):366-9. doi: 10.1038/nature13378. Epub 2014 Jun 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA [2] Howard Hughes Medical Institute, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA [3] Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, USA (T.M.C.); Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, California 92037, USA (J.A.H.). ; 1] Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA [2] Howard Hughes Medical Institute, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA. ; 1] Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA [2] Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, USA (T.M.C.); Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, California 92037, USA (J.A.H.). ; Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA. ; Molecular Biology Consortium, Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24909993" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions ; Amino Acyl-tRNA Synthetases/metabolism ; Aminoacylation ; Base Sequence ; Crystallography, X-Ray ; Models, Molecular ; *Molecular Mimicry ; Molecular Sequence Data ; *Nucleic Acid Conformation ; Protein Binding ; RNA Folding ; RNA, Guide/genetics/metabolism ; RNA, Transfer/*chemistry/genetics/metabolism ; RNA, Viral/*chemistry/genetics/*metabolism ; Ribosomes/chemistry/metabolism ; Tymovirus/*genetics
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    Genetic and epigenetic fine mapping of causal autoimmune disease variants (2014)
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    Publication Date: 2014-11-05
    Description: Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4(+) T-cell subsets, regulatory T cells, CD8(+) T cells, B cells, and monocytes. We find that approximately 90% of causal variants are non-coding, with approximately 60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10-20% directly alter recognizable transcription factor binding motifs. Rather, most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336207/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336207/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Farh, Kyle Kai-How -- Marson, Alexander -- Zhu, Jiang -- Kleinewietfeld, Markus -- Housley, William J -- Beik, Samantha -- Shoresh, Noam -- Whitton, Holly -- Ryan, Russell J H -- Shishkin, Alexander A -- Hatan, Meital -- Carrasco-Alfonso, Marlene J -- Mayer, Dita -- Luckey, C John -- Patsopoulos, Nikolaos A -- De Jager, Philip L -- Kuchroo, Vijay K -- Epstein, Charles B -- Daly, Mark J -- Hafler, David A -- Bernstein, Bradley E -- 12-0089/Worldwide Cancer Research/United Kingdom -- AI039671/AI/NIAID NIH HHS/ -- AI045757/AI/NIAID NIH HHS/ -- AI046130/AI/NIAID NIH HHS/ -- AI070352/AI/NIAID NIH HHS/ -- ES017155/ES/NIEHS NIH HHS/ -- GM093080/GM/NIGMS NIH HHS/ -- HG004570/HG/NHGRI NIH HHS/ -- NS067305/NS/NINDS NIH HHS/ -- NS24247/NS/NINDS NIH HHS/ -- P01 AI039671/AI/NIAID NIH HHS/ -- P01 AI045757/AI/NIAID NIH HHS/ -- P30 DK063720/DK/NIDDK NIH HHS/ -- R01 NS024247/NS/NINDS NIH HHS/ -- R37 NS024247/NS/NINDS NIH HHS/ -- T32 GM007748/GM/NIGMS NIH HHS/ -- U01 ES017155/ES/NIEHS NIH HHS/ -- U19 AI046130/AI/NIAID NIH HHS/ -- U19 AI070352/AI/NIAID NIH HHS/ -- U54 HG004570/HG/NHGRI NIH HHS/ -- U54 HG006991/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Feb 19;518(7539):337-43. doi: 10.1038/nature13835. Epub 2014 Oct 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Diabetes Center and Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, California 94143, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA [3] Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA [4] Center for Systems Biology and Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut 06511, USA. ; Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut 06511, USA. ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] California Institute of Technology, 1200 E California Boulevard, Pasadena, California 91125, USA. ; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02142, USA [3] Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02142, USA. ; Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363779" target="_blank"〉PubMed〈/a〉
    Keywords: Autoimmune Diseases/*genetics/immunology/pathology ; Base Sequence ; Chromatin/genetics ; Consensus Sequence/genetics ; Enhancer Elements, Genetic/genetics ; Epigenesis, Genetic/*genetics ; Epigenomics ; Genome-Wide Association Study ; Humans ; Nucleotide Motifs ; Organ Specificity ; Polymorphism, Single Nucleotide/*genetics ; T-Lymphocytes/immunology/metabolism ; Transcription Factors/metabolism
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    Structural basis for the inhibition of the eukaryotic ribosome (2014)
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    Publication Date: 2014-09-12
    Description: The ribosome is a molecular machine responsible for protein synthesis and a major target for small-molecule inhibitors. Compared to the wealth of structural information available on ribosome-targeting antibiotics in bacteria, our understanding of the binding mode of ribosome inhibitors in eukaryotes is currently limited. Here we used X-ray crystallography to determine 16 high-resolution structures of 80S ribosomes from Saccharomyces cerevisiae in complexes with 12 eukaryote-specific and 4 broad-spectrum inhibitors. All inhibitors were found associated with messenger RNA and transfer RNA binding sites. In combination with kinetic experiments, the structures suggest a model for the action of cycloheximide and lactimidomycin, which explains why lactimidomycin, the larger compound, specifically targets the first elongation cycle. The study defines common principles of targeting and resistance, provides insights into translation inhibitor mode of action and reveals the structural determinants responsible for species selectivity which could guide future drug development.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Garreau de Loubresse, Nicolas -- Prokhorova, Irina -- Holtkamp, Wolf -- Rodnina, Marina V -- Yusupova, Gulnara -- Yusupov, Marat -- 294312/European Research Council/International -- England -- Nature. 2014 Sep 25;513(7519):517-22. doi: 10.1038/nature13737. Epub 2014 Sep 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Universite de Strasbourg, 67404, Illkirch, France. ; Department of Physical Biochemistry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25209664" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Binding Sites/drug effects ; Crystallography, X-Ray ; Cycloheximide/pharmacology ; Drug Resistance/drug effects ; Eukaryotic Cells/*chemistry/drug effects/enzymology ; Kinetics ; Macrolides/pharmacology ; Models, Molecular ; Molecular Targeted Therapy ; Molecular Weight ; Peptide Chain Elongation, Translational/drug effects ; Peptidyl Transferases/chemistry/metabolism ; Piperidones/pharmacology ; Protein Synthesis Inhibitors/*chemistry/*pharmacology ; RNA, Messenger/genetics/metabolism ; RNA, Transfer/genetics/metabolism ; Ribosome Subunits, Large, Eukaryotic/chemistry/drug effects/metabolism ; Ribosomes/*chemistry/*drug effects/metabolism ; Saccharomyces cerevisiae/*chemistry ; Species Specificity ; Substrate Specificity
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    A single female-specific piRNA is the primary determiner of sex in the silkworm (2014)
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    Publication Date: 2014-05-16
    Description: The silkworm Bombyx mori uses a WZ sex determination system that is analogous to the one found in birds and some reptiles. In this system, males have two Z sex chromosomes, whereas females have Z and W sex chromosomes. The silkworm W chromosome has a dominant role in female determination, suggesting the existence of a dominant feminizing gene in this chromosome. However, the W chromosome is almost fully occupied by transposable element sequences, and no functional protein-coding gene has been identified so far. Female-enriched PIWI-interacting RNAs (piRNAs) are the only known transcripts that are produced from the sex-determining region of the W chromosome, but the function(s) of these piRNAs are unknown. Here we show that a W-chromosome-derived, female-specific piRNA is the feminizing factor of B. mori. This piRNA is produced from a piRNA precursor which we named Fem. Fem sequences were arranged in tandem in the sex-determining region of the W chromosome. Inhibition of Fem-derived piRNA-mediated signalling in female embryos led to the production of the male-specific splice variants of B. mori doublesex (Bmdsx), a gene which acts at the downstream end of the sex differentiation cascade. A target gene of Fem-derived piRNA was identified on the Z chromosome of B. mori. This gene, which we named Masc, encoded a CCCH-type zinc finger protein. We show that the silencing of Masc messenger RNA by Fem piRNA is required for the production of female-specific isoforms of Bmdsx in female embryos, and that Masc protein controls both dosage compensation and masculinization in male embryos. Our study characterizes a single small RNA that is responsible for primary sex determination in the WZ sex determination system.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kiuchi, Takashi -- Koga, Hikaru -- Kawamoto, Munetaka -- Shoji, Keisuke -- Sakai, Hiroki -- Arai, Yuji -- Ishihara, Genki -- Kawaoka, Shinpei -- Sugano, Sumio -- Shimada, Toru -- Suzuki, Yutaka -- Suzuki, Masataka G -- Katsuma, Susumu -- England -- Nature. 2014 May 29;509(7502):633-6. doi: 10.1038/nature13315. Epub 2014 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Agricultural and Environmental Biology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. ; 1] Department of Agricultural and Environmental Biology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan [2]. ; Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan. ; Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24828047" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing/genetics ; Animals ; Base Sequence ; Bombyx/embryology/*genetics ; Dosage Compensation, Genetic ; Female ; Male ; Molecular Sequence Data ; RNA, Small Interfering/*genetics ; *Sex Characteristics ; Sex Chromosomes/genetics ; Sex Determination Processes/*genetics
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    Leukaemogenesis induced by an activating beta-catenin mutation in osteoblasts (2014)
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    Publication Date: 2014-01-17
    Description: Cells of the osteoblast lineage affect the homing and the number of long-term repopulating haematopoietic stem cells, haematopoietic stem cell mobilization and lineage determination and B cell lymphopoiesis. Osteoblasts were recently implicated in pre-leukaemic conditions in mice. However, a single genetic change in osteoblasts that can induce leukaemogenesis has not been shown. Here we show that an activating mutation of beta-catenin in mouse osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukaemia with common chromosomal aberrations and cell autonomous progression. Activated beta-catenin stimulates expression of the Notch ligand jagged 1 in osteoblasts. Subsequent activation of Notch signalling in haematopoietic stem cell progenitors induces the malignant changes. Genetic or pharmacological inhibition of Notch signalling ameliorates acute myeloid leukaemia and demonstrates the pathogenic role of the Notch pathway. In 38% of patients with myelodysplastic syndromes or acute myeloid leukaemia, increased beta-catenin signalling and nuclear accumulation was identified in osteoblasts and these patients showed increased Notch signalling in haematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce acute myeloid leukaemia, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to acute myeloid leukaemia.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116754/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116754/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kode, Aruna -- Manavalan, John S -- Mosialou, Ioanna -- Bhagat, Govind -- Rathinam, Chozha V -- Luo, Na -- Khiabanian, Hossein -- Lee, Albert -- Murty, Vundavalli V -- Friedman, Richard -- Brum, Andrea -- Park, David -- Galili, Naomi -- Mukherjee, Siddhartha -- Teruya-Feldstein, Julie -- Raza, Azra -- Rabadan, Raul -- Berman, Ellin -- Kousteni, Stavroula -- P01 AG032959/AG/NIA NIH HHS/ -- P30 DK063608/DK/NIDDK NIH HHS/ -- R01 AR054447/AR/NIAMS NIH HHS/ -- R01 AR055931/AR/NIAMS NIH HHS/ -- T32 GM082797/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Feb 13;506(7487):240-4. doi: 10.1038/nature12883. Epub 2014 Jan 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA. ; Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA. ; Department of Genetics and Development College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA. ; Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, New York 10032, USA. ; Department of Pathology & Institute for Cancer Genetics Irving Cancer Research Center, Columbia University, New York, New York 10032, USA. ; Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center and Department of Biomedical Informatics, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA. ; 1] Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA [2] Department of Internal Medicine, Erasmus MC, Dr. Molewaterplein 50, NL-3015 GE Rotterdam, The Netherlands. ; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. ; Myelodysplastic Syndromes Center, Columbia University New York, New York 10032, USA. ; Departments of Medicine Hematology & Oncology Columbia University New York, New York 10032, USA. ; Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. ; 1] Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA [2] Department of Physiology & Cellular Biophysics, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24429522" target="_blank"〉PubMed〈/a〉
    Keywords: Anemia/genetics/metabolism/pathology ; Animals ; Base Sequence ; Calcium-Binding Proteins/deficiency/genetics/metabolism ; Cell Differentiation/genetics ; Cell Lineage ; Cell Nucleus/metabolism ; Cell Transformation, Neoplastic/*genetics/pathology ; Chromosome Aberrations ; Female ; Hematopoietic Stem Cells/metabolism/pathology ; Humans ; Intercellular Signaling Peptides and Proteins/deficiency/genetics/metabolism ; Leukemia, Myeloid, Acute/*genetics/metabolism/*pathology ; Ligands ; Male ; Membrane Proteins/deficiency/genetics/metabolism ; Mice ; Mutation/*genetics ; Myelodysplastic Syndromes/genetics/metabolism/pathology ; Myeloid Cells/metabolism/pathology ; Osteoblasts/*metabolism/pathology/secretion ; Receptors, Notch/metabolism ; Signal Transduction ; Tumor Microenvironment/genetics ; beta Catenin/*genetics/*metabolism
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  • 15
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    Landscape and variation of RNA secondary structure across the human transcriptome (2014)
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    Publication Date: 2014-01-31
    Description: In parallel to the genetic code for protein synthesis, a second layer of information is embedded in all RNA transcripts in the form of RNA structure. RNA structure influences practically every step in the gene expression program. However, the nature of most RNA structures or effects of sequence variation on structure are not known. Here we report the initial landscape and variation of RNA secondary structures (RSSs) in a human family trio (mother, father and their child). This provides a comprehensive RSS map of human coding and non-coding RNAs. We identify unique RSS signatures that demarcate open reading frames and splicing junctions, and define authentic microRNA-binding sites. Comparison of native deproteinized RNA isolated from cells versus refolded purified RNA suggests that the majority of the RSS information is encoded within RNA sequence. Over 1,900 transcribed single nucleotide variants (approximately 15% of all transcribed single nucleotide variants) alter local RNA structure. We discover simple sequence and spacing rules that determine the ability of point mutations to impact RSSs. Selective depletion of 'riboSNitches' versus structurally synonymous variants at precise locations suggests selection for specific RNA shapes at thousands of sites, including 3' untranslated regions, binding sites of microRNAs and RNA-binding proteins genome-wide. These results highlight the potentially broad contribution of RNA structure and its variation to gene regulation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973747/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973747/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wan, Yue -- Qu, Kun -- Zhang, Qiangfeng Cliff -- Flynn, Ryan A -- Manor, Ohad -- Ouyang, Zhengqing -- Zhang, Jiajing -- Spitale, Robert C -- Snyder, Michael P -- Segal, Eran -- Chang, Howard Y -- P30 CA034196/CA/NCI NIH HHS/ -- R01 HG004361/HG/NHGRI NIH HHS/ -- R01-HG004361/HG/NHGRI NIH HHS/ -- T32 CA009302/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jan 30;505(7485):706-9. doi: 10.1038/nature12946.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA [2] Stem Cell and Development, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672 [3]. ; 1] Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA [2]. ; Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA. ; Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovet 76100, Israel. ; 1] Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA [2] The Jackson Laboratory for Genomic Medicine, 263 Farmington Avenue, ASB Call Box 901 Farmington, Connecticut 06030, USA. ; Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24476892" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions/genetics ; Base Sequence ; Binding Sites ; Child ; Female ; Gene Expression Regulation/genetics ; Genome, Human/genetics ; Humans ; Male ; MicroRNAs/chemistry/genetics/metabolism ; *Nucleic Acid Conformation ; Open Reading Frames/genetics ; Point Mutation/genetics ; RNA/*chemistry/*genetics/metabolism ; RNA Splice Sites/genetics ; RNA-Binding Proteins/metabolism ; Transcriptome/*genetics
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  • 16
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    miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2 (2014)
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    Publication Date: 2014-07-22
    Description: Bone-resorbing osteoclasts significantly contribute to osteoporosis and bone metastases of cancer. MicroRNAs play important roles in physiology and disease, and present tremendous therapeutic potential. Nonetheless, how microRNAs regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is downregulated during osteoclast differentiation. Osteoclastic miR-34a-overexpressing transgenic mice exhibit lower bone resorption and higher bone mass. Conversely, miR-34a knockout and heterozygous mice exhibit elevated bone resorption and reduced bone mass. Consequently, ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment. Mechanistically, we identify transforming growth factor-beta-induced factor 2 (Tgif2) as an essential direct miR-34a target that is pro-osteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149606/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149606/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Krzeszinski, Jing Y -- Wei, Wei -- Huynh, HoangDinh -- Jin, Zixue -- Wang, Xunde -- Chang, Tsung-Cheng -- Xie, Xian-Jin -- He, Lin -- Mangala, Lingegowda S -- Lopez-Berestein, Gabriel -- Sood, Anil K -- Mendell, Joshua T -- Wan, Yihong -- 1P30 CA142543/CA/NCI NIH HHS/ -- 1S10RR02564801/RR/NCRR NIH HHS/ -- P01 CA134292/CA/NCI NIH HHS/ -- P30 CA142543/CA/NCI NIH HHS/ -- R01 CA120185/CA/NCI NIH HHS/ -- R01 CA139067/CA/NCI NIH HHS/ -- R01 DK089113/DK/NIDDK NIH HHS/ -- S10 RR024757/RR/NCRR NIH HHS/ -- S10 RR025648/RR/NCRR NIH HHS/ -- U54 CA151668/CA/NCI NIH HHS/ -- UH2 TR000943/TR/NCATS NIH HHS/ -- England -- Nature. 2014 Aug 28;512(7515):431-5. doi: 10.1038/nature13375. Epub 2014 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Clinical Sciences, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Division of Cellular and Developmental Biology, Molecular and Cell Biology Department, University of California at Berkeley, Berkeley, California 94705, USA. ; 1] Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3] Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043055" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Bone Neoplasms/genetics/pathology/*prevention & control/*secondary ; Bone Resorption/drug therapy/genetics ; Cell Differentiation/drug effects/*genetics ; Cell Line, Tumor ; Disease Models, Animal ; Female ; Gene Deletion ; Homeodomain Proteins/antagonists & inhibitors/genetics/metabolism ; Humans ; Male ; Mammary Neoplasms, Animal/pathology ; Mice ; Mice, Transgenic ; MicroRNAs/*genetics/pharmacology/therapeutic use ; Neoplasm Transplantation ; Organ Size/drug effects ; Osteoclasts/drug effects/*pathology ; Osteoporosis/genetics/pathology/*prevention & control ; Ovariectomy ; Repressor Proteins/antagonists & inhibitors/*deficiency/genetics/metabolism ; Skin Neoplasms/pathology ; Transgenes ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
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  • 17
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    Poly(A)-tail profiling reveals an embryonic switch in translational control (2014)
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    Publication Date: 2014-01-31
    Description: Poly(A) tails enhance the stability and translation of most eukaryotic messenger RNAs, but difficulties in globally measuring poly(A)-tail lengths have impeded greater understanding of poly(A)-tail function. Here we describe poly(A)-tail length profiling by sequencing (PAL-seq) and apply it to measure tail lengths of millions of individual RNAs isolated from yeasts, cell lines, Arabidopsis thaliana leaves, mouse liver, and zebrafish and frog embryos. Poly(A)-tail lengths were conserved between orthologous mRNAs, with mRNAs encoding ribosomal proteins and other 'housekeeping' proteins tending to have shorter tails. As expected, tail lengths were coupled to translational efficiencies in early zebrafish and frog embryos. However, this strong coupling diminished at gastrulation and was absent in non-embryonic samples, indicating a rapid developmental switch in the nature of translational control. This switch complements an earlier switch to zygotic transcriptional control and explains why the predominant effect of microRNA-mediated deadenylation concurrently shifts from translational repression to mRNA destabilization.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086860/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086860/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Subtelny, Alexander O -- Eichhorn, Stephen W -- Chen, Grace R -- Sive, Hazel -- Bartel, David P -- GM067031/GM/NIGMS NIH HHS/ -- R01 GM067031/GM/NIGMS NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32GM007753/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Apr 3;508(7494):66-71. doi: 10.1038/nature13007. Epub 2014 Jan 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA [3] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [4] Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139, USA [5]. ; 1] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA [3] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [4]. ; 1] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA [3] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24476825" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arabidopsis/genetics ; Base Sequence ; Cell Line ; Drosophila melanogaster/embryology/genetics ; Gastrulation/genetics ; Gene Expression Regulation, Developmental/*genetics ; Humans ; Liver/metabolism ; Mice ; MicroRNAs/genetics/metabolism ; Models, Genetic ; Plant Leaves/genetics ; Poly A/*analysis/genetics ; Protein Biosynthesis/*genetics ; RNA Stability/genetics ; RNA, Messenger/*genetics/metabolism ; Ribosomes/metabolism ; Sequence Analysis, RNA ; Species Specificity ; Transcription, Genetic ; Xenopus/embryology/genetics ; Yeasts/genetics ; Zebrafish/embryology/genetics ; Zygote/metabolism
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    Structural basis of the non-coding RNA RsmZ acting as a protein sponge (2014)
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    Publication Date: 2014-05-16
    Description: MicroRNA and protein sequestration by non-coding RNAs (ncRNAs) has recently generated much interest. In the bacterial Csr/Rsm system, which is considered to be the most general global post-transcriptional regulatory system responsible for bacterial virulence, ncRNAs such as CsrB or RsmZ activate translation initiation by sequestering homodimeric CsrA-type proteins from the ribosome-binding site of a subset of messenger RNAs. However, the mechanism of ncRNA-mediated protein sequestration is not understood at the molecular level. Here we show for Pseudomonas fluorescens that RsmE protein dimers assemble sequentially, specifically and cooperatively onto the ncRNA RsmZ within a narrow affinity range. This assembly yields two different native ribonucleoprotein structures. Using a powerful combination of nuclear magnetic resonance and electron paramagnetic resonance spectroscopy we elucidate these 70-kilodalton solution structures, thereby revealing the molecular mechanism of the sequestration process and how RsmE binding protects the ncRNA from RNase E degradation. Overall, our findings suggest that RsmZ is well-tuned to sequester, store and release RsmE and therefore can be viewed as an ideal protein 'sponge'.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Duss, Olivier -- Michel, Erich -- Yulikov, Maxim -- Schubert, Mario -- Jeschke, Gunnar -- Allain, Frederic H-T -- England -- Nature. 2014 May 29;509(7502):588-92. doi: 10.1038/nature13271. Epub 2014 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular Biology and Biophysics, ETH Zurich, CH-8093 Zurich, Switzerland. ; Laboratory of Physical Chemistry, ETH Zurich, CH-8093 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24828038" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Electron Spin Resonance Spectroscopy ; Escherichia coli/chemistry/genetics/metabolism ; Escherichia coli Proteins/chemistry/*metabolism ; Methyltransferases/chemistry/*metabolism ; Models, Biological ; Models, Molecular ; Molecular Weight ; Nuclear Magnetic Resonance, Biomolecular ; Nucleic Acid Conformation ; *Protein Binding ; Protein Multimerization ; RNA, Untranslated/chemistry/genetics/*metabolism ; Ribonucleases/metabolism ; Ribonucleoproteins/chemistry/genetics/metabolism
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  • 19
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    miR-34/449 miRNAs are required for motile ciliogenesis by repressing cp110 (2014)
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    Publication Date: 2014-06-06
    Description: The mir-34/449 family consists of six homologous miRNAs at three genomic loci. Redundancy of miR-34/449 miRNAs and their dominant expression in multiciliated epithelia suggest a functional significance in ciliogenesis. Here we report that mice deficient for all miR-34/449 miRNAs exhibited postnatal mortality, infertility and strong respiratory dysfunction caused by defective mucociliary clearance. In both mouse and Xenopus, miR-34/449-deficient multiciliated cells (MCCs) exhibited a significant decrease in cilia length and number, due to defective basal body maturation and apical docking. The effect of miR-34/449 on ciliogenesis was mediated, at least in part, by post-transcriptional repression of Cp110, a centriolar protein suppressing cilia assembly. Consistent with this, cp110 knockdown in miR-34/449-deficient MCCs restored ciliogenesis by rescuing basal body maturation and docking. Altogether, our findings elucidate conserved cellular and molecular mechanisms through which miR-34/449 regulate motile ciliogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119886/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119886/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Song, Rui -- Walentek, Peter -- Sponer, Nicole -- Klimke, Alexander -- Lee, Joon Sub -- Dixon, Gary -- Harland, Richard -- Wan, Ying -- Lishko, Polina -- Lize, Muriel -- Kessel, Michael -- He, Lin -- 1R21CA175560-01/CA/NCI NIH HHS/ -- GM42341/GM/NIGMS NIH HHS/ -- R01 CA139067/CA/NCI NIH HHS/ -- R01 GM042341/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jun 5;510(7503):115-20. doi: 10.1038/nature13413.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Cellular and Developmental Biology, MCB Department, University of California at Berkeley, Berkeley, California 94705, USA [2]. ; 1] Division of Genetics, Genomics and Development, Centre for Integrative Genomics, MCB Department, University of California at Berkeley, Berkeley, California 94705, USA [2]. ; Department of Molecular Cell Biology, Max Planck Institute for Biophysical Chemistry, Goettingen 37077, Germany. ; Division of Cellular and Developmental Biology, MCB Department, University of California at Berkeley, Berkeley, California 94705, USA. ; Division of Genetics, Genomics and Development, Centre for Integrative Genomics, MCB Department, University of California at Berkeley, Berkeley, California 94705, USA. ; The Third Military Medical University, Chongqing 400038, China. ; Department of Molecular Oncology, University of Goettingen, Goettingen 37073, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24899310" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; Basal Bodies/metabolism/pathology/ultrastructure ; Base Sequence ; Calmodulin-Binding Proteins/*deficiency/*genetics/metabolism ; Centrioles/metabolism ; Cilia/*genetics/pathology/*physiology/ultrastructure ; Epidermis/embryology/pathology ; Female ; Infertility/genetics/physiopathology ; Kartagener Syndrome/genetics/pathology/physiopathology ; Male ; Mice ; Mice, Knockout ; MicroRNAs/*genetics/metabolism ; Morphogenesis/*genetics ; Phenotype ; Respiratory System/pathology/physiopathology ; Survival Analysis ; Xenopus laevis/embryology
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    CRISPR-mediated direct mutation of cancer genes in the mouse liver (2014)
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    Publication Date: 2014-08-15
