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  • 1
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    Long-range oncogenic activation of Igh-c-myc translocations by the Igh 3' regulatory region (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-12-17
    Description: B-cell malignancies, such as human Burkitt's lymphoma, often contain translocations that link c-myc or other proto-oncogenes to the immunoglobulin heavy chain locus (IgH, encoded by Igh). The nature of elements that activate oncogenes within such translocations has been a long-standing question. Translocations within Igh involve DNA double-strand breaks initiated either by the RAG1/2 endonuclease during variable, diversity and joining gene segment (V(D)J) recombination, or by activation-induced cytidine deaminase (AID, also known as AICDA) during class switch recombination (CSR). V(D)J recombination in progenitor B (pro-B) cells assembles Igh variable region exons upstream of mu constant region (Cmu) exons, which are the first of several sets of C(H) exons ('C(H) genes') within a C(H) locus that span several hundred kilobases (kb). In mature B cells, CSR deletes Cmu and replaces it with a downstream C(H) gene. An intronic enhancer (iEmu) between the variable region exons and Cmu promotes V(D)J recombination in developing B cells. Furthermore, the Igh 3' regulatory region (Igh3'RR) lies downstream of the C(H) locus and modulates CSR by long-range transcriptional enhancement of C(H) genes. Transgenic mice bearing iEmu or Igh3'RR sequences fused to c-myc are predisposed to B lymphomas, demonstrating that such elements can confer oncogenic c-myc expression. However, in many B-cell lymphomas, Igh-c-myc translocations delete iEmu and place c-myc up to 200 kb upstream of the Igh3'RR. Here we address the oncogenic role of the Igh3'RR by inactivating it in two distinct mouse models for B-cell lymphoma with Igh-c-myc translocations. We show that the Igh3'RR is dispensable for pro-B-cell lymphomas with V(D)J recombination-initiated translocations, but is required for peripheral B-cell lymphomas with CSR-associated translocations. As the Igh3'RR is not required for CSR-associated Igh breaks or Igh-c-myc translocations in peripheral B-cell lymphoma progenitors, we conclude that this regulatory region confers oncogenic activity by long-range and developmental stage-specific activation of translocated c-myc genes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802177/" 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/PMC2802177/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gostissa, Monica -- Yan, Catherine T -- Bianco, Julia M -- Cogne, Michel -- Pinaud, Eric -- Alt, Frederick W -- CA92625/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Dec 10;462(7274):803-7. doi: 10.1038/nature08633