    Description: The study of cancer genes in mouse models has traditionally relied on genetically-engineered strains made via transgenesis or gene targeting in embryonic stem cells. Here we describe a new method of cancer model generation using the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) system in vivo in wild-type mice. We used hydrodynamic injection to deliver a CRISPR plasmid DNA expressing Cas9 and single guide RNAs (sgRNAs) to the liver that directly target the tumour suppressor genes Pten (ref. 5) and p53 (also known as TP53 and Trp53) (ref. 6), alone and in combination. CRISPR-mediated Pten mutation led to elevated Akt phosphorylation and lipid accumulation in hepatocytes, phenocopying the effects of deletion of the gene using Cre-LoxP technology. Simultaneous targeting of Pten and p53 induced liver tumours that mimicked those caused by Cre-loxP-mediated deletion of Pten and p53. DNA sequencing of liver and tumour tissue revealed insertion or deletion mutations of the tumour suppressor genes, including bi-allelic mutations of both Pten and p53 in tumours. Furthermore, co-injection of Cas9 plasmids harbouring sgRNAs targeting the beta-catenin gene and a single-stranded DNA oligonucleotide donor carrying activating point mutations led to the generation of hepatocytes with nuclear localization of beta-catenin. This study demonstrates the feasibility of direct mutation of tumour suppressor genes and oncogenes in the liver using the CRISPR/Cas system, which presents a new avenue for rapid development of liver cancer models and functional genomics.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199937/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199937/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xue, Wen -- Chen, Sidi -- Yin, Hao -- Tammela, Tuomas -- Papagiannakopoulos, Thales -- Joshi, Nikhil S -- Cai, Wenxin -- Yang, Gillian -- Bronson, Roderick -- Crowley, Denise G -- Zhang, Feng -- Anderson, Daniel G -- Sharp, Phillip A -- Jacks, Tyler -- 1K99CA169512/CA/NCI NIH HHS/ -- 2-P01-CA42063/CA/NCI NIH HHS/ -- 5-U54-CA151884-04/CA/NCI NIH HHS/ -- DP1 MH100706/MH/NIMH NIH HHS/ -- K99 CA169512/CA/NCI NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R00 CA169512/CA/NCI NIH HHS/ -- R01 DK097768/DK/NIDDK NIH HHS/ -- R01-CA115527/CA/NCI NIH HHS/ -- R01-CA132091/CA/NCI NIH HHS/ -- R01-CA133404/CA/NCI NIH HHS/ -- R01-EB000244/EB/NIBIB NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Oct 16;514(7522):380-4. doi: 10.1038/nature13589. Epub 2014 Aug 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2]. ; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; Tufts University and Harvard Medical School, Boston, Massachusetts 02115, USA. ; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA. ; 1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [3] Harvard-MIT Division of Health Sciences &Technology, Cambridge, Massachusetts 02139, USA [4] Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; 1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; 1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [3] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119044" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; *CRISPR-Cas Systems ; Cell Transformation, Neoplastic/genetics ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; Female ; *Genes, Tumor Suppressor ; Genes, p53/genetics ; Genetic Engineering/*methods ; Hepatocytes/metabolism/pathology ; Lipid Metabolism ; Liver/cytology/*metabolism/pathology ; Liver Neoplasms/genetics/metabolism/pathology ; Mice ; Molecular Sequence Data ; Mutagenesis/*genetics ; Mutation/*genetics ; Oncogenes/*genetics ; PTEN Phosphohydrolase/genetics ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; beta Catenin/genetics
    Print ISSN: 0028-0836
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    Changchun (2014)
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    Publication Date: 2014-12-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2014 Dec 18;516(7531):S72. doi: 10.1038/516S72a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25517243" target="_blank"〉PubMed〈/a〉
    Keywords: Chemistry ; China ; Cities ; Periodicals as Topic/statistics & numerical data ; Research/standards/*statistics & numerical data/trends ; Universities/statistics & numerical data
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  • 22
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    RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer (2014)
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    Publication Date: 2014-08-01
    Description: The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of silvestrol and related compounds. For example, eIF4A promotes T-cell acute lymphoblastic leukaemia development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with silvestrol has powerful therapeutic effects against murine and human leukaemic cells in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5' untranslated region (UTR) sequences such as the 12-nucleotide guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and silvestrol-sensitive transcripts are a number of oncogenes, superenhancer-associated transcription factors, and epigenetic regulators. Hence, the 5' UTRs of select cancer genes harbour a targetable requirement for the eIF4A RNA helicase.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492470/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492470/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wolfe, Andrew L -- Singh, Kamini -- Zhong, Yi -- Drewe, Philipp -- Rajasekhar, Vinagolu K -- Sanghvi, Viraj R -- Mavrakis, Konstantinos J -- Jiang, Man -- Roderick, Justine E -- Van der Meulen, Joni -- Schatz, Jonathan H -- Rodrigo, Christina M -- Zhao, Chunying -- Rondou, Pieter -- de Stanchina, Elisa -- Teruya-Feldstein, Julie -- Kelliher, Michelle A -- Speleman, Frank -- Porco, John A Jr -- Pelletier, Jerry -- Ratsch, Gunnar -- Wendel, Hans-Guido -- GM-067041/GM/NIGMS NIH HHS/ -- GM-073855/GM/NIGMS NIH HHS/ -- MOP-10653/Canadian Institutes of Health Research/Canada -- P30 CA008748/CA/NCI NIH HHS/ -- R01 CA142798/CA/NCI NIH HHS/ -- R01-CA142798-01/CA/NCI NIH HHS/ -- England -- Nature. 2014 Sep 4;513(7516):65-70. doi: 10.1038/nature13485. Epub 2014 Jul 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Weill Cornell Graduate School of Medical Sciences, New York, New York 10065, USA [3]. ; 1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2]. ; Computational Biology Department, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Stem Cell Center and Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; 1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Novartis, Cambridge, Massachusetts 02139, USA (K.J.M.); The University of Arizona Cancer Center, Tucson, Arizona 85719, USA (J.H.S.). ; Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 USA. ; 1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. ; 1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [3] Novartis, Cambridge, Massachusetts 02139, USA (K.J.M.); The University of Arizona Cancer Center, Tucson, Arizona 85719, USA (J.H.S.). ; Department of Chemistry, Center for Chemical Methodology and Library Development, Boston University, Boston, Massachusetts 02215, USA. ; Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. ; Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; 1] Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada [2] Department of Oncology, McGill University, Montreal, Quebec H3G 1Y6, Canada [3] The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec H3G 1Y6, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25079319" target="_blank"〉PubMed〈/a〉
    Keywords: 5' Untranslated Regions/*genetics ; Animals ; Antineoplastic Agents, Phytogenic/pharmacology/therapeutic use ; Base Sequence ; Cell Line, Tumor ; Epigenesis, Genetic ; Eukaryotic Initiation Factor-4A/*metabolism ; Female ; *G-Quadruplexes ; Humans ; Mice ; Mice, Inbred C57BL ; Nucleotide Motifs ; Oncogene Proteins/*biosynthesis/*genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug ; therapy/genetics/*metabolism ; *Protein Biosynthesis/drug effects ; Ribosomes/metabolism ; Transcription Factors/metabolism ; Transcription, Genetic/drug effects/genetics ; Triterpenes/pharmacology
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    Ribosomal frameshifting in the CCR5 mRNA is regulated by miRNAs and the NMD pathway (2014)
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    Publication Date: 2014-07-22
    Description: Programmed -1 ribosomal frameshift (-1 PRF) signals redirect translating ribosomes to slip back one base on messenger RNAs. Although well characterized in viruses, how these elements may regulate cellular gene expression is not understood. Here we describe a -1 PRF signal in the human mRNA encoding CCR5, the HIV-1 co-receptor. CCR5 mRNA-mediated -1 PRF is directed by an mRNA pseudoknot, and is stimulated by at least two microRNAs. Mapping the mRNA-miRNA interaction suggests that formation of a triplex RNA structure stimulates -1 PRF. A -1 PRF event on the CCR5 mRNA directs translating ribosomes to a premature termination codon, destabilizing it through the nonsense-mediated mRNA decay pathway. At least one additional mRNA decay pathway is also involved. Functional -1 PRF signals that seem to be regulated by miRNAs are also demonstrated in mRNAs encoding six other cytokine receptors, suggesting a novel mode through which immune responses may be fine-tuned in mammalian cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369343/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369343/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Belew, Ashton Trey -- Meskauskas, Arturas -- Musalgaonkar, Sharmishtha -- Advani, Vivek M -- Sulima, Sergey O -- Kasprzak, Wojciech K -- Shapiro, Bruce A -- Dinman, Jonathan D -- 5 R01GM058859/GM/NIGMS NIH HHS/ -- HHSN261200800001/PHS HHS/ -- R01 GM058859/GM/NIGMS NIH HHS/ -- R01 HL119439/HL/NHLBI NIH HHS/ -- R21 GM068123/GM/NIGMS NIH HHS/ -- R21GM068123/GM/NIGMS NIH HHS/ -- T32 AI051967/AI/NIAID NIH HHS/ -- T32AI051967/AI/NIAID NIH HHS/ -- T32GM080201/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2014 Aug 21;512(7514):265-9. doi: 10.1038/nature13429. Epub 2014 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA [2]. ; 1] Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA [2] Department of Biotechnology and Microbiology, Vilnius University, Vilnius, LT 03101, Lithuania [3]. ; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA. ; 1] Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA [2] VIB Center for the Biology of Disease, KU Leuven, Campus Gasthuisberg, Herestraat 49, bus 602, 3000 Leuven, Belgium. ; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA. ; Basic Research Laboratory, National Cancer Institute, Frederick, Maryland 21702, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043019" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Base Sequence ; Binding Sites ; Cell Survival ; Codon, Nonsense/genetics ; Frameshifting, Ribosomal/*genetics ; HeLa Cells ; Humans ; MicroRNAs/*genetics ; Models, Molecular ; Molecular Sequence Data ; *Nonsense Mediated mRNA Decay ; Nucleic Acid Conformation ; RNA, Messenger/chemistry/*genetics/*metabolism ; Receptors, CCR5/*genetics ; Receptors, Interleukin/genetics ; Regulatory Sequences, Ribonucleic Acid ; Ribosomes/metabolism
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    Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates (2014)
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    Publication Date: 2014-08-15
    Description: Mammalian cells possess mechanisms to detect and defend themselves from invading viruses. In the cytosol, the RIG-I-like receptors (RLRs), RIG-I (retinoic acid-inducible gene I; encoded by DDX58) and MDA5 (melanoma differentiation-associated gene 5; encoded by IFIH1) sense atypical RNAs associated with virus infection. Detection triggers a signalling cascade via the adaptor MAVS that culminates in the production of type I interferons (IFN-alpha and beta; hereafter IFN), which are key antiviral cytokines. RIG-I and MDA5 are activated by distinct viral RNA structures and much evidence indicates that RIG-I responds to RNAs bearing a triphosphate (ppp) moiety in conjunction with a blunt-ended, base-paired region at the 5'-end (reviewed in refs 1, 2, 3). Here we show that RIG-I also mediates antiviral responses to RNAs bearing 5'-diphosphates (5'pp). Genomes from mammalian reoviruses with 5'pp termini, 5'pp-RNA isolated from yeast L-A virus, and base-paired 5'pp-RNAs made by in vitro transcription or chemical synthesis, all bind to RIG-I and serve as RIG-I agonists. Furthermore, a RIG-I-dependent response to 5'pp-RNA is essential for controlling reovirus infection in cultured cells and in mice. Thus, the minimal determinant for RIG-I recognition is a base-paired RNA with 5'pp. Such RNAs are found in some viruses but not in uninfected cells, indicating that recognition of 5'pp-RNA, like that of 5'ppp-RNA, acts as a powerful means of self/non-self discrimination by the innate immune system.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201573/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201573/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goubau, Delphine -- Schlee, Martin -- Deddouche, Safia -- Pruijssers, Andrea J -- Zillinger, Thomas -- Goldeck, Marion -- Schuberth, Christine -- Van der Veen, Annemarthe G -- Fujimura, Tsutomu -- Rehwinkel, Jan -- Iskarpatyoti, Jason A -- Barchet, Winfried -- Ludwig, Janos -- Dermody, Terence S -- Hartmann, Gunther -- Reis e Sousa, Caetano -- A3598/Cancer Research UK/United Kingdom -- MC_UU_12010/8/Medical Research Council/United Kingdom -- R01 AI038296/AI/NIAID NIH HHS/ -- R37 AI038296/AI/NIAID NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2014 Oct 16;514(7522):372-5. doi: 10.1038/nature13590. Epub 2014 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Immunobiology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK [2]. ; 1] Institut fur Klinische Chemie und Klinische Pharmakologie, Universitatsklinikum Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany [2]. ; 1] Immunobiology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK [2] Drosophila Genetics and Epigenetics, Laboratory of Developmental Biology, CNRS UMR7622, Universite Pierre et Marie Curie, Paris, France (S.D.); Medical Research Council Human Immunology Unit, Radcliffe Department of Medicine, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK (J.R.). ; 1] Department of Pediatrics, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232-2581, USA [2] Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232-2581, USA. ; Institut fur Klinische Chemie und Klinische Pharmakologie, Universitatsklinikum Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany. ; Immunobiology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. ; Instituto de Biologia Funcional y Genomica. Consejo Superior de Investigaciones Cientificas/Universidad de Salamanca, Zacarias Gonzalez 2, 37007, Salamanca, Spain. ; 1] Department of Pediatrics, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232-2581, USA [2] Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232-2581, USA [3] Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232-2581, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119032" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Pairing ; Base Sequence ; DEAD-box RNA Helicases/*metabolism ; Diphosphates/*metabolism ; Female ; Genome, Viral/genetics ; *Immunity, Innate ; Male ; Mice ; RNA, Viral/*chemistry/genetics/*metabolism ; Reoviridae/*genetics/*immunology/physiology
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    A cross-chiral RNA polymerase ribozyme (2014)
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    Publication Date: 2014-11-05
    Description: Thirty years ago it was shown that the non-enzymatic, template-directed polymerization of activated mononucleotides proceeds readily in a homochiral system, but is severely inhibited by the presence of the opposing enantiomer. This finding poses a severe challenge for the spontaneous emergence of RNA-based life, and has led to the suggestion that either RNA was preceded by some other genetic polymer that is not subject to chiral inhibition or chiral symmetry was broken through chemical processes before the origin of RNA-based life. Once an RNA enzyme arose that could catalyse the polymerization of RNA, it would have been possible to distinguish among the two enantiomers, enabling RNA replication and RNA-based evolution to occur. It is commonly thought that the earliest RNA polymerase and its substrates would have been of the same handedness, but this is not necessarily the case. Replicating D- and L-RNA molecules may have emerged together, based on the ability of structured RNAs of one handedness to catalyse the templated polymerization of activated mononucleotides of the opposite handedness. Here we develop such a cross-chiral RNA polymerase, using in vitro evolution starting from a population of random-sequence RNAs. The D-RNA enzyme, consisting of 83 nucleotides, catalyses the joining of L-mono- or oligonucleotide substrates on a complementary L-RNA template, and similar behaviour occurs for the L-enzyme with D-substrates and a D-template. Chiral inhibition is avoided because the 10(6)-fold rate acceleration of the enzyme only pertains to cross-chiral substrates. The enzyme's activity is sufficient to generate full-length copies of its enantiomer through the templated joining of 11 component oligonucleotides.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239201/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239201/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sczepanski, Jonathan T -- Joyce, Gerald F -- F32 GM101741/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Nov 20;515(7527):440-2. doi: 10.1038/nature13900. Epub 2014 Oct 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363769" target="_blank"〉PubMed〈/a〉
    Keywords: Base Pairing ; Base Sequence ; Biocatalysis ; Biopolymers/biosynthesis/chemistry/metabolism ; DNA-Directed RNA Polymerases/chemistry/*metabolism ; Directed Molecular Evolution ; Evolution, Chemical ; Kinetics ; Molecular Sequence Data ; Nucleic Acid Conformation ; Oligonucleotides/chemistry/metabolism ; Origin of Life ; Polymerization ; RNA/*biosynthesis/*chemistry/metabolism ; RNA, Catalytic/*chemistry/*metabolism ; Stereoisomerism ; Templates, Genetic
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    DNA interrogation by the CRISPR RNA-guided endonuclease Cas9 (2014)
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    Publication Date: 2014-01-31
    Description: The clustered regularly interspaced short palindromic repeats (CRISPR)-associated enzyme Cas9 is an RNA-guided endonuclease that uses RNA-DNA base-pairing to target foreign DNA in bacteria. Cas9-guide RNA complexes are also effective genome engineering agents in animals and plants. Here we use single-molecule and bulk biochemical experiments to determine how Cas9-RNA interrogates DNA to find specific cleavage sites. We show that both binding and cleavage of DNA by Cas9-RNA require recognition of a short trinucleotide protospacer adjacent motif (PAM). Non-target DNA binding affinity scales with PAM density, and sequences fully complementary to the guide RNA but lacking a nearby PAM are ignored by Cas9-RNA. Competition assays provide evidence that DNA strand separation and RNA-DNA heteroduplex formation initiate at the PAM and proceed directionally towards the distal end of the target sequence. Furthermore, PAM interactions trigger Cas9 catalytic activity. These results reveal how Cas9 uses PAM recognition to quickly identify potential target sites while scanning large DNA molecules, and to regulate scission of double-stranded DNA.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106473/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106473/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sternberg, Samuel H -- Redding, Sy -- Jinek, Martin -- Greene, Eric C -- Doudna, Jennifer A -- GM074739/GM/NIGMS NIH HHS/ -- R01 GM073794/GM/NIGMS NIH HHS/ -- R01 GM074739/GM/NIGMS NIH HHS/ -- T32 GM066698/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Mar 6;507(7490):62-7. doi: 10.1038/nature13011. Epub 2014 Jan 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Chemistry, University of California, Berkeley, California 94720, USA [2]. ; 1] Department of Chemistry, Columbia University, New York, New York 10032, USA [2]. ; 1] Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA [2] Department of Biochemistry, University of Zurich, 8057 Zurich, Switzerland. ; Department of Biochemistry and Molecular Biophysics and Howard Hughes Medical Institute, Columbia University, New York, New York 10032, USA. ; 1] Department of Chemistry, University of California, Berkeley, California 94720, USA [2] Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA [3] Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA [4] Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24476820" target="_blank"〉PubMed〈/a〉
    Keywords: Apoenzymes/metabolism ; *Base Pairing ; Base Sequence ; Biocatalysis ; CRISPR-Associated Proteins/*metabolism ; *CRISPR-Cas Systems ; Clustered Regularly Interspaced Short Palindromic Repeats/*genetics ; DNA/chemistry/genetics/metabolism ; *DNA Cleavage ; Diffusion ; Endonucleases/*metabolism ; Enzyme Activation ; Genetic Engineering/methods ; Genome/genetics ; Nucleic Acid Denaturation ; Nucleic Acid Heteroduplexes/chemistry/genetics/metabolism ; Nucleotide Motifs ; RNA/chemistry/*genetics/metabolism ; Streptococcus pyogenes/enzymology/immunology ; Substrate Specificity ; Thermodynamics
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    Two independent transcription initiation codes overlap on vertebrate core promoters (2014)
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    Publication Date: 2014-02-18
    Description: A core promoter is a stretch of DNA surrounding the transcription start site (TSS) that integrates regulatory inputs and recruits general transcription factors to initiate transcription. The nature and causative relationship of the DNA sequence and chromatin signals that govern the selection of most TSSs by RNA polymerase II remain unresolved. Maternal to zygotic transition represents the most marked change of the transcriptome repertoire in the vertebrate life cycle. Early embryonic development in zebrafish is characterized by a series of transcriptionally silent cell cycles regulated by inherited maternal gene products: zygotic genome activation commences at the tenth cell cycle, marking the mid-blastula transition. This transition provides a unique opportunity to study the rules of TSS selection and the hierarchy of events linking transcription initiation with key chromatin modifications. We analysed TSS usage during zebrafish early embryonic development at high resolution using cap analysis of gene expression, and determined the positions of H3K4me3-marked promoter-associated nucleosomes. Here we show that the transition from the maternal to zygotic transcriptome is characterized by a switch between two fundamentally different modes of defining transcription initiation, which drive the dynamic change of TSS usage and promoter shape. A maternal-specific TSS selection, which requires an A/T-rich (W-box) motif, is replaced with a zygotic TSS selection grammar characterized by broader patterns of dinucleotide enrichments, precisely aligned with the first downstream (+1) nucleosome. The developmental dynamics of the H3K4me3-marked nucleosomes reveal their DNA-sequence-associated positioning at promoters before zygotic transcription and subsequent transcription-independent adjustment to the final position downstream of the zygotic TSS. The two TSS-defining grammars coexist, often physically overlapping, in core promoters of constitutively expressed genes to enable their expression in the two regulatory environments. The dissection of overlapping core promoter determinants represents a framework for future studies of promoter structure and function across different regulatory contexts.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Haberle, Vanja -- Li, Nan -- Hadzhiev, Yavor -- Plessy, Charles -- Previti, Christopher -- Nepal, Chirag -- Gehrig, Jochen -- Dong, Xianjun -- Akalin, Altuna -- Suzuki, Ana Maria -- van IJcken, Wilfred F J -- Armant, Olivier -- Ferg, Marco -- Strahle, Uwe -- Carninci, Piero -- Muller, Ferenc -- Lenhard, Boris -- MC_UP_1102/1/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2014 Mar 20;507(7492):381-5. doi: 10.1038/nature12974. Epub 2014 Feb 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biology, University of Bergen, Thormohlensgate 53A, N-5008 Bergen, Norway [2] Institute of Clinical Sciences and MRC Clinical Sciences Center, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK [3]. ; 1] School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK [2]. ; School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. ; 1] RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan [2] RIKEN Center for Life Science Technologies, Division of Genomic Technologies, RIKEN Yokohama Campus, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. ; 1] Computational Biology Unit, Uni Computing, Uni Research AS, University of Bergen, Thormohlensgate 55, N-5008 Bergen, Norway [2] German Cancer Research Center (DKFZ), Genomics & Proteomics Core Facility (GPCF), Im Neuenheimer Feld 580/TP3, Heidelberg 69120, Germany (C.Pr.); Broegelmann Research Laboratory, The Gade Institute, University of Bergen, The Laboratory Building, Haukeland University Hospital, N-5021 Bergen, Norway (C.N.); Acquifer AG, Sophienstrasse 136, 76135 Karlsruhe, Germany (J.G.); Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA (X.D.); Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland (A.A.). ; 1] School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK [2] German Cancer Research Center (DKFZ), Genomics & Proteomics Core Facility (GPCF), Im Neuenheimer Feld 580/TP3, Heidelberg 69120, Germany (C.Pr.); Broegelmann Research Laboratory, The Gade Institute, University of Bergen, The Laboratory Building, Haukeland University Hospital, N-5021 Bergen, Norway (C.N.); Acquifer AG, Sophienstrasse 136, 76135 Karlsruhe, Germany (J.G.); Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA (X.D.); Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland (A.A.). ; Erasmus Medical Center, Center for Biomics, Room Ee679b, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. ; Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Postfach 3640, 76021 Karlsruhe, Germany. ; 1] Institute of Clinical Sciences and MRC Clinical Sciences Center, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK [2] Department of Informatics, University of Bergen, Thormohlensgate 55, N-5008 Bergen, Norway.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24531765" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Embryo, Nonmammalian/embryology/metabolism ; Female ; Gene Expression Regulation, Developmental/genetics ; Histones/metabolism ; Methylation ; Mothers ; Nucleosomes/genetics ; Promoter Regions, Genetic/*genetics ; *Transcription Initiation Site ; Transcription Initiation, Genetic ; Transcriptome/genetics ; Zebrafish/embryology/*genetics ; Zygote/metabolism
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    DNA-guided DNA interference by a prokaryotic Argonaute (2014)
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    Publication Date: 2014-02-18
    Description: RNA interference is widely distributed in eukaryotes and has a variety of functions, including antiviral defence and gene regulation. All RNA interference pathways use small single-stranded RNA (ssRNA) molecules that guide proteins of the Argonaute (Ago) family to complementary ssRNA targets: RNA-guided RNA interference. The role of prokaryotic Ago variants has remained elusive, although bioinformatics analysis has suggested their involvement in host defence. Here we demonstrate that Ago of the bacterium Thermus thermophilus (TtAgo) acts as a barrier for the uptake and propagation of foreign DNA. In vivo, TtAgo is loaded with 5'-phosphorylated DNA guides, 13-25 nucleotides in length, that are mostly plasmid derived and have a strong bias for a 5'-end deoxycytidine. These small interfering DNAs guide TtAgo to cleave complementary DNA strands. Hence, despite structural homology to its eukaryotic counterparts, TtAgo functions in host defence by DNA-guided DNA interference.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697943/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697943/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Swarts, Daan C -- Jore, Matthijs M -- Westra, Edze R -- Zhu, Yifan -- Janssen, Jorijn H -- Snijders, Ambrosius P -- Wang, Yanli -- Patel, Dinshaw J -- Berenguer, Jose -- Brouns, Stan J J -- van der Oost, John -- P30 CA008748/CA/NCI NIH HHS/ -- R01 GM104962/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Mar 13;507(7491):258-61. doi: 10.1038/nature12971. Epub 2014 Feb 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Laboratory of Microbiology, Department of Agrotechnology and Food Sciences, Wageningen University, Dreijenplein 10, 6703 HB Wageningen, the Netherlands [2]. ; Laboratory of Microbiology, Department of Agrotechnology and Food Sciences, Wageningen University, Dreijenplein 10, 6703 HB Wageningen, the Netherlands. ; Clare Hall Laboratories, Cancer Research UK, London Research Institute, South Mimms EN6 3LD, UK. ; Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. ; Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Centro de Biologia Molecular Severo Ochoa, UAM-CSIC, Campus de Cantoblanco, 28049 Madrid, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24531762" target="_blank"〉PubMed〈/a〉
    Keywords: Argonaute Proteins/*metabolism ; Base Pairing/genetics ; Base Sequence ; DNA/genetics/*metabolism ; *DNA Cleavage ; Deoxycytidine/genetics/metabolism ; *Gene Silencing ; Phosphorylation ; Plasmids/genetics ; Prokaryotic Cells/*metabolism ; Thermus thermophilus/*genetics/*metabolism
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    Structural basis of PAM-dependent target DNA recognition by the Cas9 endonuclease (2014)
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    Publication Date: 2014-08-01
    Description: The CRISPR-associated protein Cas9 is an RNA-guided endonuclease that cleaves double-stranded DNA bearing sequences complementary to a 20-nucleotide segment in the guide RNA. Cas9 has emerged as a versatile molecular tool for genome editing and gene expression control. RNA-guided DNA recognition and cleavage strictly require the presence of a protospacer adjacent motif (PAM) in the target DNA. Here we report a crystal structure of Streptococcus pyogenes Cas9 in complex with a single-molecule guide RNA and a target DNA containing a canonical 5'-NGG-3' PAM. The structure reveals that the PAM motif resides in a base-paired DNA duplex. The non-complementary strand GG dinucleotide is read out via major-groove interactions with conserved arginine residues from the carboxy-terminal domain of Cas9. Interactions with the minor groove of the PAM duplex and the phosphodiester group at the +1 position in the target DNA strand contribute to local strand separation immediately upstream of the PAM. These observations suggest a mechanism for PAM-dependent target DNA melting and RNA-DNA hybrid formation. Furthermore, this study establishes a framework for the rational engineering of Cas9 enzymes with novel PAM specificities.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176945/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176945/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Anders, Carolin -- Niewoehner, Ole -- Duerst, Alessia -- Jinek, Martin -- 337284/European Research Council/International -- England -- Nature. 2014 Sep 25;513(7519):569-73. doi: 10.1038/nature13579. Epub 2014 Jul 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25079318" target="_blank"〉PubMed〈/a〉
    Keywords: Arginine/genetics/metabolism ; *Base Pairing ; Base Sequence ; CRISPR-Associated Proteins/*metabolism ; Crystallography, X-Ray ; DNA/*chemistry/genetics/*metabolism ; Endonucleases/*metabolism ; Models, Molecular ; Nucleic Acid Denaturation ; *Nucleotide Motifs ; Protein Conformation ; RNA, Guide/chemistry/genetics/metabolism ; Streptococcus pyogenes/*enzymology ; Substrate Specificity
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    Structure-based programming of lymph-node targeting in molecular vaccines (2014)
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    Publication Date: 2014-02-18
    Description: In cancer patients, visual identification of sentinel lymph nodes (LNs) is achieved by the injection of dyes that bind avidly to endogenous albumin, targeting these compounds to LNs, where they are efficiently filtered by resident phagocytes. Here we translate this 'albumin hitchhiking' approach to molecular vaccines, through the synthesis of amphiphiles (amph-vaccines) comprising an antigen or adjuvant cargo linked to a lipophilic albumin-binding tail by a solubility-promoting polar polymer chain. Administration of structurally optimized CpG-DNA/peptide amph-vaccines in mice resulted in marked increases in LN accumulation and decreased systemic dissemination relative to their parent compounds, leading to 30-fold increases in T-cell priming and enhanced anti-tumour efficacy while greatly reducing systemic toxicity. Amph-vaccines provide a simple, broadly applicable strategy to simultaneously increase the potency and safety of subunit vaccines.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069155/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069155/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Haipeng -- Moynihan, Kelly D -- Zheng, Yiran -- Szeto, Gregory L -- Li, Adrienne V -- Huang, Bonnie -- Van Egeren, Debra S -- Park, Clara -- Irvine, Darrell J -- AI091693/AI/NIAID NIH HHS/ -- AI095109/AI/NIAID NIH HHS/ -- AI104715/AI/NIAID NIH HHS/ -- F32 CA180586/CA/NCI NIH HHS/ -- P01 AI104715/AI/NIAID NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R01 AI095109/AI/NIAID NIH HHS/ -- U19 AI091693/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Mar 27;507(7493):519-22. doi: 10.1038/nature12978. Epub 2014 Feb 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [4] Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts 02139, USA [5] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24531764" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; CpG Islands/genetics/immunology ; Female ; Lymph Nodes/*immunology ; Mice ; Mice, Inbred C57BL ; T-Lymphocytes/immunology ; Vaccines, Subunit/genetics/*immunology ; Vaccines, Synthetic/genetics/*immunology
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    Hangzhou (2014)
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    Publication Date: 2014-12-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2014 Dec 18;516(7531):S69. doi: 10.1038/516S69a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25517242" target="_blank"〉PubMed〈/a〉
    Keywords: Chemistry ; China ; Cities ; Periodicals as Topic/statistics & numerical data ; Physics ; Research/standards/*statistics & numerical data/trends ; Universities/statistics & numerical data
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    UvrD facilitates DNA repair by pulling RNA polymerase backwards (2014)
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    Publication Date: 2014-01-10
    Description: UvrD helicase is required for nucleotide excision repair, although its role in this process is not well defined. Here we show that Escherichia coli UvrD binds RNA polymerase during transcription elongation and, using its helicase/translocase activity, forces RNA polymerase to slide backward along DNA. By inducing backtracking, UvrD exposes DNA lesions shielded by blocked RNA polymerase, allowing nucleotide excision repair enzymes to gain access to sites of damage. Our results establish UvrD as a bona fide transcription elongation factor that contributes to genomic integrity by resolving conflicts between transcription and DNA repair complexes. Furthermore, we show that the elongation factor NusA cooperates with UvrD in coupling transcription to DNA repair by promoting backtracking and recruiting nucleotide excision repair enzymes to exposed lesions. Because backtracking is a shared feature of all cellular RNA polymerases, we propose that this mechanism enables RNA polymerases to function as global DNA damage scanners in bacteria and eukaryotes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471481/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471481/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Epshtein, Vitaly -- Kamarthapu, Venu -- McGary, Katelyn -- Svetlov, Vladimir -- Ueberheide, Beatrix -- Proshkin, Sergey -- Mironov, Alexander -- Nudler, Evgeny -- R01 GM058750/GM/NIGMS NIH HHS/ -- T32 GM088118/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jan 16;505(7483):372-7. doi: 10.1038/nature12928. Epub 2014 Jan 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA [2]. ; 1] Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA [2] Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA [3]. ; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA. ; State Research Institute of Genetics and Selection of Industrial Microorganisms, Moscow 117545, Russia. ; 1] State Research Institute of Genetics and Selection of Industrial Microorganisms, Moscow 117545, Russia [2] Engelhardt Institute of Molecular Biology, Russian Academy of Science, Moscow 119991, Russia. ; 1] Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA [2] Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24402227" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; DNA/chemistry/metabolism ; DNA Damage ; DNA Helicases/*metabolism ; *DNA Repair ; DNA-Directed RNA Polymerases/chemistry/*metabolism ; Escherichia coli/enzymology/genetics ; Escherichia coli Proteins/*metabolism ; Models, Molecular ; Molecular Sequence Data ; *Movement ; Peptide Elongation Factors/metabolism ; Protein Binding ; Transcription Factors/metabolism ; Transcription, Genetic ; Transcriptional Elongation Factors
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    An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons (2014)
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    Publication Date: 2014-10-03
    Description: Throughout evolution primate genomes have been modified by waves of retrotransposon insertions. For each wave, the host eventually finds a way to repress retrotransposon transcription and prevent further insertions. In mouse embryonic stem cells, transcriptional silencing of retrotransposons requires KAP1 (also known as TRIM28) and its repressive complex, which can be recruited to target sites by KRAB zinc-finger (KZNF) proteins such as murine-specific ZFP809 which binds to integrated murine leukaemia virus DNA elements and recruits KAP1 to repress them. KZNF genes are one of the fastest growing gene families in primates and this expansion is hypothesized to enable primates to respond to newly emerged retrotransposons. However, the identity of KZNF genes battling retrotransposons currently active in the human genome, such as SINE-VNTR-Alu (SVA) and long interspersed nuclear element 1 (L1), is unknown. Here we show that two primate-specific KZNF genes rapidly evolved to repress these two distinct retrotransposon families shortly after they began to spread in our ancestral genome. ZNF91 underwent a series of structural changes 8-12 million years ago that enabled it to repress SVA elements. ZNF93 evolved earlier to repress the primate L1 lineage until approximately 12.5 million years ago when the L1PA3-subfamily of retrotransposons escaped ZNF93's restriction through the removal of the ZNF93-binding site. Our data support a model where KZNF gene expansion limits the activity of newly emerged retrotransposon classes, and this is followed by mutations in these retrotransposons to evade repression, a cycle of events that could explain the rapid expansion of lineage-specific KZNF genes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268317/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268317/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jacobs, Frank M J -- Greenberg, David -- Nguyen, Ngan -- Haeussler, Maximilian -- Ewing, Adam D -- Katzman, Sol -- Paten, Benedict -- Salama, Sofie R -- Haussler, David -- U24 CA143858/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Dec 11;516(7530):242-5. doi: 10.1038/nature13760. Epub 2014 Sep 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA [2] [3] Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam 1098 XH, The Netherlands (F.M.J.J.); Gladstone Institute of Virology and Immunology, San Francisco, California 94158, USA (D.G.); Mater Research Institute, University of Queensland, Queensland 4101, Australia (A.D.E.). ; 1] Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA [2] Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, California 95064, USA [3] [4] Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam 1098 XH, The Netherlands (F.M.J.J.); Gladstone Institute of Virology and Immunology, San Francisco, California 94158, USA (D.G.); Mater Research Institute, University of Queensland, Queensland 4101, Australia (A.D.E.). ; 1] Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA [2] Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA. ; Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA. ; 1] Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA [2] Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam 1098 XH, The Netherlands (F.M.J.J.); Gladstone Institute of Virology and Immunology, San Francisco, California 94158, USA (D.G.); Mater Research Institute, University of Queensland, Queensland 4101, Australia (A.D.E.). ; 1] Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA [2] Howard Hughes Medical Institute, University of California Santa Cruz, Santa Cruz, California 95064, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25274305" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Embryonic Stem Cells/cytology/metabolism ; *Evolution, Molecular ; Humans ; Kruppel-Like Transcription Factors/genetics/*metabolism ; Mice ; Mutation/genetics ; Primates/*genetics ; Retroelements/*genetics ; Zinc Fingers
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    miRNAs trigger widespread epigenetically activated siRNAs from transposons in Arabidopsis (2014)
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    Publication Date: 2014-03-29
    Description: In plants, post-transcriptional gene silencing (PTGS) is mediated by DICER-LIKE 1 (DCL1)-dependent microRNAs (miRNAs), which also trigger 21-nucleotide secondary short interfering RNAs (siRNAs) via RNA-DEPENDENT RNA POLYMERASE 6 (RDR6), DCL4 and ARGONAUTE 1 (AGO1), whereas transcriptional gene silencing (TGS) of transposons is mediated by 24-nucleotide heterochromatic (het)siRNAs, RDR2, DCL3 and AGO4 (ref. 4). Transposons can also give rise to abundant 21-nucleotide 'epigenetically activated' small interfering RNAs (easiRNAs) in DECREASED DNA METHYLATION 1 (ddm1) and DNA METHYLTRANSFERASE 1 (met1) mutants, as well as in the vegetative nucleus of pollen grains and in dedifferentiated plant cell cultures. Here we show that easiRNAs in Arabidopsis thaliana resemble secondary siRNAs, in that thousands of transposon transcripts are specifically targeted by more than 50 miRNAs for cleavage and processing by RDR6. Loss of RDR6, DCL4 or DCL1 in a ddm1 background results in loss of 21-nucleotide easiRNAs and severe infertility, but 24-nucleotide hetsiRNAs are partially restored, supporting an antagonistic relationship between PTGS and TGS. Thus miRNA-directed easiRNA biogenesis is a latent mechanism that specifically targets transposon transcripts, but only when they are epigenetically reactivated during reprogramming of the germ line. This ancient recognition mechanism may have been retained both by transposons to evade long-term heterochromatic silencing and by their hosts for genome defence.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074602/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074602/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Creasey, Kate M -- Zhai, Jixian -- Borges, Filipe -- Van Ex, Frederic -- Regulski, Michael -- Meyers, Blake C -- Martienssen, Robert A -- P30 CA045508/CA/NCI NIH HHS/ -- R01 GM067014/GM/NIGMS NIH HHS/ -- R01GM067014/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Apr 17;508(7496):411-5. doi: 10.1038/nature13069. Epub 2014 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA. ; Delaware Biotechnology Institute and Department of Plant & Soil Sciences, 15 Innovation Way, University of Delaware, Newark, Delaware 19711, USA. ; 1] Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [2] Howard Hughes Medical Institute-Gordon and Betty Moore Foundation, Cold Spring Harbor Laboratory, New York 11724, USA [3] Chaire Blaise Pascal, Institut de Biologie de l'Ecole Normale Superieure (IBENS), 75230 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670663" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*genetics ; Base Sequence ; Conserved Sequence ; DNA Transposable Elements/genetics ; *Epigenesis, Genetic ; Genome, Plant/genetics ; MicroRNAs/*genetics/metabolism ; Models, Genetic ; Open Reading Frames/genetics ; RNA, Small Interfering/biosynthesis/*genetics ; Retroelements/*genetics
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  • 35
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    Enhancer-core-promoter specificity separates developmental and housekeeping gene regulation (2014)
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    Publication Date: 2014-12-18
    Description: Gene transcription in animals involves the assembly of RNA polymerase II at core promoters and its cell-type-specific activation by enhancers that can be located more distally. However, how ubiquitous expression of housekeeping genes is achieved has been less clear. In particular, it is unknown whether ubiquitously active enhancers exist and how developmental and housekeeping gene regulation is separated. An attractive hypothesis is that different core promoters might exhibit an intrinsic specificity to certain enhancers. This is conceivable, as various core promoter sequence elements are differentially distributed between genes of different functions, including elements that are predominantly found at either developmentally regulated or at housekeeping genes. Here we show that thousands of enhancers in Drosophila melanogaster S2 and ovarian somatic cells (OSCs) exhibit a marked specificity to one of two core promoters--one derived from a ubiquitously expressed ribosomal protein gene and another from a developmentally regulated transcription factor--and confirm the existence of these two classes for five additional core promoters from genes with diverse functions. Housekeeping enhancers are active across the two cell types, while developmental enhancers exhibit strong cell-type specificity. Both enhancer classes differ in their genomic distribution, the functions of neighbouring genes, and the core promoter elements of these neighbouring genes. In addition, we identify two transcription factors--Dref and Trl--that bind and activate housekeeping versus developmental enhancers, respectively. Our results provide evidence for a sequence-encoded enhancer-core-promoter specificity that separates developmental and housekeeping gene regulatory programs for thousands of enhancers and their target genes across the entire genome.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zabidi, Muhammad A -- Arnold, Cosmas D -- Schernhuber, Katharina -- Pagani, Michaela -- Rath, Martina -- Frank, Olga -- Stark, Alexander -- England -- Nature. 2015 Feb 26;518(7540):556-9. doi: 10.1038/nature13994. Epub 2014 Dec 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Institute of Molecular Pathology IMP, Vienna Biocenter VBC, Dr Bohr-Gasse 7, 1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25517091" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Cell Line ; DNA-Binding Proteins/metabolism ; Drosophila Proteins/metabolism ; Drosophila melanogaster/*embryology/*genetics ; Enhancer Elements, Genetic/*genetics ; Gene Expression Regulation, Developmental/*genetics ; Genes, Essential/*genetics ; Genome, Insect/genetics ; Models, Genetic ; Organ Specificity ; Promoter Regions, Genetic/*genetics ; Substrate Specificity/genetics ; Transcription Factors/metabolism ; Transcriptional Activation/genetics
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    C11orf95-RELA fusions drive oncogenic NF-kappaB signalling in ependymoma (2014)
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    Publication Date: 2014-02-21
    Description: Members of the nuclear factor-kappaB (NF-kappaB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-kappaB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-kappaB activity in cancer. Here we show that more than two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-kappaB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-kappaB target genes, and rapidly transformed neural stem cells--the cell of origin of ependymoma--to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050669/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050669/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Parker, Matthew -- Mohankumar, Kumarasamypet M -- Punchihewa, Chandanamali -- Weinlich, Ricardo -- Dalton, James D -- Li, Yongjin -- Lee, Ryan -- Tatevossian, Ruth G -- Phoenix, Timothy N -- Thiruvenkatam, Radhika -- White, Elsie -- Tang, Bo -- Orisme, Wilda -- Gupta, Kirti -- Rusch, Michael -- Chen, Xiang -- Li, Yuxin -- Nagahawhatte, Panduka -- Hedlund, Erin -- Finkelstein, David -- Wu, Gang -- Shurtleff, Sheila -- Easton, John -- Boggs, Kristy -- Yergeau, Donald -- Vadodaria, Bhavin -- Mulder, Heather L -- Becksfort, Jared -- Gupta, Pankaj -- Huether, Robert -- Ma, Jing -- Song, Guangchun -- Gajjar, Amar -- Merchant, Thomas -- Boop, Frederick -- Smith, Amy A -- Ding, Li -- Lu, Charles -- Ochoa, Kerri -- Zhao, David -- Fulton, Robert S -- Fulton, Lucinda L -- Mardis, Elaine R -- Wilson, Richard K -- Downing, James R -- Green, Douglas R -- Zhang, Jinghui -- Ellison, David W -- Gilbertson, Richard J -- P01 CA096832/CA/NCI NIH HHS/ -- P01CA96832/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30CA021765/CA/NCI NIH HHS/ -- R01 CA129541/CA/NCI NIH HHS/ -- R01CA129541/CA/NCI NIH HHS/ -- England -- Nature. 2014 Feb 27;506(7489):451-5. doi: 10.1038/nature13109. Epub 2014 Feb 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [3]. ; 1] Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2]. ; 1] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2]. ; 1] Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2]. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2] Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA. ; Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; MD Anderson Cancer Center Orlando, Pediatric Hematology/Oncology, 92 West Miller MP 318, Orlando, Florida 32806, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA [3] Department of Genetics, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA [3] Department of Genetics, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA [4] Siteman Cancer Center, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA. ; Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24553141" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics/metabolism ; Animals ; Base Sequence ; Brain Neoplasms/genetics/metabolism/pathology ; Cell Line ; Cell Nucleus/metabolism ; *Cell Transformation, Neoplastic/genetics ; Chromosomes, Human, Pair 11/genetics ; Ependymoma/*genetics/*metabolism/pathology ; Female ; Humans ; Mice ; Models, Genetic ; Molecular Sequence Data ; NF-kappa B/genetics/*metabolism ; Neural Stem Cells/metabolism/pathology ; Oncogene Proteins, Fusion/genetics/metabolism ; Phosphoproteins/genetics/metabolism ; Proteins/genetics/*metabolism ; *Signal Transduction ; Transcription Factor RelA/genetics/*metabolism ; Translocation, Genetic/genetics
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    Catalysts from synthetic genetic polymers (2014)
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    Publication Date: 2014-12-04
    Description: The emergence of catalysis in early genetic polymers such as RNA is considered a key transition in the origin of life, pre-dating the appearance of protein enzymes. DNA also demonstrates the capacity to fold into three-dimensional structures and form catalysts in vitro. However, to what degree these natural biopolymers comprise functionally privileged chemical scaffolds for folding or the evolution of catalysis is not known. The ability of synthetic genetic polymers (XNAs) with alternative backbone chemistries not found in nature to fold into defined structures and bind ligands raises the possibility that these too might be capable of forming catalysts (XNAzymes). Here we report the discovery of such XNAzymes, elaborated in four different chemistries (arabino nucleic acids, ANA; 2'-fluoroarabino nucleic acids, FANA; hexitol nucleic acids, HNA; and cyclohexene nucleic acids, CeNA) directly from random XNA oligomer pools, exhibiting in trans RNA endonuclease and ligase activities. We also describe an XNA-XNA ligase metalloenzyme in the FANA framework, establishing catalysis in an entirely synthetic system and enabling the synthesis of FANA oligomers and an active RNA endonuclease FANAzyme from its constituent parts. These results extend catalysis beyond biopolymers and establish technologies for the discovery of catalysts in a wide range of polymer scaffolds not found in nature. Evolution of catalysis independent of any natural polymer has implications for the definition of chemical boundary conditions for the emergence of life on Earth and elsewhere in the Universe.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336857/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336857/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Taylor, Alexander I -- Pinheiro, Vitor B -- Smola, Matthew J -- Morgunov, Alexey S -- Peak-Chew, Sew -- Cozens, Christopher -- Weeks, Kevin M -- Herdewijn, Piet -- Holliger, Philipp -- MC_U105178804/Medical Research Council/United Kingdom -- MC_U105185859/Medical Research Council/United Kingdom -- T32 GM008570/GM/NIGMS NIH HHS/ -- U105178804/Medical Research Council/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2015 Feb 19;518(7539):427-30. doi: 10.1038/nature13982. Epub 2014 Dec 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. ; Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599-3290, USA. ; 1] KU Leuven, Rega Institute, Minderbroedersstraat 10, B 3000 Leuven, Belgium [2] Universite Evry, Institute of Systems and Synthetic Biology, 5 rue Henri Desbrueres, 91030 Evry Cedex, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470036" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Catalysis ; Endonucleases/metabolism ; Ligases/metabolism ; Nucleic Acids/*chemical synthesis/chemistry/*metabolism ; Polymers/*chemical synthesis/*chemistry/metabolism ; RNA/metabolism
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    DNMT1-interacting RNAs block gene-specific DNA methylation (2013)
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    Publication Date: 2013-10-11
    Description: DNA methylation was first described almost a century ago; however, the rules governing its establishment and maintenance remain elusive. Here we present data demonstrating that active transcription regulates levels of genomic methylation. We identify a novel RNA arising from the CEBPA gene locus that is critical in regulating the local DNA methylation profile. This RNA binds to DNMT1 and prevents CEBPA gene locus methylation. Deep sequencing of transcripts associated with DNMT1 combined with genome-scale methylation and expression profiling extend the generality of this finding to numerous gene loci. Collectively, these results delineate the nature of DNMT1-RNA interactions and suggest strategies for gene-selective demethylation of therapeutic targets in human diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870304/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870304/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Di Ruscio, Annalisa -- Ebralidze, Alexander K -- Benoukraf, Touati -- Amabile, Giovanni -- Goff, Loyal A -- Terragni, Jolyon -- Figueroa, Maria Eugenia -- De Figueiredo Pontes, Lorena Lobo -- Alberich-Jorda, Meritxell -- Zhang, Pu -- Wu, Mengchu -- D'Alo, Francesco -- Melnick, Ari -- Leone, Giuseppe -- Ebralidze, Konstantin K -- Pradhan, Sriharsa -- Rinn, John L -- Tenen, Daniel G -- CA118316/CA/NCI NIH HHS/ -- CA66996/CA/NCI NIH HHS/ -- HL56745/HL/NHLBI NIH HHS/ -- P01 CA066996/CA/NCI NIH HHS/ -- R01 CA118316/CA/NCI NIH HHS/ -- R01 HL056745/HL/NHLBI NIH HHS/ -- R01 HL112719/HL/NHLBI NIH HHS/ -- T32 HL007917-11A1/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 Nov 21;503(7476):371-6. doi: 10.1038/nature12598. Epub 2013 Oct 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA [3] Universita Cattolica del Sacro Cuore, Institute of Hematology, L.go A. Gemelli 8, Rome 00168, Italy [4].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24107992" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; CCAAT-Enhancer-Binding Proteins/*genetics ; Cell Line ; DNA/genetics/metabolism ; DNA (Cytosine-5-)-Methyltransferase/*metabolism ; DNA Methylation/*genetics ; Gene Expression Profiling ; Gene Expression Regulation/*genetics ; Genome, Human/genetics ; Humans ; RNA, Messenger/genetics/metabolism ; RNA, Untranslated/genetics/*metabolism ; RNA-Binding Proteins/metabolism ; Substrate Specificity ; Transcription, Genetic/genetics
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    A compendium of RNA-binding motifs for decoding gene regulation (2013)
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    Publication Date: 2013-07-13
    Description: RNA-binding proteins are key regulators of gene expression, yet only a small fraction have been functionally characterized. Here we report a systematic analysis of the RNA motifs recognized by RNA-binding proteins, encompassing 205 distinct genes from 24 diverse eukaryotes. The sequence specificities of RNA-binding proteins display deep evolutionary conservation, and the recognition preferences for a large fraction of metazoan RNA-binding proteins can thus be inferred from their RNA-binding domain sequence. The motifs that we identify in vitro correlate well with in vivo RNA-binding data. Moreover, we can associate them with distinct functional roles in diverse types of post-transcriptional regulation, enabling new insights into the functions of RNA-binding proteins both in normal physiology and in human disease. These data provide an unprecedented overview of RNA-binding proteins and their targets, and constitute an invaluable resource for determining post-transcriptional regulatory mechanisms in eukaryotes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929597/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929597/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ray, Debashish -- Kazan, Hilal -- Cook, Kate B -- Weirauch, Matthew T -- Najafabadi, Hamed S -- Li, Xiao -- Gueroussov, Serge -- Albu, Mihai -- Zheng, Hong -- Yang, Ally -- Na, Hong -- Irimia, Manuel -- Matzat, Leah H -- Dale, Ryan K -- Smith, Sarah A -- Yarosh, Christopher A -- Kelly, Seth M -- Nabet, Behnam -- Mecenas, Desirea -- Li, Weimin -- Laishram, Rakesh S -- Qiao, Mei -- Lipshitz, Howard D -- Piano, Fabio -- Corbett, Anita H -- Carstens, Russ P -- Frey, Brendan J -- Anderson, Richard A -- Lynch, Kristen W -- Penalva, Luiz O F -- Lei, Elissa P -- Fraser, Andrew G -- Blencowe, Benjamin J -- Morris, Quaid D -- Hughes, Timothy R -- 1R01HG00570/HG/NHGRI NIH HHS/ -- DK015602-05/DK/NIDDK NIH HHS/ -- MOP-125894/Canadian Institutes of Health Research/Canada -- MOP-14409/Canadian Institutes of Health Research/Canada -- MOP-49451/Canadian Institutes of Health Research/Canada -- MOP-67011/Canadian Institutes of Health Research/Canada -- MOP-93671/Canadian Institutes of Health Research/Canada -- P30 CA014520/CA/NCI NIH HHS/ -- R01 CA104708/CA/NCI NIH HHS/ -- R01 GM051968/GM/NIGMS NIH HHS/ -- R01 GM084034/GM/NIGMS NIH HHS/ -- R01 HG005700/HG/NHGRI NIH HHS/ -- R01GM084034/GM/NIGMS NIH HHS/ -- T32 GM008061/GM/NIGMS NIH HHS/ -- Z01 DK015602-01/Intramural NIH HHS/ -- England -- Nature. 2013 Jul 11;499(7457):172-7. doi: 10.1038/nature12311.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Donnelly Centre, University of Toronto, Toronto M5S 3E1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23846655" target="_blank"〉PubMed〈/a〉
    Keywords: Autistic Disorder/genetics ; Base Sequence ; Binding Sites/genetics ; Conserved Sequence/genetics ; Eukaryotic Cells/metabolism ; Gene Expression Regulation/*genetics ; Humans ; Molecular Sequence Data ; Nucleotide Motifs/*genetics ; Protein Structure, Tertiary/genetics ; RNA Stability/genetics ; RNA-Binding Proteins/chemistry/genetics/*metabolism
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    APOBEC3B is an enzymatic source of mutation in breast cancer (2013)
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    Publication Date: 2013-02-08
    Description: Several mutations are required for cancer development, and genome sequencing has revealed that many cancers, including breast cancer, have somatic mutation spectra dominated by C-to-T transitions. Most of these mutations occur at hydrolytically disfavoured non-methylated cytosines throughout the genome, and are sometimes clustered. Here we show that the DNA cytosine deaminase APOBEC3B is a probable source of these mutations. APOBEC3B messenger RNA is upregulated in most primary breast tumours and breast cancer cell lines. Tumours that express high levels of APOBEC3B have twice as many mutations as those that express low levels and are more likely to have mutations in TP53. Endogenous APOBEC3B protein is predominantly nuclear and the only detectable source of DNA C-to-U editing activity in breast cancer cell-line extracts. Knockdown experiments show that endogenous APOBEC3B correlates with increased levels of genomic uracil, increased mutation frequencies, and C-to-T transitions. Furthermore, induced APOBEC3B overexpression causes cell cycle deviations, cell death, DNA fragmentation, gamma-H2AX accumulation and C-to-T mutations. Our data suggest a model in which APOBEC3B-catalysed deamination provides a chronic source of DNA damage in breast cancers that could select TP53 inactivation and explain how some tumours evolve rapidly and manifest heterogeneity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907282/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907282/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Burns, Michael B -- Lackey, Lela -- Carpenter, Michael A -- Rathore, Anurag -- Land, Allison M -- Leonard, Brandon -- Refsland, Eric W -- Kotandeniya, Delshanee -- Tretyakova, Natalia -- Nikas, Jason B -- Yee, Douglas -- Temiz, Nuri A -- Donohue, Duncan E -- McDougle, Rebecca M -- Brown, William L -- Law, Emily K -- Harris, Reuben S -- 1UL1RR033183/RR/NCRR NIH HHS/ -- F31 DA033186/DA/NIDA NIH HHS/ -- F32 GM095219/GM/NIGMS NIH HHS/ -- KL2 RR033182/RR/NCRR NIH HHS/ -- P01 GM091743/GM/NIGMS NIH HHS/ -- P30 CA77598/CA/NCI NIH HHS/ -- P50 CA101955/CA/NCI NIH HHS/ -- R01 AI064046/AI/NIAID NIH HHS/ -- T32 AI083196/AI/NIAID NIH HHS/ -- T32 CA009138/CA/NCI NIH HHS/ -- UL1 TR000114/TR/NCATS NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2013 Feb 21;494(7437):366-70. doi: 10.1038/nature11881. Epub 2013 Feb 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biochemistry, Molecular Biology and Biophysics Department, University of Minnesota, Minneapolis, Minnesota 55455, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23389445" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Biocatalysis ; Breast Neoplasms/*enzymology/*genetics/pathology ; Cell Death ; Cell Line, Tumor ; Cytidine Deaminase/genetics/*metabolism ; DNA Damage/genetics ; DNA Fragmentation ; DNA, Neoplasm/genetics/metabolism ; Deamination ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Histones/metabolism ; Humans ; *Mutagenesis/genetics ; Phenotype ; *Point Mutation/genetics ; Tumor Suppressor Protein p53/genetics/metabolism ; Up-Regulation ; Uracil/metabolism
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    Three-state mechanism couples ligand and temperature sensing in riboswitches (2013)
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    Publication Date: 2013-07-12
    Description: Riboswitches are cis-acting gene-regulatory RNA elements that can function at the level of transcription, translation and RNA cleavage. The commonly accepted molecular mechanism for riboswitch function proposes a ligand-dependent conformational switch between two mutually exclusive states. According to this mechanism, ligand binding to an aptamer domain induces an allosteric conformational switch of an expression platform, leading to activation or repression of ligand-related gene expression. However, many riboswitch properties cannot be explained by a pure two-state mechanism. Here we show that the regulation mechanism of the adenine-sensing riboswitch, encoded by the add gene on chromosome II of the human Gram-negative pathogenic bacterium Vibrio vulnificus, is notably different from a two-state switch mechanism in that it involves three distinct stable conformations. We characterized the temperature and Mg(2+) dependence of the population ratios of the three conformations and the kinetics of their interconversion at nucleotide resolution. The observed temperature dependence of a pre-equilibrium involving two structurally distinct ligand-free conformations of the add riboswitch conferred efficient regulation over a physiologically relevant temperature range. Such robust switching is a key requirement for gene regulation in bacteria that have to adapt to environments with varying temperatures. The translational adenine-sensing riboswitch represents the first example, to our knowledge, of a temperature-compensated regulatory RNA element.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reining, Anke -- Nozinovic, Senada -- Schlepckow, Kai -- Buhr, Florian -- Furtig, Boris -- Schwalbe, Harald -- England -- Nature. 2013 Jul 18;499(7458):355-9. doi: 10.1038/nature12378. Epub 2013 Jul 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Biomolecular Magnetic Resonance, Institute of Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-Universitat Frankfurt am Main, Max-von-Laue-Strasse 7, 60438 Frankfurt am Main, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23842498" target="_blank"〉PubMed〈/a〉
    Keywords: Adenine/metabolism ; Base Sequence ; *Gene Expression Regulation, Bacterial ; Ligands ; Magnesium/chemistry ; Molecular Sequence Data ; Nucleic Acid Conformation ; RNA, Bacterial/*chemistry/metabolism ; *Riboswitch ; Temperature ; Vibrio vulnificus/genetics
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    Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription (2013)
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    Publication Date: 2013-06-04
    Description: Rev-Erb-alpha and Rev-Erb-beta are nuclear receptors that regulate the expression of genes involved in the control of circadian rhythm, metabolism and inflammatory responses. Rev-Erbs function as transcriptional repressors by recruiting nuclear receptor co-repressor (NCoR)-HDAC3 complexes to Rev-Erb response elements in enhancers and promoters of target genes, but the molecular basis for cell-specific programs of repression is not known. Here we present evidence that in mouse macrophages Rev-Erbs regulate target gene expression by inhibiting the functions of distal enhancers that are selected by macrophage-lineage-determining factors, thereby establishing a macrophage-specific program of repression. Remarkably, the repressive functions of Rev-Erbs are associated with their ability to inhibit the transcription of enhancer-derived RNAs (eRNAs). Furthermore, targeted degradation of eRNAs at two enhancers subject to negative regulation by Rev-Erbs resulted in reduced expression of nearby messenger RNAs, suggesting a direct role of these eRNAs in enhancer function. By precisely defining eRNA start sites using a modified form of global run-on sequencing that quantifies nascent 5' ends, we show that transfer of full enhancer activity to a target promoter requires both the sequences mediating transcription-factor binding and the specific sequences encoding the eRNA transcript. These studies provide evidence for a direct role of eRNAs in contributing to enhancer functions and suggest that Rev-Erbs act to suppress gene expression at a distance by repressing eRNA transcription.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839578/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839578/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lam, Michael T Y -- Cho, Han -- Lesch, Hanna P -- Gosselin, David -- Heinz, Sven -- Tanaka-Oishi, Yumiko -- Benner, Christopher -- Kaikkonen, Minna U -- Kim, Aneeza S -- Kosaka, Mika -- Lee, Cindy Y -- Watt, Andy -- Grossman, Tamar R -- Rosenfeld, Michael G -- Evans, Ronald M -- Glass, Christopher K -- CA014195/CA/NCI NIH HHS/ -- CA17390/CA/NCI NIH HHS/ -- CA52599/CA/NCI NIH HHS/ -- DK057978/DK/NIDDK NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK091183/DK/NIDDK NIH HHS/ -- HL088093/HL/NHLBI NIH HHS/ -- HL105278/HL/NHLBI NIH HHS/ -- P01 DK074868/DK/NIDDK NIH HHS/ -- P01 HL088093/HL/NHLBI NIH HHS/ -- P30 CA014195/CA/NCI NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- R01 CA052599/CA/NCI NIH HHS/ -- R01 CA173903/CA/NCI NIH HHS/ -- R01 DK018477/DK/NIDDK NIH HHS/ -- R01 DK091183/DK/NIDDK NIH HHS/ -- R01 HL105278/HL/NHLBI NIH HHS/ -- R37 DK057978/DK/NIDDK NIH HHS/ -- T32 GM007198-37/GM/NIGMS NIH HHS/ -- T32 GM008666/GM/NIGMS NIH HHS/ -- U19 DK062434/DK/NIDDK NIH HHS/ -- U19DK62434/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jun 27;498(7455):511-5. doi: 10.1038/nature12209. Epub 2013 Jun 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23728303" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Base Sequence ; Binding Sites ; Down-Regulation/*genetics ; Enhancer Elements, Genetic/*genetics ; Gene Knockdown Techniques ; Macrophages/*metabolism ; Mice ; Nuclear Receptor Subfamily 1, Group D, Member 1/deficiency/genetics/*metabolism ; Organ Specificity ; Promoter Regions, Genetic/genetics ; RNA, Messenger/genetics/metabolism ; Response Elements/genetics ; Transcription, Genetic/*genetics
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    Effect of natural genetic variation on enhancer selection and function (2013)
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    Publication Date: 2013-10-15
    Description: The mechanisms by which genetic variation affects transcription regulation and phenotypes at the nucleotide level are incompletely understood. Here we use natural genetic variation as an in vivo mutagenesis screen to assess the genome-wide effects of sequence variation on lineage-determining and signal-specific transcription factor binding, epigenomics and transcriptional outcomes in primary macrophages from different mouse strains. We find substantial genetic evidence to support the concept that lineage-determining transcription factors define epigenetic and transcriptomic states by selecting enhancer-like regions in the genome in a collaborative fashion and facilitating binding of signal-dependent factors. This hierarchical model of transcription factor function suggests that limited sets of genomic data for lineage-determining transcription factors and informative histone modifications can be used for the prioritization of disease-associated regulatory variants.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994126/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994126/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Heinz, S -- Romanoski, C E -- Benner, C -- Allison, K A -- Kaikkonen, M U -- Orozco, L D -- Glass, C K -- 5T32DK007494/DK/NIDDK NIH HHS/ -- CA17390/CA/NCI NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK091183/DK/NIDDK NIH HHS/ -- P01 DK074868/DK/NIDDK NIH HHS/ -- P30 CA023100/CA/NCI NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- R01 CA173903/CA/NCI NIH HHS/ -- R01 DK091183/DK/NIDDK NIH HHS/ -- T32 AR059033/AR/NIAMS NIH HHS/ -- England -- Nature. 2013 Nov 28;503(7477):487-92. doi: 10.1038/nature12615. Epub 2013 Oct 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, Mail Code 0651, La Jolla, California 92093, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24121437" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs/genetics ; Animals ; Base Sequence ; Cell Lineage/genetics ; DNA-Binding Proteins/metabolism ; Enhancer Elements, Genetic/*genetics ; Gene Expression Regulation/*genetics ; Genetic Variation/*genetics ; Histones/chemistry/metabolism ; Macrophages/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Models, Biological ; Mutation/genetics ; NF-kappa B/metabolism ; Protein Binding ; Reproducibility of Results ; Selection, Genetic/*genetics ; Transcription Factor RelA/metabolism ; Transcription Factors/*metabolism
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    Unusual base pairing during the decoding of a stop codon by the ribosome (2013)
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    Publication Date: 2013-07-03
    Description: During normal translation, the binding of a release factor to one of the three stop codons (UGA, UAA or UAG) results in the termination of protein synthesis. However, modification of the initial uridine to a pseudouridine (Psi) allows efficient recognition and read-through of these stop codons by a transfer RNA (tRNA), although it requires the formation of two normally forbidden purine-purine base pairs. Here we determined the crystal structure at 3.1 A resolution of the 30S ribosomal subunit in complex with the anticodon stem loop of tRNA(Ser) bound to the PsiAG stop codon in the A site. The PsiA base pair at the first position is accompanied by the formation of purine-purine base pairs at the second and third positions of the codon, which show an unusual Watson-Crick/Hoogsteen geometry. The structure shows a previously unsuspected ability of the ribosomal decoding centre to accommodate non-canonical base pairs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732562/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732562/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fernandez, Israel S -- Ng, Chyan Leong -- Kelley, Ann C -- Wu, Guowei -- Yu, Yi-Tao -- Ramakrishnan, V -- 096570/Wellcome Trust/United Kingdom -- GM104077/GM/NIGMS NIH HHS/ -- MC_U105184332/Medical Research Council/United Kingdom -- R01 GM104077/GM/NIGMS NIH HHS/ -- R21 AG039559/AG/NIA NIH HHS/ -- U105184332/Medical Research Council/United Kingdom -- England -- Nature. 2013 Aug 1;500(7460):107-10. doi: 10.1038/nature12302. Epub 2013 Jun 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23812587" target="_blank"〉PubMed〈/a〉
    Keywords: Anticodon/chemistry/genetics/metabolism ; *Base Pairing ; Base Sequence ; Codon, Terminator/chemistry/*genetics/*metabolism ; Crystallography, X-Ray ; Models, Molecular ; Nucleic Acid Conformation ; Protein Conformation ; Pseudouridine/chemistry/genetics/metabolism ; RNA, Transfer, Ser/chemistry/genetics/metabolism ; Ribosome Subunits, Small, Bacterial/chemistry/genetics/metabolism ; Ribosomes/*chemistry/genetics/*metabolism
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    Chromosome-specific nonrandom sister chromatid segregation during stem-cell division (2013)
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    Publication Date: 2013-05-07
    Description: Adult stem cells undergo asymmetric cell division to self-renew and give rise to differentiated cells that comprise mature tissue. Sister chromatids may be distinguished and segregated nonrandomly in asymmetrically dividing stem cells, although the underlying mechanism and the purpose it may serve remain elusive. Here we develop the CO-FISH (chromosome orientation fluorescence in situ hybridization) technique with single-chromosome resolution and show that sister chromatids of X and Y chromosomes, but not autosomes, are segregated nonrandomly during asymmetric divisions of Drosophila male germline stem cells. This provides the first direct evidence, to our knowledge, that two sister chromatids containing identical genetic information can be distinguished and segregated nonrandomly during asymmetric stem-cell divisions. We further show that the centrosome, SUN-KASH nuclear envelope proteins and Dnmt2 (also known as Mt2) are required for nonrandom sister chromatid segregation. Our data indicate that the information on X and Y chromosomes that enables nonrandom segregation is primed during gametogenesis in the parents. Moreover, we show that sister chromatid segregation is randomized in germline stem cell overproliferation and dedifferentiated germline stem cells. We propose that nonrandom sister chromatid segregation may serve to transmit distinct information carried on two sister chromatids to the daughters of asymmetrically dividing stem cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711665/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711665/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yadlapalli, Swathi -- Yamashita, Yukiko M -- 1F31HD071727-01/HD/NICHD NIH HHS/ -- F31 HD071727/HD/NICHD NIH HHS/ -- England -- Nature. 2013 Jun 13;498(7453):251-4. doi: 10.1038/nature12106. Epub 2013 May 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Life Sciences Institute, Center for Stem Cell Biology, University of Michigan, Ann Arbor, Michigan 48109, USA. swathi@umich.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23644460" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Cell Dedifferentiation ; Cell Division ; Centrosome/metabolism ; Chromatids/genetics/*metabolism ; *Chromosome Segregation ; DNA (Cytosine-5-)-Methyltransferase ; Drosophila Proteins ; Drosophila melanogaster/*cytology/genetics/*metabolism ; Male ; Molecular Sequence Data ; Spermatogonia/cytology ; Stem Cells/*cytology/metabolism ; Testis/cytology ; X Chromosome/genetics/metabolism ; Y Chromosome/genetics/metabolism
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    Femtosecond switching of magnetism via strongly correlated spin-charge quantum excitations (2013)
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    Publication Date: 2013-04-05
    Description: The technological demand to push the gigahertz (10(9) hertz) switching speed limit of today's magnetic memory and logic devices into the terahertz (10(12) hertz) regime underlies the entire field of spin-electronics and integrated multi-functional devices. This challenge is met by all-optical magnetic switching based on coherent spin manipulation. By analogy to femtosecond chemistry and photosynthetic dynamics--in which photoproducts of chemical and biochemical reactions can be influenced by creating suitable superpositions of molecular states--femtosecond-laser-excited coherence between electronic states can switch magnetic order by 'suddenly' breaking the delicate balance between competing phases of correlated materials: for example, manganites exhibiting colossal magneto-resistance suitable for applications. Here we show femtosecond (10(-15) seconds) photo-induced switching from antiferromagnetic to ferromagnetic ordering in Pr0.7Ca0.3MnO3, by observing the establishment (within about 120 femtoseconds) of a huge temperature-dependent magnetization with photo-excitation threshold behaviour absent in the optical reflectivity. The development of ferromagnetic correlations during the femtosecond laser pulse reveals an initial quantum coherent regime of magnetism, distinguished from the picosecond (10(-12) seconds) lattice-heating regime characterized by phase separation without threshold behaviour. Our simulations reproduce the nonlinear femtosecond spin generation and underpin fast quantum spin-flip fluctuations correlated with coherent superpositions of electronic states to initiate local ferromagnetic correlations. These results merge two fields, femtosecond magnetism in metals and band insulators, and non-equilibrium phase transitions of strongly correlated electrons, in which local interactions exceeding the kinetic energy produce a complex balance of competing orders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Tianqi -- Patz, Aaron -- Mouchliadis, Leonidas -- Yan, Jiaqiang -- Lograsso, Thomas A -- Perakis, Ilias E -- Wang, Jigang -- England -- Nature. 2013 Apr 4;496(7443):69-73. doi: 10.1038/nature11934.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physics and Astronomy, Iowa State University, Ames, Iowa 50011, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23552945" target="_blank"〉PubMed〈/a〉
    Keywords: Biology ; Chemistry ; Circular Dichroism ; Electronics ; Iron/chemistry ; *Magnetic Phenomena ; Magnetics ; Optics and Photonics ; Photosynthesis ; *Quantum Theory ; Temperature ; Time Factors
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    Structural mechanism of cytosolic DNA sensing by cGAS (2013)
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    Publication Date: 2013-06-01
    Description: Cytosolic DNA arising from intracellular bacterial or viral infections is a powerful pathogen-associated molecular pattern (PAMP) that leads to innate immune host defence by the production of type I interferon and inflammatory cytokines. Recognition of cytosolic DNA by the recently discovered cyclic-GMP-AMP (cGAMP) synthase (cGAS) induces the production of cGAMP to activate the stimulator of interferon genes (STING). Here we report the crystal structure of cGAS alone and in complex with DNA, ATP and GTP along with functional studies. Our results explain the broad DNA sensing specificity of cGAS, show how cGAS catalyses dinucleotide formation and indicate activation by a DNA-induced structural switch. cGAS possesses a remarkable structural similarity to the antiviral cytosolic double-stranded RNA sensor 2'-5'oligoadenylate synthase (OAS1), but contains a unique zinc thumb that recognizes B-form double-stranded DNA. Our results mechanistically unify dsRNA and dsDNA innate immune sensing by OAS1 and cGAS nucleotidyl transferases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3768140/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3768140/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Civril, Filiz -- Deimling, Tobias -- de Oliveira Mann, Carina C -- Ablasser, Andrea -- Moldt, Manuela -- Witte, Gregor -- Hornung, Veit -- Hopfner, Karl-Peter -- 243046/European Research Council/International -- U19 AI083025/AI/NIAID NIH HHS/ -- U19AI083025/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Jun 20;498(7454):332-7. doi: 10.1038/nature12305. Epub 2013 May 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Gene Center, Ludwig-Maximilians-University, 81377 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23722159" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/chemistry/metabolism ; Animals ; Base Sequence ; Catalytic Domain ; Crystallography, X-Ray ; *Cytosol ; DNA/chemistry/*metabolism/pharmacology ; Guanosine Triphosphate/chemistry/metabolism ; HEK293 Cells ; Humans ; Membrane Proteins/genetics/metabolism ; Mice ; Models, Biological ; Models, Molecular ; Mutation ; Nucleotidyltransferases/*chemistry/genetics/metabolism ; Protein Conformation/drug effects ; Structure-Activity Relationship ; Substrate Specificity ; Swine ; Uridine Triphosphate/chemistry/metabolism ; Zinc/chemistry/metabolism
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    Hidden specificity in an apparently nonspecific RNA-binding protein (2013)
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    Publication Date: 2013-09-24
    Description: Nucleic-acid-binding proteins are generally viewed as either specific or nonspecific, depending on characteristics of their binding sites in DNA or RNA. Most studies have focused on specific proteins, which identify cognate sites by binding with highest affinities to regions with defined signatures in sequence, structure or both. Proteins that bind to sites devoid of defined sequence or structure signatures are considered nonspecific. Substrate binding by these proteins is poorly understood, and it is not known to what extent seemingly nonspecific proteins discriminate between different binding sites, aside from those sequestered by nucleic acid structures. Here we systematically examine substrate binding by the apparently nonspecific RNA-binding protein C5, and find clear discrimination between different binding site variants. C5 is the protein subunit of the transfer RNA processing ribonucleoprotein enzyme RNase P from Escherichia coli. The protein binds 5' leaders of precursor tRNAs at a site without sequence or structure signatures. We measure functional binding of C5 to all possible sequence variants in its substrate binding site, using a high-throughput sequencing kinetics approach (HITS-KIN) that simultaneously follows processing of thousands of RNA species. C5 binds different substrate variants with affinities varying by orders of magnitude. The distribution of functional affinities of C5 for all substrate variants resembles affinity distributions of highly specific nucleic acid binding proteins. Unlike these specific proteins, C5 does not bind its physiological RNA targets with the highest affinity, but with affinities near the median of the distribution, a region that is not associated with a sequence signature. We delineate defined rules governing substrate recognition by C5, which reveal specificity that is hidden in cellular substrates for RNase P. Our findings suggest that apparently nonspecific and specific RNA-binding modes may not differ fundamentally, but represent distinct parts of common affinity distributions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800043/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800043/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guenther, Ulf-Peter -- Yandek, Lindsay E -- Niland, Courtney N -- Campbell, Frank E -- Anderson, David -- Anderson, Vernon E -- Harris, Michael E -- Jankowsky, Eckhard -- GM056740/GM/NIGMS NIH HHS/ -- GM067700/GM/NIGMS NIH HHS/ -- GM096000/GM/NIGMS NIH HHS/ -- GM099720/GM/NIGMS NIH HHS/ -- R01 GM056740/GM/NIGMS NIH HHS/ -- R01 GM067700/GM/NIGMS NIH HHS/ -- R01 GM096000/GM/NIGMS NIH HHS/ -- R01 GM099720/GM/NIGMS NIH HHS/ -- T32 GM008056/GM/NIGMS NIH HHS/ -- UL1 TR000439/TR/NCATS NIH HHS/ -- UL1RR024989/RR/NCRR NIH HHS/ -- England -- Nature. 2013 Oct 17;502(7471):385-8. doi: 10.1038/nature12543. Epub 2013 Sep 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for RNA Molecular Biology, Case Western Reserve University, Cleveland, Ohio 44106, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24056935" target="_blank"〉PubMed〈/a〉
    Keywords: 5' Untranslated Regions/genetics ; Base Sequence ; Escherichia coli/*enzymology/genetics ; Escherichia coli Proteins/chemistry/genetics/*metabolism ; Kinetics ; Nucleic Acid Conformation ; RNA Precursors/chemistry/genetics/metabolism ; RNA, Bacterial/chemistry/genetics/metabolism ; RNA, Transfer/chemistry/genetics/*metabolism ; RNA, Transfer, Met/chemistry/genetics/metabolism ; Ribonuclease P/chemistry/genetics/*metabolism ; Substrate Specificity
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    Chemistry: A festive ferment (2013)
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    Publication Date: 2013-12-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McGee, Harold -- England -- Nature. 2013 Dec 19;504(7480):372-4. doi: 10.1038/504372a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24352277" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Aspergillus/metabolism ; Beer/microbiology ; Cheese/microbiology ; Chemistry ; *Fermentation ; *Food Technology ; Microbiology ; Saccharomyces cerevisiae/metabolism
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    The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis (2013)
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    Publication Date: 2013-05-28
    Description: A complex interaction of signalling events, including the Wnt pathway, regulates sprouting of blood vessels from pre-existing vasculature during angiogenesis. Here we show that two distinct mutations in the (uro)chordate-specific gumby (also called Fam105b) gene cause an embryonic angiogenic phenotype in gumby mice. Gumby interacts with disheveled 2 (DVL2), is expressed in canonical Wnt-responsive endothelial cells and encodes an ovarian tumour domain class of deubiquitinase that specifically cleaves linear ubiquitin linkages. A crystal structure of gumby in complex with linear diubiquitin reveals how the identified mutations adversely affect substrate binding and catalytic function in line with the severity of their angiogenic phenotypes. Gumby interacts with HOIP (also called RNF31), a key component of the linear ubiquitin assembly complex, and decreases linear ubiquitination and activation of NF-kappaB-dependent transcription. This work provides support for the biological importance of linear (de)ubiquitination in angiogenesis, craniofacial and neural development and in modulating Wnt signalling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rivkin, Elena -- Almeida, Stephanie M -- Ceccarelli, Derek F -- Juang, Yu-Chi -- MacLean, Teresa A -- Srikumar, Tharan -- Huang, Hao -- Dunham, Wade H -- Fukumura, Ryutaro -- Xie, Gang -- Gondo, Yoichi -- Raught, Brian -- Gingras, Anne-Claude -- Sicheri, Frank -- Cordes, Sabine P -- IHO 94384/Canadian Institutes of Health Research/Canada -- MOP 111199/Canadian Institutes of Health Research/Canada -- MOP 97966/Canadian Institutes of Health Research/Canada -- MOP119289/Canadian Institutes of Health Research/Canada -- England -- Nature. 2013 Jun 20;498(7454):318-24. doi: 10.1038/nature12296. Epub 2013 May 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23708998" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/metabolism ; Alleles ; Amino Acid Sequence ; Animals ; Base Sequence ; Crystallography, X-Ray ; Embryo, Mammalian/blood supply/embryology/metabolism ; Endopeptidases/*chemistry/deficiency/genetics/*metabolism ; Female ; Gene Expression Profiling ; HEK293 Cells ; Humans ; Mice ; Models, Molecular ; Molecular Sequence Data ; *Neovascularization, Physiologic/genetics ; Phenotype ; Phosphoproteins/metabolism ; Protein Conformation ; Ubiquitin/*chemistry/*metabolism ; Ubiquitin-Protein Ligases/metabolism ; *Ubiquitination ; Wnt Signaling Pathway
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    Two replication fork maintenance pathways fuse inverted repeats to rearrange chromosomes (2013)
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    Publication Date: 2013-09-10
    Description: Replication fork maintenance pathways preserve chromosomes, but their faulty application at nonallelic repeats could generate rearrangements causing cancer, genomic disorders and speciation. Potential causal mechanisms are homologous recombination and error-free postreplication repair (EF-PRR). Homologous recombination repairs damage-induced DNA double-strand breaks (DSBs) and single-ended DSBs within replication. To facilitate homologous recombination, the recombinase RAD51 and mediator BRCA2 form a filament on the 3' DNA strand at a break to enable annealing to the complementary sister chromatid while the RecQ helicase, BLM (Bloom syndrome mutated) suppresses crossing over to prevent recombination. Homologous recombination also stabilizes and restarts replication forks without a DSB. EF-PRR bypasses DNA incongruities that impede replication by ubiquitinating PCNA (proliferating cell nuclear antigen) using the RAD6-RAD18 and UBC13-MMS2-RAD5 ubiquitin ligase complexes. Some components are common to both homologous recombination and EF-PRR such as RAD51 and RAD18. Here we delineate two pathways that spontaneously fuse inverted repeats to generate unstable chromosomal rearrangements in wild-type mouse embryonic stem (ES) cells. Gamma-radiation induced a BLM-regulated pathway that selectively fused identical, but not mismatched, repeats. By contrast, ultraviolet light induced a RAD18-dependent pathway that efficiently fused mismatched repeats. Furthermore, TREX2 (a 3'--〉5' exonuclease) suppressed identical repeat fusion but enhanced mismatched repeat fusion, clearly separating these pathways. TREX2 associated with UBC13 and enhanced PCNA ubiquitination in response to ultraviolet light, consistent with it being a novel member of EF-PRR. RAD18 and TREX2 also suppressed replication fork stalling in response to nucleotide depletion. Interestingly, replication fork stalling induced fusion for identical and mismatched repeats, implicating faulty replication as a causal mechanism for both pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805358/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805358/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hu, Lingchuan -- Kim, Tae Moon -- Son, Mi Young -- Kim, Sung-A -- Holland, Cory L -- Tateishi, Satoshi -- Kim, Dong Hyun -- Yew, P Renee -- Montagna, Cristina -- Dumitrache, Lavinia C -- Hasty, Paul -- 1 R01 CA123203-01A1/CA/NCI NIH HHS/ -- 2P01AG017242-12/AG/NIA NIH HHS/ -- P30 CA054174/CA/NCI NIH HHS/ -- P30CA013330/CA/NCI NIH HHS/ -- R01 CA123203/CA/NCI NIH HHS/ -- England -- Nature. 2013 Sep 26;501(7468):569-72. doi: 10.1038/nature12500. Epub 2013 Sep 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Medicine/Institute of Biotechnology, The Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245-3207, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24013173" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Chromosomal Instability/*genetics ; Chromosome Breakage ; Chromosomes, Mammalian/*genetics ; DNA Breaks, Double-Stranded ; DNA Repair/*genetics ; DNA Replication/*genetics ; DNA-Binding Proteins/metabolism ; Embryonic Stem Cells/metabolism ; Exodeoxyribonucleases/metabolism ; Homologous Recombination/*genetics ; Hydroxyurea/pharmacology ; Inverted Repeat Sequences/*genetics ; Mice ; Nucleotides/deficiency/metabolism ; Proliferating Cell Nuclear Antigen/metabolism ; Rad51 Recombinase/metabolism ; RecQ Helicases/metabolism ; Ubiquitin-Conjugating Enzymes/metabolism ; Ubiquitination/radiation effects ; Ultraviolet Rays
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    Draft genome of the wheat A-genome progenitor Triticum urartu (2013)
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    Publication Date: 2013-03-29
    Description: Bread wheat (Triticum aestivum, AABBDD) is one of the most widely cultivated and consumed food crops in the world. However, the complex polyploid nature of its genome makes genetic and functional analyses extremely challenging. The A genome, as a basic genome of bread wheat and other polyploid wheats, for example, T. turgidum (AABB), T. timopheevii (AAGG) and T. zhukovskyi (AAGGA(m)A(m)), is central to wheat evolution, domestication and genetic improvement. The progenitor species of the A genome is the diploid wild einkorn wheat T. urartu, which resembles cultivated wheat more extensively than do Aegilops speltoides (the ancestor of the B genome) and Ae. tauschii (the donor of the D genome), especially in the morphology and development of spike and seed. Here we present the generation, assembly and analysis of a whole-genome shotgun draft sequence of the T. urartu genome. We identified protein-coding gene models, performed genome structure analyses and assessed its utility for analysing agronomically important genes and for developing molecular markers. Our T. urartu genome assembly provides a diploid reference for analysis of polyploid wheat genomes and is a valuable resource for the genetic improvement of wheat.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ling, Hong-Qing -- Zhao, Shancen -- Liu, Dongcheng -- Wang, Junyi -- Sun, Hua -- Zhang, Chi -- Fan, Huajie -- Li, Dong -- Dong, Lingli -- Tao, Yong -- Gao, Chuan -- Wu, Huilan -- Li, Yiwen -- Cui, Yan -- Guo, Xiaosen -- Zheng, Shusong -- Wang, Biao -- Yu, Kang -- Liang, Qinsi -- Yang, Wenlong -- Lou, Xueyuan -- Chen, Jie -- Feng, Mingji -- Jian, Jianbo -- Zhang, Xiaofei -- Luo, Guangbin -- Jiang, Ying -- Liu, Junjie -- Wang, Zhaobao -- Sha, Yuhui -- Zhang, Bairu -- Wu, Huajun -- Tang, Dingzhong -- Shen, Qianhua -- Xue, Pengya -- Zou, Shenhao -- Wang, Xiujie -- Liu, Xin -- Wang, Famin -- Yang, Yanping -- An, Xueli -- Dong, Zhenying -- Zhang, Kunpu -- Zhang, Xiangqi -- Luo, Ming-Cheng -- Dvorak, Jan -- Tong, Yiping -- Wang, Jian -- Yang, Huanming -- Li, Zhensheng -- Wang, Daowen -- Zhang, Aimin -- Wang, Jun -- England -- Nature. 2013 Apr 4;496(7443):87-90. doi: 10.1038/nature11997. Epub 2013 Mar 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Plant Cell and Chromosome Engineering, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23535596" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Brachypodium/genetics ; Crops, Agricultural/classification/genetics ; Diploidy ; Genetic Markers/genetics ; Genome, Plant/*genetics ; Molecular Sequence Data ; Oryza/genetics ; Phylogeny ; Sorghum/genetics ; Synteny/genetics ; Triticum/classification/*genetics ; Zea mays/genetics
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    Pif1 family helicases suppress genome instability at G-quadruplex motifs (2013)
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    Publication Date: 2013-05-10
    Description: The Saccharomyces cerevisiae Pif1 helicase is the prototypical member of the Pif1 DNA helicase family, which is conserved from bacteria to humans. Here we show that exceptionally potent G-quadruplex unwinding is conserved among Pif1 helicases. Moreover, Pif1 helicases from organisms separated by more than 3 billion years of evolution suppressed DNA damage at G-quadruplex motifs in yeast. The G-quadruplex-induced damage generated in the absence of Pif1 helicases led to new genetic and epigenetic changes. Furthermore, when expressed in yeast, human PIF1 suppressed both G-quadruplex-associated DNA damage and telomere lengthening.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680789/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680789/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Paeschke, Katrin -- Bochman, Matthew L -- Garcia, P Daniela -- Cejka, Petr -- Friedman, Katherine L -- Kowalczykowski, Stephen C -- Zakian, Virginia A -- R01 GM026938/GM/NIGMS NIH HHS/ -- R01 GM041347/GM/NIGMS NIH HHS/ -- R01 GM043265/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 May 23;497(7450):458-62. doi: 10.1038/nature12149. Epub 2013 May 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23657261" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Conserved Sequence ; DNA Damage/genetics ; DNA Helicases/deficiency/genetics/*metabolism ; Epigenesis, Genetic ; Evolution, Molecular ; *G-Quadruplexes ; Gene Silencing ; Genetic Complementation Test ; *Genomic Instability ; Humans ; Molecular Sequence Data ; Mutation Rate ; Saccharomyces cerevisiae/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Telomere Homeostasis/genetics
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    Q&A: The technology starter. Interview by Valerie Gerard (2013)
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    Publication Date: 2013-10-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shechtman, Dan -- England -- Nature. 2013 Oct 17;502(7471):S54-5. doi: 10.1038/502S54a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24132333" target="_blank"〉PubMed〈/a〉
    Keywords: Chemistry ; Developing Countries ; Education/statistics & numerical data ; Entrepreneurship/*economics ; Leadership ; Nobel Prize ; Research ; Technology/*economics
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    The microRNA miR-235 couples blast-cell quiescence to the nutritional state (2013)
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    Publication Date: 2013-05-07
    Description: The coordination of stem- and blast-cell behaviours, such as self-renewal, differentiation and quiescence, with physiological changes underlies growth, regeneration and tissue homeostasis. Germline stem and somatic blast cells in newly hatched Caenorhabditis elegans larvae can suspend postembryonic development, which consists of diverse cellular events such as migration, proliferation and differentiation, until the nutritional state becomes favourable (termed L1 diapause). Although previous studies showed that the insulin/insulin-like growth factor (IGF) signalling (IIS) pathway regulates this developmental quiescence, the detailed mechanism by which the IIS pathway enables these multipotent cells to respond to nutrient availability is unknown. Here we show in C. elegans that the microRNA (miRNA) miR-235, a sole orthologue of mammalian miR-92 from the oncogenic miR-17-92 cluster, acts in the hypodermis and glial cells to arrest postembryonic developmental events in both neuroblasts and mesoblasts. Expression of mir-235 persists during L1 diapause, and decreases upon feeding in a manner dependent on the IIS pathway. Upregulation of one of the miR-235 targets, nhr-91, which encodes an orthologue of mammalian germ cell nuclear factor, is responsible for defects caused by loss of the miRNA. Our findings establish a novel role of a miR-92 orthologue in coupling blast-cell behaviours to the nutritional state.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kasuga, Hidefumi -- Fukuyama, Masamitsu -- Kitazawa, Aya -- Kontani, Kenji -- Katada, Toshiaki -- England -- Nature. 2013 May 23;497(7450):503-6. doi: 10.1038/nature12117. Epub 2013 May 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23644454" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Caenorhabditis elegans/*genetics/growth & development/immunology/*metabolism ; Down-Regulation ; Embryo, Nonmammalian/metabolism ; Food Deprivation ; Humans ; Insulin/metabolism ; Insulin-Like Growth Factor I/metabolism ; Larva/cytology/metabolism ; Lymphocyte Activation/*genetics/physiology ; MicroRNAs/*genetics/*metabolism ; Molecular Sequence Data ; Neural Stem Cells/cytology/metabolism ; Neuroglia/metabolism ; *Nutritional Status/genetics ; Signal Transduction ; Subcutaneous Tissue/metabolism
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    In vivo genome-wide profiling of RNA secondary structure reveals novel regulatory features (2013)
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    Publication Date: 2013-11-26
    Description: RNA structure has critical roles in processes ranging from ligand sensing to the regulation of translation, polyadenylation and splicing. However, a lack of genome-wide in vivo RNA structural data has limited our understanding of how RNA structure regulates gene expression in living cells. Here we present a high-throughput, genome-wide in vivo RNA structure probing method, structure-seq, in which dimethyl sulphate methylation of unprotected adenines and cytosines is identified by next-generation sequencing. Application of this method to Arabidopsis thaliana seedlings yielded the first in vivo genome-wide RNA structure map at nucleotide resolution for any organism, with quantitative structural information across more than 10,000 transcripts. Our analysis reveals a three-nucleotide periodic repeat pattern in the structure of coding regions, as well as a less-structured region immediately upstream of the start codon, and shows that these features are strongly correlated with translation efficiency. We also find patterns of strong and weak secondary structure at sites of alternative polyadenylation, as well as strong secondary structure at 5' splice sites that correlates with unspliced events. Notably, in vivo structures of messenger RNAs annotated for stress responses are poorly predicted in silico, whereas mRNA structures of genes related to cell function maintenance are well predicted. Global comparison of several structural features between these two categories shows that the mRNAs associated with stress responses tend to have more single-strandedness, longer maximal loop length and higher free energy per nucleotide, features that may allow these RNAs to undergo conformational changes in response to environmental conditions. Structure-seq allows the RNA structurome and its biological roles to be interrogated on a genome-wide scale and should be applicable to any organism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ding, Yiliang -- Tang, Yin -- Kwok, Chun Kit -- Zhang, Yu -- Bevilacqua, Philip C -- Assmann, Sarah M -- England -- Nature. 2014 Jan 30;505(7485):696-700. doi: 10.1038/nature12756. Epub 2013 Nov 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA [2] Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, USA [3] Center for RNA Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA [4]. ; 1] Department of Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA [2] Center for RNA Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA [3] Bioinformatics and Genomics Graduate Program, Pennsylvania State University, University Park, Pennsylvania 16802, USA [4]. ; 1] Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, USA [2] Center for RNA Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA [3]. ; 1] Bioinformatics and Genomics Graduate Program, Pennsylvania State University, University Park, Pennsylvania 16802, USA [2] Department of Statistics, Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; 1] Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, USA [2] Center for RNA Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA [3] Plant Biology Graduate Program, Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; 1] Department of Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA [2] Center for RNA Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA [3] Bioinformatics and Genomics Graduate Program, Pennsylvania State University, University Park, Pennsylvania 16802, USA [4] Plant Biology Graduate Program, Pennsylvania State University, University Park, Pennsylvania 16802, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24270811" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*genetics ; Base Sequence ; Codon, Initiator/genetics ; Computational Biology ; Genome, Plant/*genetics ; Molecular Sequence Data ; *Nucleic Acid Conformation ; Phylogeny ; Polyadenylation/genetics ; Protein Biosynthesis/genetics ; RNA Splice Sites/genetics ; RNA, Messenger/chemistry/genetics/metabolism ; RNA, Plant/analysis/*chemistry/genetics/*metabolism ; RNA, Ribosomal, 18S/chemistry/genetics/metabolism ; *Regulatory Sequences, Ribonucleic Acid/genetics ; Sequence Analysis, RNA ; Stress, Physiological/genetics ; Structure-Activity Relationship
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    Structural visualization of key steps in human transcription initiation (2013)
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    Publication Date: 2013-03-01
    Description: Eukaryotic transcription initiation requires the assembly of general transcription factors into a pre-initiation complex that ensures the accurate loading of RNA polymerase II (Pol II) at the transcription start site. The molecular mechanism and function of this assembly have remained elusive due to lack of structural information. Here we have used an in vitro reconstituted system to study the stepwise assembly of human TBP, TFIIA, TFIIB, Pol II, TFIIF, TFIIE and TFIIH onto promoter DNA using cryo-electron microscopy. Our structural analyses provide pseudo-atomic models at various stages of transcription initiation that illuminate critical molecular interactions, including how TFIIF engages Pol II and promoter DNA to stabilize both the closed pre-initiation complex and the open-promoter complex, and to regulate start--initiation complexes, combined with the localization of the TFIIH helicases XPD and XPB, support a DNA translocation model of XPB and explain its essential role in promoter opening.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612373/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612373/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉He, Yuan -- Fang, Jie -- Taatjes, Dylan J -- Nogales, Eva -- CA127364/CA/NCI NIH HHS/ -- GM63072/GM/NIGMS NIH HHS/ -- R01 CA127364/CA/NCI NIH HHS/ -- R01 GM063072/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Mar 28;495(7442):481-6. doi: 10.1038/nature11991. Epub 2013 Feb 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23446344" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Cryoelectron Microscopy ; DNA/chemistry/genetics/metabolism ; DNA Helicases/chemistry/metabolism ; Humans ; Models, Molecular ; Molecular Sequence Data ; Promoter Regions, Genetic/*genetics ; Protein Conformation ; RNA Polymerase II/*chemistry/metabolism/*ultrastructure ; TATA-Box Binding Protein/chemistry/metabolism ; Transcription Factor TFIIH/chemistry/metabolism ; Transcription Factors, TFII/*chemistry/metabolism/*ultrastructure ; Transcription Initiation Site ; Transcription Initiation, Genetic/*physiology
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    An Sp1 transcription factor coordinates caspase-dependent and -independent apoptotic pathways (2013)
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    Publication Date: 2013-07-16
    Description: During animal development, the proper regulation of apoptosis requires the precise spatial and temporal execution of cell-death programs, which can include both caspase-dependent and caspase-independent pathways. Although the mechanisms of caspase-dependent and -independent cell killing have been examined extensively, how these pathways are coordinated within a single cell that is fated to die is unknown. Here we show that the Caenorhabditis elegans Sp1 transcription factor SPTF-3 specifies the programmed cell deaths of at least two cells-the sisters of the pharyngeal M4 motor neuron and the AQR sensory neuron-by transcriptionally activating both caspase-dependent and -independent apoptotic pathways. SPTF-3 directly drives the transcription of the gene egl-1, which encodes a BH3-only protein that promotes apoptosis through the activation of the CED-3 caspase. In addition, SPTF-3 directly drives the transcription of the AMP-activated protein kinase-related gene pig-1, which encodes a protein kinase and functions in apoptosis of the M4 sister and AQR sister independently of the pathway that activates CED-3 (refs 4, 5). Thus, a single transcription factor controls two distinct cell-killing programs that act in parallel to drive apoptosis. Our findings reveal a bivalent regulatory node for caspase-dependent and -independent pathways in the regulation of cell-type-specific apoptosis. We propose that such nodes might act as features of a general mechanism for regulating cell-type-specific apoptosis and could be therapeutic targets for diseases involving the dysregulation of apoptosis through multiple cell-killing mechanisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748152/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748152/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hirose, Takashi -- Horvitz, H Robert -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Aug 15;500(7462):354-8. doi: 10.1038/nature12329. Epub 2013 Jul 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23851392" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis/*genetics ; Base Sequence ; Caenorhabditis elegans/*genetics/*metabolism ; Caenorhabditis elegans Proteins/genetics/metabolism ; Caspases/*metabolism ; Gene Expression Regulation, Developmental ; Molecular Sequence Data ; Protein-Serine-Threonine Kinases/genetics/metabolism ; Repressor Proteins/genetics/metabolism ; Sequence Alignment ; Sp1 Transcription Factor/*genetics/*metabolism
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    A bacteriophage encodes its own CRISPR/Cas adaptive response to evade host innate immunity (2013)
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    Publication Date: 2013-03-01
    Description: Bacteriophages (or phages) are the most abundant biological entities on earth, and are estimated to outnumber their bacterial prey by tenfold. The constant threat of phage predation has led to the evolution of a broad range of bacterial immunity mechanisms that in turn result in the evolution of diverse phage immune evasion strategies, leading to a dynamic co-evolutionary arms race. Although bacterial innate immune mechanisms against phage abound, the only documented bacterial adaptive immune system is the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) system, which provides sequence-specific protection from invading nucleic acids, including phage. Here we show a remarkable turn of events, in which a phage-encoded CRISPR/Cas system is used to counteract a phage inhibitory chromosomal island of the bacterial host. A successful lytic infection by the phage is dependent on sequence identity between CRISPR spacers and the target chromosomal island. In the absence of such targeting, the phage-encoded CRISPR/Cas system can acquire new spacers to evolve rapidly and ensure effective targeting of the chromosomal island to restore phage replication.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587790/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587790/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seed, Kimberley D -- Lazinski, David W -- Calderwood, Stephen B -- Camilli, Andrew -- AI045746/AI/NIAID NIH HHS/ -- AI055058/AI/NIAID NIH HHS/ -- AI058935/AI/NIAID NIH HHS/ -- R01 AI045746/AI/NIAID NIH HHS/ -- R01 AI055058/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Feb 28;494(7438):489-91. doi: 10.1038/nature11927.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23446421" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Bacteriolysis ; Bacteriophages/*genetics/growth & development/*immunology/pathogenicity ; Base Sequence ; Biological Evolution ; Chromosomes, Bacterial/genetics ; Gene Deletion ; Genes, Viral/*genetics/immunology ; Genome, Viral/genetics ; Genomic Islands/genetics ; *Immunity, Innate ; Inverted Repeat Sequences/genetics ; Molecular Sequence Data ; Substrate Specificity ; Vibrio cholerae/genetics/*immunology/*virology
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    Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX (2013)
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    Publication Date: 2013-04-09
    Description: TET (ten-eleven-translocation) proteins are Fe(ii)- and alpha-ketoglutarate-dependent dioxygenases that modify the methylation status of DNA by successively oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxycytosine, potential intermediates in the active erasure of DNA-methylation marks. Here we show that IDAX (also known as CXXC4), a reported inhibitor of Wnt signalling that has been implicated in malignant renal cell carcinoma and colonic villous adenoma, regulates TET2 protein expression. IDAX was originally encoded within an ancestral TET2 gene that underwent a chromosomal gene inversion during evolution, thus separating the TET2 CXXC domain from the catalytic domain. The IDAX CXXC domain binds DNA sequences containing unmethylated CpG dinucleotides, localizes to promoters and CpG islands in genomic DNA and interacts directly with the catalytic domain of TET2. Unexpectedly, IDAX expression results in caspase activation and TET2 protein downregulation, in a manner that depends on DNA binding through the IDAX CXXC domain, suggesting that IDAX recruits TET2 to DNA before degradation. IDAX depletion prevents TET2 downregulation in differentiating mouse embryonic stem cells, and short hairpin RNA against IDAX increases TET2 protein expression in the human monocytic cell line U937. Notably, we find that the expression and activity of TET3 is also regulated through its CXXC domain. Taken together, these results establish the separate and linked CXXC domains of TET2 and TET3, respectively, as previously unknown regulators of caspase activation and TET enzymatic activity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3643997/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3643997/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ko, Myunggon -- An, Jungeun -- Bandukwala, Hozefa S -- Chavez, Lukas -- Aijo, Tarmo -- Pastor, William A -- Segal, Matthew F -- Li, Huiming -- Koh, Kian Peng -- Lahdesmaki, Harri -- Hogan, Patrick G -- Aravind, L -- Rao, Anjana -- CA151535/CA/NCI NIH HHS/ -- R01 AI040127/AI/NIAID NIH HHS/ -- R01 AI044432/AI/NIAID NIH HHS/ -- R01 AI40127/AI/NIAID NIH HHS/ -- R01 CA151535/CA/NCI NIH HHS/ -- R01 HD065812/HD/NICHD NIH HHS/ -- England -- Nature. 2013 May 2;497(7447):122-6. doi: 10.1038/nature12052. Epub 2013 Apr 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Signaling and Gene Expression, La Jolla Institute for Allergy & Immunology, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23563267" target="_blank"〉PubMed〈/a〉
    Keywords: 5-Methylcytosine/*metabolism ; Animals ; Base Sequence ; Caspases/metabolism ; Catalytic Domain ; CpG Islands/genetics ; DNA Methylation/genetics ; DNA-Binding Proteins/biosynthesis/*chemistry/deficiency/genetics/*metabolism ; Dioxygenases/chemistry/genetics/metabolism ; Down-Regulation ; Embryonic Stem Cells/metabolism ; Enzyme Activation ; HEK293 Cells ; Humans ; Mice ; Oxidation-Reduction ; Promoter Regions, Genetic/genetics ; Protein Interaction Domains and Motifs ; Protein Structure, Tertiary ; Proto-Oncogene Proteins/biosynthesis/chemistry/genetics/*metabolism ; Transcription Factors/*chemistry/deficiency/genetics/*metabolism ; U937 Cells
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    Balancing privacy with public benefit (2013)
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    Publication Date: 2013-08-09
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bobrow, Martin -- England -- Nature. 2013 Aug 8;500(7461):123. doi: 10.1038/500123a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Cambridge, UK. mb238@cam.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23925206" target="_blank"〉PubMed〈/a〉
    Keywords: *Access to Information ; Base Sequence ; Confidentiality ; Databases, Factual/standards ; Humans ; *Information Dissemination ; International Cooperation ; Research/economics/standards
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    Towards practical, high-capacity, low-maintenance information storage in synthesized DNA (2013)
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    Publication Date: 2013-01-29
    Description: Digital production, transmission and storage have revolutionized how we access and use information but have also made archiving an increasingly complex task that requires active, continuing maintenance of digital media. This challenge has focused some interest on DNA as an attractive target for information storage because of its capacity for high-density information encoding, longevity under easily achieved conditions and proven track record as an information bearer. Previous DNA-based information storage approaches have encoded only trivial amounts of information or were not amenable to scaling-up, and used no robust error-correction and lacked examination of their cost-efficiency for large-scale information archival. Here we describe a scalable method that can reliably store more information than has been handled before. We encoded computer files totalling 739 kilobytes of hard-disk storage and with an estimated Shannon information of 5.2 x 10(6) bits into a DNA code, synthesized this DNA, sequenced it and reconstructed the original files with 100% accuracy. Theoretical analysis indicates that our DNA-based storage scheme could be scaled far beyond current global information volumes and offers a realistic technology for large-scale, long-term and infrequently accessed digital archiving. In fact, current trends in technological advances are reducing DNA synthesis costs at a pace that should make our scheme cost-effective for sub-50-year archiving within a decade.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672958/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672958/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goldman, Nick -- Bertone, Paul -- Chen, Siyuan -- Dessimoz, Christophe -- LeProust, Emily M -- Sipos, Botond -- Birney, Ewan -- 088151/Wellcome Trust/United Kingdom -- England -- Nature. 2013 Feb 7;494(7435):77-80. doi: 10.1038/nature11875. Epub 2013 Jan 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK. goldman@ebi.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23354052" target="_blank"〉PubMed〈/a〉
    Keywords: *Archives ; Base Sequence ; Computers ; DNA/*chemical synthesis/*chemistry/economics ; Information Management/economics/*methods ; Molecular Sequence Data ; Sequence Analysis, DNA/economics ; Synthetic Biology/economics/methods
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    orco mutant mosquitoes lose strong preference for humans and are not repelled by volatile DEET (2013)
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    Publication Date: 2013-05-31
    Description: Female mosquitoes of some species are generalists and will blood-feed on a variety of vertebrate hosts, whereas others display marked host preference. Anopheles gambiae and Aedes aegypti have evolved a strong preference for humans, making them dangerously efficient vectors of malaria and Dengue haemorrhagic fever. Specific host odours probably drive this strong preference because other attractive cues, including body heat and exhaled carbon dioxide (CO2), are common to all warm-blooded hosts. Insects sense odours via several chemosensory receptor families, including the odorant receptors (ORs), membrane proteins that form heteromeric odour-gated ion channels comprising a variable ligand-selective subunit and an obligate co-receptor called Orco (ref. 6). Here we use zinc-finger nucleases to generate targeted mutations in the orco gene of A. aegypti to examine the contribution of Orco and the odorant receptor pathway to mosquito host selection and sensitivity to the insect repellent DEET (N,N-diethyl-meta-toluamide). orco mutant olfactory sensory neurons have greatly reduced spontaneous activity and lack odour-evoked responses. Behaviourally, orco mutant mosquitoes have severely reduced attraction to honey, an odour cue related to floral nectar, and do not respond to human scent in the absence of CO2. However, in the presence of CO2, female orco mutant mosquitoes retain strong attraction to both human and animal hosts, but no longer strongly prefer humans. orco mutant females are attracted to human hosts even in the presence of DEET, but are repelled upon contact, indicating that olfactory- and contact-mediated effects of DEET are mechanistically distinct. We conclude that the odorant receptor pathway is crucial for an anthropophilic vector mosquito to discriminate human from non-human hosts and to be effectively repelled by volatile DEET.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696029/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696029/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DeGennaro, Matthew -- McBride, Carolyn S -- Seeholzer, Laura -- Nakagawa, Takao -- Dennis, Emily J -- Goldman, Chloe -- Jasinskiene, Nijole -- James, Anthony A -- Vosshall, Leslie B -- AI29746/AI/NIAID NIH HHS/ -- DC012069/DC/NIDCD NIH HHS/ -- R01 AI029746/AI/NIAID NIH HHS/ -- R37 AI029746/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jun 27;498(7455):487-91. doi: 10.1038/nature12206. Epub 2013 May 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Neurogenetics and Behavior, and Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23719379" target="_blank"〉PubMed〈/a〉
    Keywords: Aedes/drug effects/*genetics/*physiology ; Amino Acid Sequence ; Animals ; Base Sequence ; DEET/administration & dosage/*pharmacology ; Drug Resistance/drug effects ; Female ; Genes, Insect/*genetics ; Honey ; Host Specificity/drug effects/*genetics ; Humans ; Insect Repellents/administration & dosage/*pharmacology ; Male ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Mutation/*genetics ; Neurons/cytology/drug effects ; Odors/analysis ; Olfactory Pathways/cytology/drug effects ; Volatilization
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    N6-methyladenosine-dependent regulation of messenger RNA stability (2013)
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    Publication Date: 2013-11-29
    Description: N(6)-methyladenosine (m(6)A) is the most prevalent internal (non-cap) modification present in the messenger RNA of all higher eukaryotes. Although essential to cell viability and development, the exact role of m(6)A modification remains to be determined. The recent discovery of two m(6)A demethylases in mammalian cells highlighted the importance of m(6)A in basic biological functions and disease. Here we show that m(6)A is selectively recognized by the human YTH domain family 2 (YTHDF2) 'reader' protein to regulate mRNA degradation. We identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include non-coding RNAs, with a conserved core motif of G(m(6)A)C. We further establish the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies. The carboxy-terminal domain of YTHDF2 selectively binds to m(6)A-containing mRNA, whereas the amino-terminal domain is responsible for the localization of the YTHDF2-mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m(6)A modification is recognized by selectively binding proteins to affect the translation status and lifetime of mRNA.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877715/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877715/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Xiao -- Lu, Zhike -- Gomez, Adrian -- Hon, Gary C -- Yue, Yanan -- Han, Dali -- Fu, Ye -- Parisien, Marc -- Dai, Qing -- Jia, Guifang -- Ren, Bing -- Pan, Tao -- He, Chuan -- GM071440/GM/NIGMS NIH HHS/ -- GM088599/GM/NIGMS NIH HHS/ -- K01 HG006699/HG/NHGRI NIH HHS/ -- R01 GM071440/GM/NIGMS NIH HHS/ -- R01 GM088599/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jan 2;505(7481):117-20. doi: 10.1038/nature12730. Epub 2013 Nov 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA. ; Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, UCSD Moores Cancer Center and Institute of Genome Medicine, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653, USA. ; Department of Biochemistry and Molecular Biology and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA. ; 1] Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA [2] Department of Chemical Biology and Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24284625" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine/*analogs & derivatives/metabolism/pharmacology ; Base Sequence ; DNA-Binding Proteins/genetics ; HeLa Cells ; Humans ; Nucleotide Motifs ; Organelles/genetics/metabolism ; Protein Binding ; Protein Biosynthesis ; *RNA Stability/drug effects ; RNA Transport ; RNA, Messenger/*chemistry/*metabolism ; RNA, Untranslated/chemistry/metabolism ; RNA-Binding Proteins/chemistry/classification/*metabolism ; Substrate Specificity
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    Crystal structures of the Lsm complex bound to the 3' end sequence of U6 small nuclear RNA (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-11-19
    Description: Splicing of precursor messenger RNA (pre-mRNA) in eukaryotic cells is carried out by the spliceosome, which consists of five small nuclear ribonucleoproteins (snRNPs) and a number of accessory factors and enzymes. Each snRNP contains a ring-shaped subcomplex of seven proteins and a specific RNA molecule. The U6 snRNP contains a unique heptameric Lsm protein complex, which specifically recognizes the U6 small nuclear RNA at its 3' end. Here we report the crystal structures of the heptameric Lsm complex, both by itself and in complex with a 3' fragment of U6 snRNA, at 2.8 A resolution. Each of the seven Lsm proteins interacts with two neighbouring Lsm components to form a doughnut-shaped assembly, with the order Lsm3-2-8-4-7-5-6. The four uridine nucleotides at the 3' end of U6 snRNA are modularly recognized by Lsm3, Lsm2, Lsm8 and Lsm4, with the uracil base specificity conferred by a highly conserved asparagine residue. The uracil base at the extreme 3' end is sandwiched by His 36 and Arg 69 from Lsm3, through pi-pi and cation-pi interactions, respectively. The distinctive end-recognition of U6 snRNA by the Lsm complex contrasts with RNA binding by the Sm complex in the other snRNPs. The structural features and associated biochemical analyses deepen mechanistic understanding of the U6 snRNP function in pre-mRNA splicing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Lijun -- Hang, Jing -- Zhou, Yulin -- Wan, Ruixue -- Lu, Guifeng -- Yin, Ping -- Yan, Chuangye -- Shi, Yigong -- England -- Nature. 2014 Feb 6;506(7486):116-20. doi: 10.1038/nature12803. Epub 2013 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Ministry of Education Key Laboratory of Protein Science, Tsinghua University, Beijing 100084, China [2] Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [3]. ; 1] Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [2] State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China [3]. ; Ministry of Education Key Laboratory of Protein Science, Tsinghua University, Beijing 100084, China. ; State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China. ; Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. ; 1] Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [2] State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China. ; 1] Ministry of Education Key Laboratory of Protein Science, Tsinghua University, Beijing 100084, China [2] Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24240276" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Asparagine/chemistry ; Base Sequence ; Crystallography, X-Ray ; Histidine/chemistry ; Models, Molecular ; Molecular Sequence Data ; Multiprotein Complexes/*chemistry/metabolism ; Protein Binding ; Protein Structure, Quaternary ; RNA, Small Nuclear/*chemistry/*genetics/metabolism ; RNA-Binding Proteins/*chemistry/metabolism ; Ribonucleoproteins, Small Nuclear/chemistry/metabolism ; Saccharomyces cerevisiae/chemistry ; Saccharomyces cerevisiae Proteins/*chemistry/metabolism ; Uracil/chemistry/metabolism
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    The human CST complex is a terminator of telomerase activity (2012)
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    Publication Date: 2012-07-06
    Description: The lengths of human telomeres, which protect chromosome ends from degradation and end fusions, are crucial determinants of cell lifespan. During embryogenesis and in cancer, the telomerase enzyme counteracts telomeric DNA shortening. As shown in cancer cells, human telomerase binds the shelterin component TPP1 at telomeres during the S phase of the cell cycle, and adds ~60 nucleotides in a single round of extension, after which telomerase is turned off by unknown mechanisms. Here we show that the human CST (CTC1, STN1 and TEN1) complex, previously implicated in telomere protection and DNA metabolism, inhibits telomerase activity through primer sequestration and physical interaction with the protection of telomeres 1 (POT1)-TPP1 telomerase processivity factor. CST competes with POT1-TPP1 for telomeric DNA, and CST-telomeric-DNA binding increases during late S/G2 phase only on telomerase action, coinciding with telomerase shut-off. Depletion of CST allows excessive telomerase activity, promoting telomere elongation. We propose that through binding of the telomerase-extended telomere, CST limits telomerase action at individual telomeres to approximately one binding and extension event per cell cycle. Our findings define the sequence of events that occur to first enable and then terminate telomerase-mediated telomere elongation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Liuh-Yow -- Redon, Sophie -- Lingner, Joachim -- 232812/European Research Council/International -- England -- Nature. 2012 Aug 23;488(7412):540-4. doi: 10.1038/nature11269.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Federale de Lausanne, Station 19, 1015 Lausanne, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763445" target="_blank"〉PubMed〈/a〉
    Keywords: Aminopeptidases/metabolism ; Base Sequence ; Cell Line, Tumor ; DNA/genetics/metabolism ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism ; Electrophoretic Mobility Shift Assay ; Enzyme Assays ; G2 Phase ; HEK293 Cells ; Humans ; Longevity ; Multiprotein Complexes/chemistry/genetics/*metabolism ; Protein Binding ; S Phase ; Serine Proteases/metabolism ; Telomerase/*antagonists & inhibitors/metabolism ; Telomere/genetics/metabolism ; Telomere-Binding Proteins/genetics/*metabolism
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    Structure of yeast Argonaute with guide RNA (2012)
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    Publication Date: 2012-06-23
    Description: The RNA-induced silencing complex, comprising Argonaute and guide RNA, mediates RNA interference. Here we report the 3.2 A crystal structure of Kluyveromyces polysporus Argonaute (KpAGO) fortuitously complexed with guide RNA originating from small-RNA duplexes autonomously loaded by recombinant KpAGO. Despite their diverse sequences, guide-RNA nucleotides 1-8 are positioned similarly, with sequence-independent contacts to bases, phosphates and 2'-hydroxyl groups pre-organizing the backbone of nucleotides 2-8 in a near-A-form conformation. Compared with prokaryotic Argonautes, KpAGO has numerous surface-exposed insertion segments, with a cluster of conserved insertions repositioning the N domain to enable full propagation of guide-target pairing. Compared with Argonautes in inactive conformations, KpAGO has a hydrogen-bond network that stabilizes an expanded and repositioned loop, which inserts an invariant glutamate into the catalytic pocket. Mutation analyses and analogies to ribonuclease H indicate that insertion of this glutamate finger completes a universally conserved catalytic tetrad, thereby activating Argonaute for RNA cleavage.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853139/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853139/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nakanishi, Kotaro -- Weinberg, David E -- Bartel, David P -- Patel, Dinshaw J -- AI068776/AI/NIAID NIH HHS/ -- GM61835/GM/NIGMS NIH HHS/ -- R01 AI068776/AI/NIAID NIH HHS/ -- R01 GM061835/GM/NIGMS NIH HHS/ -- R37 GM061835/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jun 20;486(7403):368-74. doi: 10.1038/nature11211.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722195" target="_blank"〉PubMed〈/a〉
    Keywords: Argonaute Proteins/*chemistry/*metabolism ; Base Sequence ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Eukaryotic Cells/chemistry/enzymology ; Fungal Proteins/*chemistry/*metabolism ; Kluyveromyces/*chemistry/enzymology ; Models, Molecular ; Molecular Conformation ; Molecular Sequence Data ; RNA, Guide/*chemistry/genetics/*metabolism ; Saccharomycetales/enzymology/genetics
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    Telomerase RNA biogenesis involves sequential binding by Sm and Lsm complexes (2012)
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    Publication Date: 2012-03-27
    Description: In most eukaryotes, the progressive loss of chromosome-terminal DNA sequences is counteracted by the enzyme telomerase, a reverse transcriptase that uses part of an RNA subunit as template to synthesize telomeric repeats. Many cancer cells express high telomerase activity, and mutations in telomerase subunits are associated with degenerative syndromes including dyskeratosis congenita and aplastic anaemia. The therapeutic value of altering telomerase activity thus provides ample impetus to study the biogenesis and regulation of this enzyme in human cells and model systems. We have previously identified a precursor of the fission yeast telomerase RNA subunit (TER1) and demonstrated that the mature 3'-end is generated by the spliceosome in a single cleavage reaction akin to the first step of splicing. Directly upstream and partly overlapping with the spliceosomal cleavage site is a putative binding site for Sm proteins. Sm and like-Sm (LSm) proteins belong to an ancient family of RNA-binding proteins represented in all three domains of life. Members of this family form ring complexes on specific sets of target RNAs and have critical roles in their biogenesis, function and turnover. Here we demonstrate that the canonical Sm ring and the Lsm2-8 complex sequentially associate with fission yeast TER1. The Sm ring binds to the TER1 precursor, stimulates spliceosomal cleavage and promotes the hypermethylation of the 5'-cap by Tgs1. Sm proteins are then replaced by the Lsm2-8 complex, which promotes the association with the catalytic subunit and protects the mature 3'-end of TER1 from exonucleolytic degradation. Our findings define the sequence of events that occur during telomerase biogenesis and characterize roles for Sm and Lsm complexes as well as for the methylase Tgs1.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326189/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326189/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tang, Wen -- Kannan, Ram -- Blanchette, Marco -- Baumann, Peter -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 25;484(7393):260-4. doi: 10.1038/nature10924.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Kansas City, Missouri 64110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22446625" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Chromosomes, Fungal/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Methyltransferases/metabolism ; Multiprotein Complexes/chemistry/*metabolism ; Protein Binding ; RNA/*biosynthesis/genetics ; RNA Splicing ; RNA, Fungal/genetics/metabolism ; RNA-Binding Proteins/*metabolism ; Schizosaccharomyces/enzymology/*genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Spliceosomes/*metabolism ; Telomerase/*biosynthesis/genetics ; Telomere/genetics/metabolism ; tRNA Methyltransferases/metabolism
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    Cryptic peroxisomal targeting via alternative splicing and stop codon read-through in fungi (2012)
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    Publication Date: 2012-05-25
    Description: Peroxisomes are eukaryotic organelles important for the metabolism of long-chain fatty acids. Here we show that in numerous fungal species, several core enzymes of glycolysis, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and 3-phosphoglycerate kinase (PGK), reside in both the cytoplasm and peroxisomes. We detected in these enzymes cryptic type 1 peroxisomal targeting signals (PTS1), which are activated by post-transcriptional processes. Notably, the molecular mechanisms that generate the peroxisomal isoforms vary considerably among different species. In the basidiomycete plant pathogen Ustilago maydis, peroxisomal targeting of Pgk1 results from ribosomal read-through, whereas alternative splicing generates the PTS1 of Gapdh. In the filamentous ascomycete Aspergillus nidulans, peroxisomal targeting of these enzymes is achieved by exactly the opposite mechanisms. We also detected PTS1 motifs in the glycolytic enzymes triose-phosphate isomerase and fructose-bisphosphate aldolase. U. maydis mutants lacking the peroxisomal isoforms of Gapdh or Pgk1 showed reduced virulence. In addition, mutational analysis suggests that GAPDH, together with other peroxisomal NADH-dependent dehydrogenases, has a role in redox homeostasis. Owing to its hidden nature, partial peroxisomal targeting of well-studied cytoplasmic enzymes has remained undetected. Thus, we anticipate that further bona fide cytoplasmic proteins exhibit similar dual targeting.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Freitag, Johannes -- Ast, Julia -- Bolker, Michael -- England -- Nature. 2012 May 23;485(7399):522-5. doi: 10.1038/nature11051.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Philipps University Marburg, Karl-von-Frisch-Strasse 8, D-35032 Marburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22622582" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing/*genetics ; Amino Acid Sequence ; Aspergillus nidulans/cytology/enzymology/metabolism/pathogenicity ; Base Sequence ; Codon, Terminator/*genetics ; Fungi/*cytology/*genetics/metabolism/pathogenicity ; Glyceraldehyde-3-Phosphate Dehydrogenases/chemistry/genetics/metabolism ; Glycolysis ; Isoenzymes/chemistry/genetics/metabolism ; Molecular Sequence Data ; Peroxisomes/enzymology/*metabolism ; Phosphoglycerate Kinase/chemistry/genetics/metabolism ; Protein Sorting Signals/*genetics/physiology ; Protein Transport ; Ustilago/cytology/enzymology/growth & development/pathogenicity ; Virulence
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    A unifying model for mTORC1-mediated regulation of mRNA translation (2012)
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    Publication Date: 2012-05-04
    Description: The mTOR complex 1 (mTORC1) kinase nucleates a pathway that promotes cell growth and proliferation and is the target of rapamycin, a drug with many clinical uses. mTORC1 regulates messenger RNA translation, but the overall translational program is poorly defined and no unifying model exists to explain how mTORC1 differentially controls the translation of specific mRNAs. Here we use high-resolution transcriptome-scale ribosome profiling to monitor translation in mouse cells acutely treated with the mTOR inhibitor Torin 1, which, unlike rapamycin, fully inhibits mTORC1 (ref. 2). Our data reveal a surprisingly simple model of the mRNA features and mechanisms that confer mTORC1-dependent translation control. The subset of mRNAs that are specifically regulated by mTORC1 consists almost entirely of transcripts with established 5' terminal oligopyrimidine (TOP) motifs, or, like Hsp90ab1 and Ybx1, with previously unrecognized TOP or related TOP-like motifs that we identified. We find no evidence to support proposals that mTORC1 preferentially regulates mRNAs with increased 5' untranslated region length or complexity. mTORC1 phosphorylates a myriad of translational regulators, but how it controls TOP mRNA translation is unknown. Remarkably, loss of just the 4E-BP family of translational repressors, arguably the best characterized mTORC1 substrates, is sufficient to render TOP and TOP-like mRNA translation resistant to Torin 1. The 4E-BPs inhibit translation initiation by interfering with the interaction between the cap-binding protein eIF4E and eIF4G1. Loss of this interaction diminishes the capacity of eIF4E to bind TOP and TOP-like mRNAs much more than other mRNAs, explaining why mTOR inhibition selectively suppresses their translation. Our results clarify the translational program controlled by mTORC1 and identify 4E-BPs and eIF4G1 as its master effectors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347774/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347774/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thoreen, Carson C -- Chantranupong, Lynne -- Keys, Heather R -- Wang, Tim -- Gray, Nathanael S -- Sabatini, David M -- CA103866/CA/NCI NIH HHS/ -- CA129105/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA103866-08/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA129105-05/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 2;485(7396):109-13. doi: 10.1038/nature11083.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Dana Farber Cancer Institute, 250 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22552098" target="_blank"〉PubMed〈/a〉
    Keywords: 5' Untranslated Regions/genetics ; Animals ; Base Sequence ; Cell Line, Tumor ; Eukaryotic Initiation Factor-4E/metabolism ; Eukaryotic Initiation Factor-4G/metabolism ; *Gene Expression Regulation/drug effects ; Humans ; Male ; Mice ; *Models, Biological ; Multiprotein Complexes ; Naphthyridines/pharmacology ; Nucleotide Motifs ; Phosphorylation ; Prostatic Neoplasms/genetics/pathology ; Protein Binding ; *Protein Biosynthesis/drug effects ; Proteins/antagonists & inhibitors/*metabolism ; RNA, Messenger/genetics/metabolism ; Ribosomes/metabolism ; TOR Serine-Threonine Kinases
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    Control of a Salmonella virulence locus by an ATP-sensing leader messenger RNA (2012)
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    Publication Date: 2012-06-16
    Description: The facultative intracellular pathogen Salmonella enterica resides within a membrane-bound compartment inside macrophages. This compartment must be acidified for Salmonella to survive within macrophages, possibly because acidic pH promotes expression of Salmonella virulence proteins. We reasoned that Salmonella might sense its surroundings have turned acidic not only upon protonation of the extracytoplasmic domain of a protein sensor but also by an increase in cytosolic ATP levels, because conditions that enhance the proton gradient across the bacterial inner membrane stimulate ATP synthesis. Here we report that an increase in cytosolic ATP promotes transcription of the coding region for the virulence gene mgtC, which is the most highly induced horizontally acquired gene when Salmonella is inside macrophages. This transcript is induced both upon media acidification and by physiological conditions that increase ATP levels independently of acidification. ATP is sensed by the coupling/uncoupling of transcription of the unusually long mgtC leader messenger RNA and translation of a short open reading frame located in this region. A mutation in the mgtC leader messenger RNA that eliminates the response to ATP hinders mgtC expression inside macrophages and attenuates Salmonella virulence in mice. Our results define a singular example of an ATP-sensing leader messenger RNA. Moreover, they indicate that pathogens can interpret extracellular cues by the impact they have on cellular metabolites.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711680/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711680/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Eun-Jin -- Groisman, Eduardo A -- AI49561/AI/NIAID NIH HHS/ -- R01 AI049561/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jun 13;486(7402):271-5. doi: 10.1038/nature11090.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Yale School of Medicine, Section of Microbial Pathogenesis, New Haven, Connecticut 06536-0812, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22699622" target="_blank"〉PubMed〈/a〉
    Keywords: 5' Untranslated Regions/genetics/*physiology ; Adenosine Triphosphate/*metabolism ; Animals ; *Bacterial Proteins/genetics/metabolism ; Base Sequence ; *Cation Transport Proteins/genetics/metabolism ; Female ; Gene Expression Regulation, Bacterial ; Hydrogen-Ion Concentration ; Macrophages/microbiology ; Mice ; Mice, Inbred C3H ; Molecular Sequence Data ; Mutation/genetics ; Salmonella Infections/mortality/pathology ; Salmonella typhimurium/genetics/metabolism/*pathogenicity ; Sequence Alignment ; Virulence/*genetics
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    The anti-Shine-Dalgarno sequence drives translational pausing and codon choice in bacteria (2012)
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    Publication Date: 2012-03-30
    Description: Protein synthesis by ribosomes takes place on a linear substrate but at non-uniform speeds. Transient pausing of ribosomes can affect a variety of co-translational processes, including protein targeting and folding. These pauses are influenced by the sequence of the messenger RNA. Thus, redundancy in the genetic code allows the same protein to be translated at different rates. However, our knowledge of both the position and the mechanism of translational pausing in vivo is highly limited. Here we present a genome-wide analysis of translational pausing in bacteria by ribosome profiling--deep sequencing of ribosome-protected mRNA fragments. This approach enables the high-resolution measurement of ribosome density profiles along most transcripts at unperturbed, endogenous expression levels. Unexpectedly, we found that codons decoded by rare transfer RNAs do not lead to slow translation under nutrient-rich conditions. Instead, Shine-Dalgarno-(SD)-like features within coding sequences cause pervasive translational pausing. Using an orthogonal ribosome possessing an altered anti-SD sequence, we show that pausing is due to hybridization between the mRNA and 16S ribosomal RNA of the translating ribosome. In protein-coding sequences, internal SD sequences are disfavoured, which leads to biased usage, avoiding codons and codon pairs that resemble canonical SD sites. Our results indicate that internal SD-like sequences are a major determinant of translation rates and a global driving force for the coding of bacterial genomes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338875/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338875/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Gene-Wei -- Oh, Eugene -- Weissman, Jonathan S -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 28;484(7395):538-41. doi: 10.1038/nature10965.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22456704" target="_blank"〉PubMed〈/a〉
    Keywords: Bacillus subtilis/*genetics ; Base Sequence ; Codon/*genetics/metabolism ; Escherichia coli/*genetics ; Genome, Bacterial/genetics ; Models, Genetic ; Peptide Chain Termination, Translational/genetics ; Protein Biosynthesis/*genetics ; RNA, Bacterial/genetics/metabolism ; RNA, Ribosomal, 16S/genetics/metabolism ; Ribosomes/*metabolism
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    Genome-wide protein-DNA binding dynamics suggest a molecular clutch for transcription factor function (2012)
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    Publication Date: 2012-04-14
    Description: Dynamic access to genetic information is central to organismal development and environmental response. Consequently, genomic processes must be regulated by mechanisms that alter genome function relatively rapidly. Conventional chromatin immunoprecipitation (ChIP) experiments measure transcription factor occupancy, but give no indication of kinetics and are poor predictors of transcription factor function at a given locus. To measure transcription-factor-binding dynamics across the genome, we performed competition ChIP (refs 6, 7) with a sequence-specific Saccharomyces cerevisiae transcription factor, Rap1 (ref. 8). Rap1-binding dynamics and Rap1 occupancy were only weakly correlated (R(2) = 0.14), but binding dynamics were more strongly linked to function than occupancy. Long Rap1 residence was coupled to transcriptional activation, whereas fast binding turnover, which we refer to as 'treadmilling', was linked to low transcriptional output. Thus, DNA-binding events that seem identical by conventional ChIP may have different underlying modes of interaction that lead to opposing functional outcomes. We propose that transcription factor binding turnover is a major point of regulation in determining the functional consequences of transcription factor binding, and is mediated mainly by control of competition between transcription factors and nucleosomes. Our model predicts a clutch-like mechanism that rapidly engages a treadmilling transcription factor into a stable binding state, or vice versa, to modulate transcription factor function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341663/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341663/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lickwar, Colin R -- Mueller, Florian -- Hanlon, Sean E -- McNally, James G -- Lieb, Jason D -- R01 GM072518/GM/NIGMS NIH HHS/ -- R01 GM072518-05/GM/NIGMS NIH HHS/ -- R01-GM072518/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2012 Apr 11;484(7393):251-5. doi: 10.1038/nature10985.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3280, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22498630" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Binding Sites ; Binding, Competitive ; Chromatin Immunoprecipitation ; DNA, Fungal/genetics/*metabolism ; Gene Expression Regulation, Fungal ; *Genome, Fungal ; Histone Acetyltransferases/metabolism ; *Models, Biological ; Nucleosomes/genetics/metabolism ; Protein Binding ; RNA Polymerase II/metabolism ; RNA, Messenger/biosynthesis/genetics ; Saccharomyces cerevisiae/classification/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere-Binding Proteins/*metabolism ; Time Factors ; Transcription Factors/*metabolism
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    The let-7-Imp axis regulates ageing of the Drosophila testis stem-cell niche (2012)
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    Publication Date: 2012-06-05
    Description: Adult stem cells support tissue homeostasis and repair throughout the life of an individual. During ageing, numerous intrinsic and extrinsic changes occur that result in altered stem-cell behaviour and reduced tissue maintenance and regeneration. In the Drosophila testis, ageing results in a marked decrease in the self-renewal factor Unpaired (Upd), leading to a concomitant loss of germline stem cells. Here we demonstrate that IGF-II messenger RNA binding protein (Imp) counteracts endogenous small interfering RNAs to stabilize upd (also known as os) RNA. However, similar to upd, Imp expression decreases in the hub cells of older males, which is due to the targeting of Imp by the heterochronic microRNA let-7. In the absence of Imp, upd mRNA therefore becomes unprotected and susceptible to degradation. Understanding the mechanistic basis for ageing-related changes in stem-cell behaviour will lead to the development of strategies to treat age-onset diseases and facilitate stem-cell-based therapies in older individuals.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Toledano, Hila -- D'Alterio, Cecilia -- Czech, Benjamin -- Levine, Erel -- Jones, D Leanne -- R01 AG028092/AG/NIA NIH HHS/ -- R01 AG040288/AG/NIA NIH HHS/ -- England -- Nature. 2012 May 23;485(7400):605-10. doi: 10.1038/nature11061.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22660319" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins/metabolism ; Base Sequence ; Cell Aging/*physiology ; Drosophila Proteins/biosynthesis/genetics/*metabolism ; Drosophila melanogaster/*cytology/genetics/*metabolism ; Female ; Male ; MicroRNAs/*genetics ; Organ Specificity ; RNA Helicases/metabolism ; RNA, Messenger/genetics/metabolism ; RNA, Small Interfering/antagonists & inhibitors/genetics/metabolism ; RNA-Binding Proteins/biosynthesis/genetics/*metabolism ; Ribonuclease III/metabolism ; Stem Cell Niche/genetics/*physiology ; Testis/*cytology ; Transcription Factors/genetics/metabolism
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    B12 cofactors directly stabilize an mRNA regulatory switch (2012)
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    Publication Date: 2012-10-16
    Description: Structures of riboswitch receptor domains bound to their effector have shown how messenger RNAs recognize diverse small molecules, but mechanistic details linking the structures to the regulation of gene expression remain elusive. To address this, here we solve crystal structures of two different classes of cobalamin (vitamin B(12))-binding riboswitches that include the structural switch of the downstream regulatory domain. These classes share a common cobalamin-binding core, but use distinct peripheral extensions to recognize different B(12) derivatives. In each case, recognition is accomplished through shape complementarity between the RNA and cobalamin, with relatively few hydrogen bonding interactions that typically govern RNA-small molecule recognition. We show that a composite cobalamin-RNA scaffold stabilizes an unusual long-range intramolecular kissing-loop interaction that controls mRNA expression. This is the first, to our knowledge, riboswitch crystal structure detailing how the receptor and regulatory domains communicate in a ligand-dependent fashion to regulate mRNA expression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518761/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518761/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Johnson, James E Jr -- Reyes, Francis E -- Polaski, Jacob T -- Batey, Robert T -- 1S10RR026516/RR/NCRR NIH HHS/ -- F32 GM095121/GM/NIGMS NIH HHS/ -- F32GM095121/GM/NIGMS NIH HHS/ -- GM073850/GM/NIGMS NIH HHS/ -- R01 GM073850/GM/NIGMS NIH HHS/ -- S10 RR026516/RR/NCRR NIH HHS/ -- England -- Nature. 2012 Dec 6;492(7427):133-7. doi: 10.1038/nature11607. Epub 2012 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80309-0596, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23064232" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Calorimetry ; Crystallography, X-Ray ; Escherichia coli/genetics ; Gene Expression Regulation/drug effects ; Hydrogen Bonding/drug effects ; Ligands ; Models, Molecular ; Nucleic Acid Conformation/*drug effects ; RNA, Bacterial/genetics ; RNA, Messenger/*chemistry/drug effects/genetics/metabolism ; Riboswitch/*drug effects/genetics ; Thermodynamics ; Vitamin B 12/*chemistry/metabolism/*pharmacology
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    Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq (2012)
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    Publication Date: 2012-05-12
    Description: An extensive repertoire of modifications is known to underlie the versatile coding, structural and catalytic functions of RNA, but it remains largely uncharted territory. Although biochemical studies indicate that N(6)-methyladenosine (m(6)A) is the most prevalent internal modification in messenger RNA, an in-depth study of its distribution and functions has been impeded by a lack of robust analytical methods. Here we present the human and mouse m(6)A modification landscape in a transcriptome-wide manner, using a novel approach, m(6)A-seq, based on antibody-mediated capture and massively parallel sequencing. We identify over 12,000 m(6)A sites characterized by a typical consensus in the transcripts of more than 7,000 human genes. Sites preferentially appear in two distinct landmarks--around stop codons and within long internal exons--and are highly conserved between human and mouse. Although most sites are well preserved across normal and cancerous tissues and in response to various stimuli, a subset of stimulus-dependent, dynamically modulated sites is identified. Silencing the m(6)A methyltransferase significantly affects gene expression and alternative splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis. Our findings therefore suggest that RNA decoration by m(6)A has a fundamental role in regulation of gene expression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dominissini, Dan -- Moshitch-Moshkovitz, Sharon -- Schwartz, Schraga -- Salmon-Divon, Mali -- Ungar, Lior -- Osenberg, Sivan -- Cesarkas, Karen -- Jacob-Hirsch, Jasmine -- Amariglio, Ninette -- Kupiec, Martin -- Sorek, Rotem -- Rechavi, Gideon -- England -- Nature. 2012 Apr 29;485(7397):201-6. doi: 10.1038/nature11112.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22575960" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine/*analogs & derivatives/*genetics ; Alternative Splicing ; Animals ; Base Sequence ; Cell Line, Tumor ; Conserved Sequence ; Evolution, Molecular ; Hep G2 Cells ; Humans ; *Metabolome/genetics ; Methylation ; Methyltransferases/deficiency/genetics/metabolism ; Mice ; RNA/genetics/*metabolism ; RNA, Ribosomal/genetics/metabolism ; RNA, Transfer/genetics/metabolism ; RNA-Binding Proteins/metabolism ; Transcriptome/genetics
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    Control of somatic tissue differentiation by the long non-coding RNA TINCR (2012)
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    Publication Date: 2012-12-04
    Description: Several of the thousands of human long non-coding RNAs (lncRNAs) have been functionally characterized; however, potential roles for lncRNAs in somatic tissue differentiation remain poorly understood. Here we show that a 3.7-kilobase lncRNA, terminal differentiation-induced ncRNA (TINCR), controls human epidermal differentiation by a post-transcriptional mechanism. TINCR is required for high messenger RNA abundance of key differentiation genes, many of which are mutated in human skin diseases, including FLG, LOR, ALOXE3, ALOX12B, ABCA12, CASP14 and ELOVL3. TINCR-deficient epidermis lacked terminal differentiation ultrastructure, including keratohyalin granules and intact lamellar bodies. Genome-scale RNA interactome analysis revealed that TINCR interacts with a range of differentiation mRNAs. TINCR-mRNA interaction occurs through a 25-nucleotide 'TINCR box' motif that is strongly enriched in interacting mRNAs and required for TINCR binding. A high-throughput screen to analyse TINCR binding capacity to approximately 9,400 human recombinant proteins revealed direct binding of TINCR RNA to the staufen1 (STAU1) protein. STAU1-deficient tissue recapitulated the impaired differentiation seen with TINCR depletion. Loss of UPF1 and UPF2, both of which are required for STAU1-mediated RNA decay, however, did not have differentiation effects. Instead, the TINCR-STAU1 complex seems to mediate stabilization of differentiation mRNAs, such as KRT80. These data identify TINCR as a key lncRNA required for somatic tissue differentiation, which occurs through lncRNA binding to differentiation mRNAs to ensure their expression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674581/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674581/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kretz, Markus -- Siprashvili, Zurab -- Chu, Ci -- Webster, Dan E -- Zehnder, Ashley -- Qu, Kun -- Lee, Carolyn S -- Flockhart, Ross J -- Groff, Abigail F -- Chow, Jennifer -- Johnston, Danielle -- Kim, Grace E -- Spitale, Robert C -- Flynn, Ryan A -- Zheng, Grace X Y -- Aiyer, Subhadra -- Raj, Arjun -- Rinn, John L -- Chang, Howard Y -- Khavari, Paul A -- AR49737/AR/NIAMS NIH HHS/ -- DP2 OD008514/OD/NIH HHS/ -- P30 CA124435/CA/NCI NIH HHS/ -- R01 AR049737/AR/NIAMS NIH HHS/ -- R01 HG004361/HG/NHGRI NIH HHS/ -- R01-HG004361/HG/NHGRI NIH HHS/ -- T32 AR007422/AR/NIAMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jan 10;493(7431):231-5. doi: 10.1038/nature11661. Epub 2012 Dec 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23201690" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Cell Differentiation/*genetics ; Cells, Cultured ; Cytoskeletal Proteins/metabolism ; Epidermis/*cytology/*metabolism ; Gene Expression Regulation ; High-Throughput Screening Assays ; Humans ; Keratinocytes ; Mutation ; Nucleotide Motifs/genetics ; Protein Binding ; RNA Stability/genetics ; RNA, Long Noncoding/*genetics/*metabolism ; RNA, Messenger/genetics/metabolism ; RNA-Binding Proteins/metabolism ; Skin Diseases/genetics
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    FMRP targets distinct mRNA sequence elements to regulate protein expression (2012)
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    Publication Date: 2012-12-14
    Description: Fragile X syndrome (FXS) is a multi-organ disease that leads to mental retardation, macro-orchidism in males and premature ovarian insufficiency in female carriers. FXS is also a prominent monogenic disease associated with autism spectrum disorders (ASDs). FXS is typically caused by the loss of fragile X mental retardation 1 (FMR1) expression, which codes for the RNA-binding protein FMRP. Here we report the discovery of distinct RNA-recognition elements that correspond to the two independent RNA-binding domains of FMRP, in addition to the binding sites within the messenger RNA targets for wild-type and I304N mutant FMRP isoforms and the FMRP paralogues FXR1P and FXR2P (also known as FXR1 and FXR2). RNA-recognition-element frequency, ratio and distribution determine target mRNA association with FMRP. Among highly enriched targets, we identify many genes involved in ASD and show that FMRP affects their protein levels in human cell culture, mouse ovaries and human brain. Notably, we discovered that these targets are also dysregulated in Fmr1(-/-) mouse ovaries showing signs of premature follicular overdevelopment. These results indicate that FMRP targets share signalling pathways across different cellular contexts. As the importance of signalling pathways in both FXS and ASD is becoming increasingly apparent, our results provide a ranked list of genes as basis for the pursuit of new therapeutic targets for these neurological disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528815/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528815/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ascano, Manuel Jr -- Mukherjee, Neelanjan -- Bandaru, Pradeep -- Miller, Jason B -- Nusbaum, Jeffrey D -- Corcoran, David L -- Langlois, Christine -- Munschauer, Mathias -- Dewell, Scott -- Hafner, Markus -- Williams, Zev -- Ohler, Uwe -- Tuschl, Thomas -- HD068546/HD/NICHD NIH HHS/ -- K08 HD068546/HD/NICHD NIH HHS/ -- R01 GM104962/GM/NIGMS NIH HHS/ -- R01 MH080442/MH/NIMH NIH HHS/ -- UL1RR024143/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Dec 20;492(7429):382-6. doi: 10.1038/nature11737. Epub 2012 Dec 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, The Rockefeller University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23235829" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Binding Sites ; Brain/metabolism ; Child ; Child Development Disorders, Pervasive/genetics/metabolism ; Cross-Linking Reagents ; Female ; Fragile X Mental Retardation Protein/*genetics/*metabolism ; Gene Expression Regulation/*genetics ; HEK293 Cells ; Humans ; Immunoprecipitation ; Mice ; Molecular Sequence Data ; Multigene Family ; Mutation ; Ovary/metabolism/pathology ; Protein Biosynthesis/*genetics ; RNA, Messenger/*genetics/metabolism ; Regulatory Sequences, Ribonucleic Acid/*genetics ; Response Elements/genetics ; Signal Transduction ; Substrate Specificity
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    The complex of tmRNA-SmpB and EF-G on translocating ribosomes (2012)
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    Publication Date: 2012-05-25
    Description: Bacterial ribosomes stalled at the 3' end of malfunctioning messenger RNAs can be rescued by transfer-messenger RNA (tmRNA)-mediated trans-translation. The SmpB protein forms a complex with the tmRNA, and the transfer-RNA-like domain (TLD) of the tmRNA then enters the A site of the ribosome. Subsequently, the TLD-SmpB module is translocated to the P site, a process that is facilitated by the elongation factor EF-G, and translation is switched to the mRNA-like domain (MLD) of the tmRNA. Accurate loading of the MLD into the mRNA path is an unusual initiation mechanism. Despite various snapshots of different ribosome-tmRNA complexes at low to intermediate resolution, it is unclear how the large, highly structured tmRNA is translocated and how the MLD is loaded. Here we present a cryo-electron microscopy reconstruction of a fusidic-acid-stalled ribosomal 70S-tmRNA-SmpB-EF-G complex (carrying both of the large ligands, that is, EF-G and tmRNA) at 8.3 A resolution. This post-translocational intermediate (TI(POST)) presents the TLD-SmpB module in an intrasubunit ap/P hybrid site and a tRNA(fMet) in an intrasubunit pe/E hybrid site. Conformational changes in the ribosome and tmRNA occur in the intersubunit space and on the solvent side. The key underlying event is a unique extra-large swivel movement of the 30S head, which is crucial for both tmRNA-SmpB translocation and MLD loading, thereby coupling translocation to MLD loading. This mechanism exemplifies the versatile, dynamic nature of the ribosome, and it shows that the conformational modes of the ribosome that normally drive canonical translation can also be used in a modified form to facilitate more complex tasks in specialized non-canonical pathways.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ramrath, David J F -- Yamamoto, Hiroshi -- Rother, Kristian -- Wittek, Daniela -- Pech, Markus -- Mielke, Thorsten -- Loerke, Justus -- Scheerer, Patrick -- Ivanov, Pavel -- Teraoka, Yoshika -- Shpanchenko, Olga -- Nierhaus, Knud H -- Spahn, Christian M T -- England -- Nature. 2012 May 6;485(7399):526-9. doi: 10.1038/nature11006.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut fur Medizinische Physik und Biophysik, Charite - Universitatsmedizin Berlin, Ziegelstrasse 5-9, 10117 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22622583" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Cryoelectron Microscopy ; Escherichia coli/*chemistry ; Fusidic Acid/metabolism ; Ligands ; Models, Molecular ; Nucleic Acid Conformation ; Peptide Elongation Factor G/chemistry/*metabolism/ultrastructure ; Protein Binding ; *Protein Biosynthesis ; Protein Conformation ; RNA, Bacterial/*chemistry/genetics/*metabolism/ultrastructure ; RNA-Binding Proteins/chemistry/*metabolism/ultrastructure ; Ribosome Subunits/chemistry/genetics/metabolism/ultrastructure ; Ribosomes/chemistry/genetics/*metabolism/ultrastructure
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    Targeting nuclear RNA for in vivo correction of myotonic dystrophy (2012)
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    Publication Date: 2012-08-04
    Description: Antisense oligonucleotides (ASOs) hold promise for gene-specific knockdown in diseases that involve RNA or protein gain-of-function effects. In the hereditary degenerative disease myotonic dystrophy type 1 (DM1), transcripts from the mutant allele contain an expanded CUG repeat and are retained in the nucleus. The mutant RNA exerts a toxic gain-of-function effect, making it an appropriate target for therapeutic ASOs. However, despite improvements in ASO chemistry and design, systemic use of ASOs is limited because uptake in many tissues, including skeletal and cardiac muscle, is not sufficient to silence target messenger RNAs. Here we show that nuclear-retained transcripts containing expanded CUG (CUG(exp)) repeats are unusually sensitive to antisense silencing. In a transgenic mouse model of DM1, systemic administration of ASOs caused a rapid knockdown of CUG(exp) RNA in skeletal muscle, correcting the physiological, histopathologic and transcriptomic features of the disease. The effect was sustained for up to 1 year after treatment was discontinued. Systemically administered ASOs were also effective for muscle knockdown of Malat1, a long non-coding RNA (lncRNA) that is retained in the nucleus. These results provide a general strategy to correct RNA gain-of-function effects and to modulate the expression of expanded repeats, lncRNAs and other transcripts with prolonged nuclear residence.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221572/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221572/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wheeler, Thurman M -- Leger, Andrew J -- Pandey, Sanjay K -- MacLeod, A Robert -- Nakamori, Masayuki -- Cheng, Seng H -- Wentworth, Bruce M -- Bennett, C Frank -- Thornton, Charles A -- AR/NS48143/AR/NIAMS NIH HHS/ -- AR049077/AR/NIAMS NIH HHS/ -- K08 NS064293/NS/NINDS NIH HHS/ -- K08NS064293/NS/NINDS NIH HHS/ -- U01NS072323/NS/NINDS NIH HHS/ -- U54 NS048843/NS/NINDS NIH HHS/ -- U54NS48843/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Aug 2;488(7409):111-5. doi: 10.1038/nature11362.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology, University of Rochester, 601 Elmwood Avenue, Rochester, New York 14642, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22859208" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Base Sequence ; Cell Nucleus/drug effects/*genetics ; Disease Models, Animal ; Gene Knockdown Techniques ; *Gene Silencing ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred mdx ; Mice, Transgenic ; Muscle, Skeletal/drug effects/metabolism ; Myotonic Dystrophy/*genetics/pathology/physiopathology/*therapy ; Myotonin-Protein Kinase ; Oligonucleotides, Antisense/genetics/pharmacology/therapeutic use ; Protein-Serine-Threonine Kinases/genetics ; RNA/*antagonists & inhibitors/*genetics/metabolism ; RNA, Long Noncoding ; RNA, Messenger/antagonists & inhibitors/genetics/metabolism ; RNA, Untranslated/genetics ; Ribonuclease H/metabolism ; Transcriptome/drug effects/genetics ; Trinucleotide Repeat Expansion/genetics
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    Proto-genes and de novo gene birth (2012)
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    Publication Date: 2012-06-23
    Description: Novel protein-coding genes can arise either through re-organization of pre-existing genes or de novo. Processes involving re-organization of pre-existing genes, notably after gene duplication, have been extensively described. In contrast, de novo gene birth remains poorly understood, mainly because translation of sequences devoid of genes, or 'non-genic' sequences, is expected to produce insignificant polypeptides rather than proteins with specific biological functions. Here we formalize an evolutionary model according to which functional genes evolve de novo through transitory proto-genes generated by widespread translational activity in non-genic sequences. Testing this model at the genome scale in Saccharomyces cerevisiae, we detect translation of hundreds of short species-specific open reading frames (ORFs) located in non-genic sequences. These translation events seem to provide adaptive potential, as suggested by their differential regulation upon stress and by signatures of retention by natural selection. In line with our model, we establish that S. cerevisiae ORFs can be placed within an evolutionary continuum ranging from non-genic sequences to genes. We identify ~1,900 candidate proto-genes among S. cerevisiae ORFs and find that de novo gene birth from such a reservoir may be more prevalent than sporadic gene duplication. Our work illustrates that evolution exploits seemingly dispensable sequences to generate adaptive functional innovation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401362/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401362/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Carvunis, Anne-Ruxandra -- Rolland, Thomas -- Wapinski, Ilan -- Calderwood, Michael A -- Yildirim, Muhammed A -- Simonis, Nicolas -- Charloteaux, Benoit -- Hidalgo, Cesar A -- Barbette, Justin -- Santhanam, Balaji -- Brar, Gloria A -- Weissman, Jonathan S -- Regev, Aviv -- Thierry-Mieg, Nicolas -- Cusick, Michael E -- Vidal, Marc -- R01 HG006061/HG/NHGRI NIH HHS/ -- R01-HG006061/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jul 19;487(7407):370-4. doi: 10.1038/nature11184.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Cancer Systems Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722833" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Conserved Sequence ; *Evolution, Molecular ; Genes, Fungal/*genetics ; Genetic Variation ; Molecular Sequence Data ; Open Reading Frames ; Phylogeny ; Protein Biosynthesis ; Saccharomyces/classification/*genetics ; Saccharomyces cerevisiae/classification/genetics ; Sequence Alignment
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    SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation (2012)
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    Publication Date: 2012-06-23
    Description: Sirtuin proteins regulate diverse cellular pathways that influence genomic stability, metabolism and ageing. SIRT7 is a mammalian sirtuin whose biochemical activity, molecular targets and physiological functions have been unclear. Here we show that SIRT7 is an NAD(+)-dependent H3K18Ac (acetylated lysine 18 of histone H3) deacetylase that stabilizes the transformed state of cancer cells. Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. The spectrum of SIRT7 target genes is defined in part by its interaction with the cancer-associated E26 transformed specific (ETS) transcription factor ELK4, and comprises numerous genes with links to tumour suppression. Notably, selective hypoacetylation of H3K18Ac has been linked to oncogenic transformation, and in patients is associated with aggressive tumour phenotypes and poor prognosis. We find that deacetylation of H3K18Ac by SIRT7 is necessary for maintaining essential features of human cancer cells, including anchorage-independent growth and escape from contact inhibition. Moreover, SIRT7 is necessary for a global hypoacetylation of H3K18Ac associated with cellular transformation by the viral oncoprotein E1A. Finally, SIRT7 depletion markedly reduces the tumorigenicity of human cancer cell xenografts in mice. Together, our work establishes SIRT7 as a highly selective H3K18Ac deacetylase and demonstrates a pivotal role for SIRT7 in chromatin regulation, cellular transformation programs and tumour formation in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412143/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412143/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barber, Matthew F -- Michishita-Kioi, Eriko -- Xi, Yuanxin -- Tasselli, Luisa -- Kioi, Mitomu -- Moqtaderi, Zarmik -- Tennen, Ruth I -- Paredes, Silvana -- Young, Nicolas L -- Chen, Kaifu -- Struhl, Kevin -- Garcia, Benjamin A -- Gozani, Or -- Li, Wei -- Chua, Katrin F -- 1018438-142/PHS HHS/ -- 3T32DK007217-36S1/DK/NIDDK NIH HHS/ -- DP2OD007447/OD/NIH HHS/ -- GM 30186/GM/NIGMS NIH HHS/ -- HG 4558/HG/NHGRI NIH HHS/ -- K08 AG028961/AG/NIA NIH HHS/ -- R01 AG028867/AG/NIA NIH HHS/ -- R01 GM030186/GM/NIGMS NIH HHS/ -- R01 GM079641/GM/NIGMS NIH HHS/ -- T32 CA009302/CA/NCI NIH HHS/ -- U01 DA025956/DA/NIDA NIH HHS/ -- U01 DA025956-01/DA/NIDA NIH HHS/ -- U01DA025956/DA/NIDA NIH HHS/ -- England -- Nature. 2012 Jul 5;487(7405):114-8. doi: 10.1038/nature11043.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722849" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Adenovirus E1A Proteins/genetics/metabolism ; Animals ; Base Sequence ; Binding Sites ; Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics/*metabolism/pathology ; Chromatin/metabolism ; Contact Inhibition ; Disease Progression ; Histone Deacetylases/*metabolism ; Histones/*metabolism ; Humans ; Lysine/*metabolism ; Mice ; Neoplasm Transplantation ; Nucleotide Motifs ; Phenotype ; Promoter Regions, Genetic ; Repressor Proteins/metabolism ; Sirtuins/deficiency/genetics/*metabolism ; Transcription, Genetic ; Transplantation, Heterologous ; ets-Domain Protein Elk-4/metabolism
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    In vivo genome editing using a high-efficiency TALEN system (2012)
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    Publication Date: 2012-09-25
    Description: The zebrafish (Danio rerio) is increasingly being used to study basic vertebrate biology and human disease with a rich array of in vivo genetic and molecular tools. However, the inability to readily modify the genome in a targeted fashion has been a bottleneck in the field. Here we show that improvements in artificial transcription activator-like effector nucleases (TALENs) provide a powerful new approach for targeted zebrafish genome editing and functional genomic applications. Using the GoldyTALEN modified scaffold and zebrafish delivery system, we show that this enhanced TALEN toolkit has a high efficiency in inducing locus-specific DNA breaks in somatic and germline tissues. At some loci, this efficacy approaches 100%, including biallelic conversion in somatic tissues that mimics phenotypes seen using morpholino-based targeted gene knockdowns. With this updated TALEN system, we successfully used single-stranded DNA oligonucleotides to precisely modify sequences at predefined locations in the zebrafish genome through homology-directed repair, including the introduction of a custom-designed EcoRV site and a modified loxP (mloxP) sequence into somatic tissue in vivo. We further show successful germline transmission of both EcoRV and mloxP engineered chromosomes. This combined approach offers the potential to model genetic variation as well as to generate targeted conditional alleles.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491146/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491146/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bedell, Victoria M -- Wang, Ying -- Campbell, Jarryd M -- Poshusta, Tanya L -- Starker, Colby G -- Krug, Randall G 2nd -- Tan, Wenfang -- Penheiter, Sumedha G -- Ma, Alvin C -- Leung, Anskar Y H -- Fahrenkrug, Scott C -- Carlson, Daniel F -- Voytas, Daniel F -- Clark, Karl J -- Essner, Jeffrey J -- Ekker, Stephen C -- DA032194/DA/NIDA NIH HHS/ -- DK083219/DK/NIDDK NIH HHS/ -- F30 DK083219/DK/NIDDK NIH HHS/ -- GM088424/GM/NIGMS NIH HHS/ -- GM63904/GM/NIGMS NIH HHS/ -- P30 DK084567/DK/NIDDK NIH HHS/ -- P30DK084567/DK/NIDDK NIH HHS/ -- R01 GM063904/GM/NIGMS NIH HHS/ -- R01 GM088424/GM/NIGMS NIH HHS/ -- R21 DA032194/DA/NIDA NIH HHS/ -- R41 HL108440/HL/NHLBI NIH HHS/ -- R41HL108440/HL/NHLBI NIH HHS/ -- R56 GM063904/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Nov 1;491(7422):114-8. doi: 10.1038/nature11537. Epub 2012 Sep 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23000899" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Attachment Sites, Microbiological/genetics ; Base Sequence ; Chromosomes/genetics ; DNA Breaks ; DNA, Single-Stranded/genetics ; Deoxyribonucleases/*metabolism ; Deoxyribonucleases, Type II Site-Specific/metabolism ; Gene Targeting/*methods ; Genetic Engineering/*methods ; Genome/*genetics ; Genomics/methods ; Genotype ; Germ-Line Mutation/genetics ; Molecular Sequence Data ; Mutagenesis, Site-Directed/methods ; RNA, Messenger/genetics/metabolism ; Receptors, Corticotropin-Releasing Hormone/genetics ; Recombinational DNA Repair/genetics ; Zebrafish/*genetics
    Print ISSN: 0028-0836
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    Structure and function of Zucchini endoribonuclease in piRNA biogenesis (2012)
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    Publication Date: 2012-10-16
    Description: PIWI-interacting RNAs (piRNAs) silence transposons to maintain genome integrity in animal germ lines. piRNAs are classified as primary and secondary piRNAs, depending on their biogenesis machinery. Primary piRNAs are processed from long non-coding RNA precursors transcribed from piRNA clusters in the genome through the primary processing pathway. Although the existence of a ribonuclease participating in this pathway has been predicted, its molecular identity remained unknown. Here we show that Zucchini (Zuc), a mitochondrial phospholipase D (PLD) superfamily member, is an endoribonuclease essential for primary piRNA biogenesis. We solved the crystal structure of Drosophila melanogaster Zuc (DmZuc) at 1.75 A resolution. The structure revealed that DmZuc has a positively charged, narrow catalytic groove at the dimer interface, which could accommodate a single-stranded, but not a double-stranded, RNA. DmZuc and the mouse homologue MmZuc (also known as Pld6 and MitoPLD) showed endoribonuclease activity for single-stranded RNAs in vitro. The RNA cleavage products bear a 5'-monophosphate group, a hallmark of mature piRNAs. Mutational analyses revealed that the conserved active-site residues of DmZuc are critical for the ribonuclease activity in vitro, and for piRNA maturation and transposon silencing in vivo. We propose a model for piRNA biogenesis in animal germ lines, in which the Zuc endoribonuclease has a key role in primary piRNA maturation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nishimasu, Hiroshi -- Ishizu, Hirotsugu -- Saito, Kuniaki -- Fukuhara, Satoshi -- Kamatani, Miharu K -- Bonnefond, Luc -- Matsumoto, Naoki -- Nishizawa, Tomohiro -- Nakanaga, Keita -- Aoki, Junken -- Ishitani, Ryuichiro -- Siomi, Haruhiko -- Siomi, Mikiko C -- Nureki, Osamu -- England -- Nature. 2012 Nov 8;491(7423):284-7. doi: 10.1038/nature11509. Epub 2012 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23064230" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; DNA Transposable Elements/genetics ; Drosophila Proteins/*chemistry/*metabolism ; Drosophila melanogaster/*enzymology/genetics ; Endoribonucleases/*chemistry/*metabolism ; Gene Silencing ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; RNA, Small Interfering/biosynthesis/chemistry/genetics/*metabolism ; Structure-Activity Relationship
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    Genetic recombination is directed away from functional genomic elements in mice (2012)
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    Publication Date: 2012-06-05
    Description: Genetic recombination occurs during meiosis, the key developmental programme of gametogenesis. Recombination in mammals has been recently linked to the activity of a histone H3 methyltransferase, PR domain containing 9 (PRDM9), the product of the only known speciation-associated gene in mammals. PRDM9 is thought to determine the preferred recombination sites--recombination hotspots--through sequence-specific binding of its highly polymorphic multi-Zn-finger domain. Nevertheless, Prdm9 knockout mice are proficient at initiating recombination. Here we map and analyse the genome-wide distribution of recombination initiation sites in Prdm9 knockout mice and in two mouse strains with different Prdm9 alleles and their F(1) hybrid. We show that PRDM9 determines the positions of practically all hotspots in the mouse genome, with the exception of the pseudo-autosomal region (PAR)--the only area of the genome that undergoes recombination in 100% of cells. Surprisingly, hotspots are still observed in Prdm9 knockout mice, and as in wild type, these hotspots are found at H3 lysine 4 (H3K4) trimethylation marks. However, in the absence of PRDM9, most recombination is initiated at promoters and at other sites of PRDM9-independent H3K4 trimethylation. Such sites are rarely targeted in wild-type mice, indicating an unexpected role of the PRDM9 protein in sequestering the recombination machinery away from gene-promoter regions and other functional genomic elements.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367396/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367396/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brick, Kevin -- Smagulova, Fatima -- Khil, Pavel -- Camerini-Otero, R Daniel -- Petukhova, Galina V -- 1R01GM084104-01A1/GM/NIGMS NIH HHS/ -- R01 GM084104/GM/NIGMS NIH HHS/ -- R01 GM084104-01A1/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2012 May 13;485(7400):642-5. doi: 10.1038/nature11089.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22660327" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Amino Acid Sequence ; Animals ; Base Sequence ; *DNA Breaks, Double-Stranded ; Genome/*genetics ; Histone-Lysine N-Methyltransferase/deficiency/genetics/*metabolism ; Histones/chemistry/metabolism ; Meiosis/genetics ; Methylation ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Promoter Regions, Genetic/*genetics ; Recombination, Genetic/*genetics
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    Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities (2012)
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    Publication Date: 2012-01-24
    Description: Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278668/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278668/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boyden, Lynn M -- Choi, Murim -- Choate, Keith A -- Nelson-Williams, Carol J -- Farhi, Anita -- Toka, Hakan R -- Tikhonova, Irina R -- Bjornson, Robert -- Mane, Shrikant M -- Colussi, Giacomo -- Lebel, Marcel -- Gordon, Richard D -- Semmekrot, Ben A -- Poujol, Alain -- Valimaki, Matti J -- De Ferrari, Maria E -- Sanjad, Sami A -- Gutkin, Michael -- Karet, Fiona E -- Tucci, Joseph R -- Stockigt, Jim R -- Keppler-Noreuil, Kim M -- Porter, Craig C -- Anand, Sudhir K -- Whiteford, Margo L -- Davis, Ira D -- Dewar, Stephanie B -- Bettinelli, Alberto -- Fadrowski, Jeffrey J -- Belsha, Craig W -- Hunley, Tracy E -- Nelson, Raoul D -- Trachtman, Howard -- Cole, Trevor R P -- Pinsk, Maury -- Bockenhauer, Detlef -- Shenoy, Mohan -- Vaidyanathan, Priya -- Foreman, John W -- Rasoulpour, Majid -- Thameem, Farook -- Al-Shahrouri, Hania Z -- Radhakrishnan, Jai -- Gharavi, Ali G -- Goilav, Beatrice -- Lifton, Richard P -- KL2 RR024138/RR/NCRR NIH HHS/ -- KL2 RR024138-07/RR/NCRR NIH HHS/ -- P30 DK079310/DK/NIDDK NIH HHS/ -- P30 DK079310-04S1/DK/NIDDK NIH HHS/ -- P30-DK079310/DK/NIDDK NIH HHS/ -- UL1-RR024139/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 22;482(7383):98-102. doi: 10.1038/nature10814.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22266938" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Base Sequence ; Blood Pressure/genetics ; Carrier Proteins/chemistry/*genetics ; Cohort Studies ; Cullin Proteins/chemistry/*genetics ; Electrolytes ; Exons/genetics ; Female ; Gene Expression Profiling ; Genes, Dominant/genetics ; Genes, Recessive/genetics ; Genotype ; Homeostasis/genetics ; Humans ; Hydrogen-Ion Concentration ; Hypertension/complications/*genetics/physiopathology ; Male ; Mice ; Models, Molecular ; Molecular Sequence Data ; Mutation/*genetics ; Phenotype ; Potassium/metabolism ; Pseudohypoaldosteronism/complications/*genetics/physiopathology ; Sodium Chloride/metabolism ; Water-Electrolyte Imbalance/complications/*genetics/physiopathology
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    Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma (2012)
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    Publication Date: 2012-01-31
    Description: Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (alpha-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schwartzentruber, Jeremy -- Korshunov, Andrey -- Liu, Xiao-Yang -- Jones, David T W -- Pfaff, Elke -- Jacob, Karine -- Sturm, Dominik -- Fontebasso, Adam M -- Quang, Dong-Anh Khuong -- Tonjes, Martje -- Hovestadt, Volker -- Albrecht, Steffen -- Kool, Marcel -- Nantel, Andre -- Konermann, Carolin -- Lindroth, Anders -- Jager, Natalie -- Rausch, Tobias -- Ryzhova, Marina -- Korbel, Jan O -- Hielscher, Thomas -- Hauser, Peter -- Garami, Miklos -- Klekner, Almos -- Bognar, Laszlo -- Ebinger, Martin -- Schuhmann, Martin U -- Scheurlen, Wolfram -- Pekrun, Arnulf -- Fruhwald, Michael C -- Roggendorf, Wolfgang -- Kramm, Christoph -- Durken, Matthias -- Atkinson, Jeffrey -- Lepage, Pierre -- Montpetit, Alexandre -- Zakrzewska, Magdalena -- Zakrzewski, Krzystof -- Liberski, Pawel P -- Dong, Zhifeng -- Siegel, Peter -- Kulozik, Andreas E -- Zapatka, Marc -- Guha, Abhijit -- Malkin, David -- Felsberg, Jorg -- Reifenberger, Guido -- von Deimling, Andreas -- Ichimura, Koichi -- Collins, V Peter -- Witt, Hendrik -- Milde, Till -- Witt, Olaf -- Zhang, Cindy -- Castelo-Branco, Pedro -- Lichter, Peter -- Faury, Damien -- Tabori, Uri -- Plass, Christoph -- Majewski, Jacek -- Pfister, Stefan M -- Jabado, Nada -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2012 Jan 29;482(7384):226-31. doi: 10.1038/nature10833.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉McGill University and Genome Quebec Innovation Centre, Montreal, Quebec H3A 1A4, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22286061" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics ; Base Sequence ; Child ; Chromatin/*genetics/metabolism ; Chromatin Assembly and Disassembly/*genetics ; DNA Helicases/genetics ; DNA Mutational Analysis ; Exome/genetics ; Gene Expression Profiling ; Glioblastoma/*genetics ; Histones/*genetics/metabolism ; Humans ; Molecular Sequence Data ; Mutation/*genetics ; Nuclear Proteins/genetics ; Telomere/genetics ; Tumor Suppressor Protein p53/genetics
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    A new understanding of the decoding principle on the ribosome (2012)
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    Publication Date: 2012-03-23
    Description: During protein synthesis, the ribosome accurately selects transfer RNAs (tRNAs) in accordance with the messenger RNA (mRNA) triplet in the decoding centre. tRNA selection is initiated by elongation factor Tu, which delivers tRNA to the aminoacyl tRNA-binding site (A site) and hydrolyses GTP upon establishing codon-anticodon interactions in the decoding centre. At the following proofreading step the ribosome re-examines the tRNA and rejects it if it does not match the A codon. It was suggested that universally conserved G530, A1492 and A1493 of 16S ribosomal RNA, critical for tRNA binding in the A site, actively monitor cognate tRNA, and that recognition of the correct codon-anticodon duplex induces an overall ribosome conformational change (domain closure). Here we propose an integrated mechanism for decoding based on six X-ray structures of the 70S ribosome determined at 3.1-3.4 A resolution, modelling cognate or near-cognate states of the decoding centre at the proofreading step. We show that the 30S subunit undergoes an identical domain closure upon binding of either cognate or near-cognate tRNA. This conformational change of the 30S subunit forms a decoding centre that constrains the mRNA in such a way that the first two nucleotides of the A codon are limited to form Watson-Crick base pairs. When U.G and G.U mismatches, generally considered to form wobble base pairs, are at the first or second codon-anticodon position, the decoding centre forces this pair to adopt the geometry close to that of a canonical C.G pair. This by itself, or with distortions in the codon-anticodon mini-helix and the anticodon loop, causes the near-cognate tRNA to dissociate from the ribosome.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Demeshkina, Natalia -- Jenner, Lasse -- Westhof, Eric -- Yusupov, Marat -- Yusupova, Gulnara -- 294312/European Research Council/International -- England -- Nature. 2012 Mar 21;484(7393):256-9. doi: 10.1038/nature10913.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departement de Biologie et de Genomique Structurales, Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch 67400, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22437501" target="_blank"〉PubMed〈/a〉
    Keywords: Anticodon/genetics/metabolism ; Base Pairing ; Base Sequence ; Codon/genetics/metabolism ; Crystallography, X-Ray ; *Models, Biological ; Models, Genetic ; Models, Molecular ; Nucleic Acid Conformation ; Protein Biosynthesis ; Protein Conformation ; RNA, Messenger/genetics/metabolism ; RNA, Ribosomal, 23S/genetics/metabolism ; RNA, Transfer, Amino Acid-Specific/chemistry/genetics/metabolism ; Ribosomes/*chemistry/genetics/*metabolism ; Thermus thermophilus
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    Visualizing transient low-populated structures of RNA (2012)
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    Publication Date: 2012-10-09
    Description: The visualization of RNA conformational changes has provided fundamental insights into how regulatory RNAs carry out their biological functions. The RNA structural transitions that have been characterized so far involve long-lived species that can be captured by structure characterization techniques. Here we report the nuclear magnetic resonance visualization of RNA transitions towards 'invisible' excited states (ESs), which exist in too little abundance (2-13%) and for too short a duration (45-250 mus) to allow structural characterization by conventional techniques. Transitions towards ESs result in localized rearrangements in base-pairing that alter building block elements of RNA architecture, including helix-junction-helix motifs and apical loops. The ES can inhibit function by sequestering residues involved in recognition and signalling or promote ATP-independent strand exchange. Thus, RNAs do not adopt a single conformation, but rather exist in rapid equilibrium with alternative ESs, which can be stabilized by cellular cues to affect functional outcomes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590852/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590852/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dethoff, Elizabeth A -- Petzold, Katja -- Chugh, Jeetender -- Casiano-Negroni, Anette -- Al-Hashimi, Hashim M -- R01 AI066975/AI/NIAID NIH HHS/ -- England -- Nature. 2012 Nov 29;491(7426):724-8. doi: 10.1038/nature11498. Epub 2012 Oct 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry & Biophysics, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1055, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23041928" target="_blank"〉PubMed〈/a〉
    Keywords: Base Pairing ; Base Sequence ; HIV Long Terminal Repeat/*genetics ; HIV-1/*genetics ; Nuclear Magnetic Resonance, Biomolecular ; *Nucleic Acid Conformation ; RNA, Viral/*chemistry/genetics ; Ribosomes/chemistry/metabolism ; Structure-Activity Relationship
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    Fluoride ion encapsulation by Mg2+ ions and phosphates in a fluoride riboswitch (2012)
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    Publication Date: 2012-06-09
    Description: Significant advances in our understanding of RNA architecture, folding and recognition have emerged from structure-function studies on riboswitches, non-coding RNAs whose sensing domains bind small ligands and whose adjacent expression platforms contain RNA elements involved in the control of gene regulation. We now report on the ligand-bound structure of the Thermotoga petrophila fluoride riboswitch, which adopts a higher-order RNA architecture stabilized by pseudoknot and long-range reversed Watson-Crick and Hoogsteen A*U pair formation. The bound fluoride ion is encapsulated within the junctional architecture, anchored in place through direct coordination to three Mg(2+) ions, which in turn are octahedrally coordinated to water molecules and five inwardly pointing backbone phosphates. Our structure of the fluoride riboswitch in the bound state shows how RNA can form a binding pocket selective for fluoride, while discriminating against larger halide ions. The T. petrophila fluoride riboswitch probably functions in gene regulation through a transcription termination mechanism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744881/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744881/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ren, Aiming -- Rajashankar, Kanagalaghatta R -- Patel, Dinshaw J -- GM34504/GM/NIGMS NIH HHS/ -- R01 GM034504/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 May 13;486(7401):85-9. doi: 10.1038/nature11152.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology Program, Memorial Sloan-Kettering Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22678284" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Binding Sites ; Cations, Divalent/*chemistry ; Fluorides/*chemistry/*metabolism ; Gene Expression Regulation, Bacterial ; Gram-Negative Anaerobic Straight, Curved, and Helical Rods/*genetics ; Ligands ; Magnesium/*chemistry ; Models, Molecular ; Nucleic Acid Conformation ; Nucleotide Motifs ; Phosphates/*chemistry/metabolism ; Riboswitch/*genetics ; Structure-Activity Relationship ; Substrate Specificity ; Water/chemistry/metabolism
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    Differential oestrogen receptor binding is associated with clinical outcome in breast cancer (2012)
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    Publication Date: 2012-01-06
    Description: Oestrogen receptor-alpha (ER) is the defining and driving transcription factor in the majority of breast cancers and its target genes dictate cell growth and endocrine response, yet genomic understanding of ER function has been restricted to model systems. Here we map genome-wide ER-binding events, by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), in primary breast cancers from patients with different clinical outcomes and in distant ER-positive metastases. We find that drug-resistant cancers still recruit ER to the chromatin, but that ER binding is a dynamic process, with the acquisition of unique ER-binding regions in tumours from patients that are likely to relapse. The acquired ER regulatory regions associated with poor clinical outcome observed in primary tumours reveal gene signatures that predict clinical outcome in ER-positive disease exclusively. We find that the differential ER-binding programme observed in tumours from patients with poor outcome is not due to the selection of a rare subpopulation of cells, but is due to the FOXA1-mediated reprogramming of ER binding on a rapid timescale. The parallel redistribution of ER and FOXA1 binding events in drug-resistant cellular contexts is supported by histological co-expression of ER and FOXA1 in metastatic samples. By establishing transcription-factor mapping in primary tumour material, we show that there is plasticity in ER-binding capacity, with distinct combinations of cis-regulatory elements linked with the different clinical outcomes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272464/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272464/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ross-Innes, Caryn S -- Stark, Rory -- Teschendorff, Andrew E -- Holmes, Kelly A -- Ali, H Raza -- Dunning, Mark J -- Brown, Gordon D -- Gojis, Ondrej -- Ellis, Ian O -- Green, Andrew R -- Ali, Simak -- Chin, Suet-Feung -- Palmieri, Carlo -- Caldas, Carlos -- Carroll, Jason S -- A10178/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Jan 4;481(7381):389-93. doi: 10.1038/nature10730.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22217937" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Breast Neoplasms/*diagnosis/drug therapy/*genetics/pathology ; Cell Line, Tumor ; Drug Resistance, Neoplasm/drug effects/genetics ; Female ; *Gene Expression Regulation, Neoplastic/drug effects ; Hepatocyte Nuclear Factor 3-alpha/metabolism ; Humans ; Neoplasm Metastasis/genetics ; Prognosis ; Protein Binding ; Receptors, Estrogen/*metabolism ; Regulatory Sequences, Nucleic Acid/genetics ; Survival Analysis ; Tamoxifen/pharmacology/therapeutic use ; Treatment Outcome
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    BATF-JUN is critical for IRF4-mediated transcription in T cells (2012)
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    Publication Date: 2012-09-21
    Description: Interferon regulatory factor 4 (IRF4) is an IRF family transcription factor with critical roles in lymphoid development and in regulating the immune response. IRF4 binds DNA weakly owing to a carboxy-terminal auto-inhibitory domain, but cooperative binding with factors such as PU.1 or SPIB in B cells increases binding affinity, allowing IRF4 to regulate genes containing ETS-IRF composite elements (EICEs; 5'-GGAAnnGAAA-3'). Here we show that in mouse CD4(+) T cells, where PU.1/SPIB expression is low, and in B cells, where PU.1 is well expressed, IRF4 unexpectedly can cooperate with activator protein-1 (AP1) complexes to bind to AP1-IRF4 composite (5'-TGAnTCA/GAAA-3') motifs that we denote as AP1-IRF composite elements (AICEs). Moreover, BATF-JUN family protein complexes cooperate with IRF4 in binding to AICEs in pre-activated CD4(+) T cells stimulated with IL-21 and in T(H)17 differentiated cells. Importantly, BATF binding was diminished in Irf4(-/-) T cells and IRF4 binding was diminished in Batf(-/-) T cells, consistent with functional cooperation between these factors. Moreover, we show that AP1 and IRF complexes cooperatively promote transcription of the Il10 gene, which is expressed in T(H)17 cells and potently regulated by IL-21. These findings reveal that IRF4 can signal via complexes containing ETS or AP1 motifs depending on the cellular context, thus indicating new approaches for modulating IRF4-dependent transcription.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537508/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537508/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Peng -- Spolski, Rosanne -- Liao, Wei -- Wang, Lu -- Murphy, Theresa L -- Murphy, Kenneth M -- Leonard, Warren J -- ZIA HL005402-20/Intramural NIH HHS/ -- ZIA HL005402-21/Intramural NIH HHS/ -- ZIA HL005408-05/Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Oct 25;490(7421):543-6. doi: 10.1038/nature11530. Epub 2012 Sep 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1674, USA. lip3@nhlbi.nih.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22992523" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; B-Lymphocytes/metabolism ; Base Sequence ; Basic-Leucine Zipper Transcription Factors/deficiency/genetics/*metabolism ; Binding Sites ; CD4-Positive T-Lymphocytes/cytology/*metabolism ; Cell Differentiation ; Female ; Interferon Regulatory Factors/deficiency/genetics/*metabolism ; Interleukin-10/genetics ; Interleukins/immunology ; Lymphocyte Activation ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Nucleotide Motifs ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-jun/*metabolism ; Signal Transduction ; Th17 Cells/cytology/immunology ; Trans-Activators/metabolism ; Transcription Factor AP-1/metabolism ; *Transcription, Genetic ; Up-Regulation
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    Autoregulation of microRNA biogenesis by let-7 and Argonaute (2012)
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    Publication Date: 2012-06-23
    Description: MicroRNAs (miRNAs) comprise a large family of small RNA molecules that post-transcriptionally regulate gene expression in many biological pathways. Most miRNAs are derived from long primary transcripts that undergo processing by Drosha to produce ~65-nucleotide precursors that are then cleaved by Dicer, resulting in the mature 22-nucleotide forms. Serving as guides in Argonaute protein complexes, mature miRNAs use imperfect base pairing to recognize sequences in messenger RNA transcripts, leading to translational repression and destabilization of the target messenger RNAs. Here we show that the miRNA complex also targets and regulates non-coding RNAs that serve as substrates for the miRNA-processing pathway. We found that the Argonaute protein in Caenorhabditis elegans, ALG-1, binds to a specific site at the 3' end of let-7 miRNA primary transcripts and promotes downstream processing events. This interaction is mediated by mature let-7 miRNA through a conserved complementary site in its own primary transcript, thus creating a positive-feedback loop. We further show that ALG-1 associates with let-7 primary transcripts in nuclear fractions. Argonaute also binds let-7 primary transcripts in human cells, demonstrating that the miRNA pathway targets non-coding RNAs in addition to protein-coding messenger RNAs across species. Moreover, our studies in C. elegans reveal a novel role for Argonaute in promoting biogenesis of a targeted transcript, expanding the functions of the miRNA pathway in gene regulation. This discovery of autoregulation of let-7 biogenesis establishes a new mechanism for controlling miRNA expression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387326/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387326/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zisoulis, Dimitrios G -- Kai, Zoya S -- Chang, Roger K -- Pasquinelli, Amy E -- GM071654/GM/NIGMS NIH HHS/ -- R01 GM071654/GM/NIGMS NIH HHS/ -- R01 GM071654-09/GM/NIGMS NIH HHS/ -- T32 CA009523/CA/NCI NIH HHS/ -- England -- Nature. 2012 Jun 28;486(7404):541-4. doi: 10.1038/nature11134.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biology, University of California, San Diego, La Jolla, California 92093-0349, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722835" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Pairing ; Base Sequence ; Binding Sites ; Caenorhabditis elegans/classification/cytology/*genetics/*metabolism ; Caenorhabditis elegans Proteins/*metabolism ; Cell Nucleus/genetics/metabolism ; Feedback, Physiological ; *Gene Expression Regulation ; MicroRNAs/*biosynthesis/*genetics/metabolism ; Protein Binding ; RNA Processing, Post-Transcriptional ; RNA, Messenger/biosynthesis/genetics/metabolism ; RNA-Binding Proteins/*metabolism ; Transcription, Genetic
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    Spontaneous network formation among cooperative RNA replicators (2012)
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    Publication Date: 2012-10-19
    Description: The origins of life on Earth required the establishment of self-replicating chemical systems capable of maintaining and evolving biological information. In an RNA world, single self-replicating RNAs would have faced the extreme challenge of possessing a mutation rate low enough both to sustain their own information and to compete successfully against molecular parasites with limited evolvability. Thus theoretical analyses suggest that networks of interacting molecules were more likely to develop and sustain life-like behaviour. Here we show that mixtures of RNA fragments that self-assemble into self-replicating ribozymes spontaneously form cooperative catalytic cycles and networks. We find that a specific three-membered network has highly cooperative growth dynamics. When such cooperative networks are competed directly against selfish autocatalytic cycles, the former grow faster, indicating an intrinsic ability of RNA populations to evolve greater complexity through cooperation. We can observe the evolvability of networks through in vitro selection. Our experiments highlight the advantages of cooperative behaviour even at the molecular stages of nascent life.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vaidya, Nilesh -- Manapat, Michael L -- Chen, Irene A -- Xulvi-Brunet, Ramon -- Hayden, Eric J -- Lehman, Niles -- England -- Nature. 2012 Nov 1;491(7422):72-7. doi: 10.1038/nature11549. Epub 2012 Oct 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Portland State University, PO Box 751, Portland, Oregon 97207, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23075853" target="_blank"〉PubMed〈/a〉
    Keywords: Azoarcus/enzymology/genetics ; Base Pairing ; Base Sequence ; *Biocatalysis ; *Evolution, Chemical ; Introns/genetics ; *Models, Biological ; Models, Genetic ; Molecular Sequence Data ; *Origin of Life ; RNA, Catalytic/*biosynthesis/chemistry/genetics/*metabolism ; Recombinases/biosynthesis/chemistry/genetics/metabolism
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    Recurrent R-spondin fusions in colon cancer (2012)
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    Publication Date: 2012-08-17
    Description: Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690621/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690621/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seshagiri, Somasekar -- Stawiski, Eric W -- Durinck, Steffen -- Modrusan, Zora -- Storm, Elaine E -- Conboy, Caitlin B -- Chaudhuri, Subhra -- Guan, Yinghui -- Janakiraman, Vasantharajan -- Jaiswal, Bijay S -- Guillory, Joseph -- Ha, Connie -- Dijkgraaf, Gerrit J P -- Stinson, Jeremy -- Gnad, Florian -- Huntley, Melanie A -- Degenhardt, Jeremiah D -- Haverty, Peter M -- Bourgon, Richard -- Wang, Weiru -- Koeppen, Hartmut -- Gentleman, Robert -- Starr, Timothy K -- Zhang, Zemin -- Largaespada, David A -- Wu, Thomas D -- de Sauvage, Frederic J -- R00 CA151672/CA/NCI NIH HHS/ -- R01 CA134759/CA/NCI NIH HHS/ -- R01-CA134759/CA/NCI NIH HHS/ -- T32 CA009138/CA/NCI NIH HHS/ -- England -- Nature. 2012 Aug 30;488(7413):660-4. doi: 10.1038/nature11282.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA. sekar@gene.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22895193" target="_blank"〉PubMed〈/a〉
    Keywords: Ataxia Telangiectasia Mutated Proteins ; Base Sequence ; Cell Cycle Proteins/genetics ; Colonic Neoplasms/*genetics/metabolism/pathology ; DNA Copy Number Variations/genetics ; DNA-Binding Proteins/genetics ; Dioxygenases/genetics ; Exome/genetics ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/genetics ; Gene Fusion/*genetics ; Genes, APC ; Genes, Neoplasm/*genetics ; Humans ; Insulin-Like Growth Factor II/genetics ; Intercellular Signaling Peptides and Proteins/*genetics ; Molecular Sequence Data ; Mutation/genetics ; Polymorphism, Single Nucleotide/genetics ; Protein-Serine-Threonine Kinases/genetics ; Proto-Oncogene Proteins/genetics ; Receptor, ErbB-3/genetics ; Sequence Analysis, RNA ; Signal Transduction/genetics ; Thrombospondins/*genetics ; Transcription Factor 7-Like 2 Protein/genetics ; Tumor Suppressor Proteins/genetics ; Wnt Proteins/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    A PPARgamma-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-04-24
    Description: Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood. Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPARgamma (peroxisome proliferator activated receptor gamma), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs. FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes. Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions. We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPARgamma acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARgamma-FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358516/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358516/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jonker, Johan W -- Suh, Jae Myoung -- Atkins, Annette R -- Ahmadian, Maryam -- Li, Pingping -- Whyte, Jamie -- He, Mingxiao -- Juguilon, Henry -- Yin, Yun-Qiang -- Phillips, Colin T -- Yu, Ruth T -- Olefsky, Jerrold M -- Henry, Robert R -- Downes, Michael -- Evans, Ronald M -- DK057978/DK/NIDDK NIH HHS/ -- DK062434/DK/NIDDK NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK090962/DK/NIDDK NIH HHS/ -- HL105278/HL/NHLBI NIH HHS/ -- P30 CA014195/CA/NCI NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- R01 DK033651/DK/NIDDK NIH HHS/ -- R01 HL105278/HL/NHLBI NIH HHS/ -- R01 HL105278-21/HL/NHLBI NIH HHS/ -- R24 DK090962/DK/NIDDK NIH HHS/ -- R24 DK090962-02/DK/NIDDK NIH HHS/ -- R37 DK033651/DK/NIDDK NIH HHS/ -- R37 DK057978/DK/NIDDK NIH HHS/ -- R37 DK057978-34/DK/NIDDK NIH HHS/ -- U19 DK062434/DK/NIDDK NIH HHS/ -- U19 DK062434-10/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 17;485(7398):391-4. doi: 10.1038/nature10998.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22522926" target="_blank"〉PubMed〈/a〉
    Keywords: Adipocytes/drug effects/metabolism/pathology ; Animals ; Base Sequence ; Cell Size/drug effects ; Diabetes Mellitus, Experimental/chemically induced/genetics/pathology ; Diet, High-Fat/adverse effects ; Fibroblast Growth Factor 1/deficiency/*genetics/*metabolism ; *Homeostasis/drug effects ; Humans ; Inflammation/genetics ; Insulin/metabolism ; Insulin Resistance ; Intra-Abdominal Fat/drug effects/*metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Necrosis/enzymology ; PPAR gamma/*metabolism ; Promoter Regions, Genetic/genetics ; Response Elements/genetics
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Structural basis for RNA-duplex recognition and unwinding by the DEAD-box helicase Mss116p (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-09-04
    Description: DEAD-box proteins are the largest family of nucleic acid helicases, and are crucial to RNA metabolism throughout all domains of life. They contain a conserved 'helicase core' of two RecA-like domains (domains (D)1 and D2), which uses ATP to catalyse the unwinding of short RNA duplexes by non-processive, local strand separation. This mode of action differs from that of translocating helicases and allows DEAD-box proteins to remodel large RNAs and RNA-protein complexes without globally disrupting RNA structure. However, the structural basis for this distinctive mode of RNA unwinding remains unclear. Here, structural, biochemical and genetic analyses of the yeast DEAD-box protein Mss116p indicate that the helicase core domains have modular functions that enable a novel mechanism for RNA-duplex recognition and unwinding. By investigating D1 and D2 individually and together, we find that D1 acts as an ATP-binding domain and D2 functions as an RNA-duplex recognition domain. D2 contains a nucleic-acid-binding pocket that is formed by conserved DEAD-box protein sequence motifs and accommodates A-form but not B-form duplexes, providing a basis for RNA substrate specificity. Upon a conformational change in which the two core domains join to form a 'closed state' with an ATPase active site, conserved motifs in D1 promote the unwinding of duplex substrates bound to D2 by excluding one RNA strand and bending the other. Our results provide a comprehensive structural model for how DEAD-box proteins recognize and unwind RNA duplexes. This model explains key features of DEAD-box protein function and affords a new perspective on how the evolutionarily related cores of other RNA and DNA helicases diverged to use different mechanisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465527/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465527/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mallam, Anna L -- Del Campo, Mark -- Gilman, Benjamin -- Sidote, David J -- Lambowitz, Alan M -- GM037951/GM/NIGMS NIH HHS/ -- R01 GM037951/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Oct 4;490(7418):121-5. doi: 10.1038/nature11402. Epub 2012 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cellular and Molecular Biology, Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22940866" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/chemistry/metabolism ; Adenosine Triphosphate/metabolism ; Amino Acid Motifs ; Base Sequence ; Catalytic Domain ; Conserved Sequence ; Crystallography, X-Ray ; DEAD-box RNA Helicases/*chemistry/*metabolism ; Evolution, Molecular ; GC Rich Sequence/genetics ; Models, Molecular ; *Nucleic Acid Conformation ; Protein Structure, Tertiary ; RNA, Double-Stranded/*chemistry/genetics/*metabolism ; RNA-Binding Proteins/chemistry/metabolism ; Saccharomyces cerevisiae/*enzymology ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism ; Structure-Activity Relationship ; Substrate Specificity
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Functional complexity and regulation through RNA dynamics (2012)
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    Publication Date: 2012-02-18
    Description: Changes to the conformation of coding and non-coding RNAs form the basis of elements of genetic regulation and provide an important source of complexity, which drives many of the fundamental processes of life. Although the structure of RNA is highly flexible, the underlying dynamics of RNA are robust and are limited to transitions between the few conformations that preserve favourable base-pairing and stacking interactions. The mechanisms by which cellular processes harness the intrinsic dynamic behaviour of RNA and use it within functionally productive pathways are complex. The versatile functions and ease by which it is integrated into a wide variety of genetic circuits and biochemical pathways suggests there is a general and fundamental role for RNA dynamics in cellular processes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320162/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320162/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dethoff, Elizabeth A -- Chugh, Jeetender -- Mustoe, Anthony M -- Al-Hashimi, Hashim M -- R01 AI066975/AI/NIAID NIH HHS/ -- R01 AI066975-07/AI/NIAID NIH HHS/ -- R01 GM089846/GM/NIGMS NIH HHS/ -- R01 GM089846-03/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Feb 15;482(7385):322-30. doi: 10.1038/nature10885.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Biophysics, The University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1055, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22337051" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Models, Molecular ; Molecular Chaperones/metabolism ; Nucleic Acid Conformation ; RNA/*chemistry/genetics/*metabolism ; RNA Helicases/metabolism ; RNA, Untranslated/chemistry/genetics/metabolism ; Thermodynamics
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Cis-regulatory control of corticospinal system development and evolution (2012)
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    Publication Date: 2012-06-09
    Description: The co-emergence of a six-layered cerebral neocortex and its corticospinal output system is one of the evolutionary hallmarks of mammals. However, the genetic programs that underlie their development and evolution remain poorly understood. Here we identify a conserved non-exonic element (E4) that acts as a cortex-specific enhancer for the nearby gene Fezf2 (also known as Fezl and Zfp312), which is required for the specification of corticospinal neuron identity and connectivity. We find that SOX4 and SOX11 functionally compete with the repressor SOX5 in the transactivation of E4. Cortex-specific double deletion of Sox4 and Sox11 leads to the loss of Fezf2 expression, failed specification of corticospinal neurons and, independent of Fezf2, a reeler-like inversion of layers. We show evidence supporting the emergence of functional SOX-binding sites in E4 during tetrapod evolution, and their subsequent stabilization in mammals and possibly amniotes. These findings reveal that SOX transcription factors converge onto a cis-acting element of Fezf2 and form critical components of a regulatory network controlling the identity and connectivity of corticospinal neurons.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375921/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375921/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shim, Sungbo -- Kwan, Kenneth Y -- Li, Mingfeng -- Lefebvre, Veronique -- Sestan, Nenad -- AR54153/AR/NIAMS NIH HHS/ -- MH081896/MH/NIMH NIH HHS/ -- NS054273/NS/NINDS NIH HHS/ -- R01 AR054153/AR/NIAMS NIH HHS/ -- R01 HD045481/HD/NICHD NIH HHS/ -- R01 HD045481-05/HD/NICHD NIH HHS/ -- R01 NS054273/NS/NINDS NIH HHS/ -- R01 NS054273-08/NS/NINDS NIH HHS/ -- U01 MH081896/MH/NIMH NIH HHS/ -- U01 MH081896-04/MH/NIMH NIH HHS/ -- England -- Nature. 2012 May 30;486(7401):74-9. doi: 10.1038/nature11094.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22678282" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Axons/metabolism ; Base Sequence ; Binding Sites ; DNA-Binding Proteins/genetics ; Enhancer Elements, Genetic/*genetics ; *Evolution, Molecular ; Gene Expression Regulation, Developmental/*genetics ; Genetic Variation/genetics ; Mice ; Mice, Knockout ; Mice, Transgenic ; Molecular Sequence Data ; Neocortex/cytology/*embryology/*metabolism ; Nerve Tissue Proteins/genetics ; Organ Specificity ; SOXC Transcription Factors/metabolism ; Spinal Cord/cytology/*embryology/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Rational enthusiasm (2011)
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    Publication Date: 2011-10-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lehn, Jean-Marie -- England -- Nature. 2011 Oct 12;478(7368):S8-9. doi: 10.1038/478S8a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21993827" target="_blank"〉PubMed〈/a〉
    Keywords: Chemistry ; Exobiology ; Hippocratic Oath ; Knowledge ; Motivation ; *Nobel Prize ; *Research Personnel/ethics/psychology/standards
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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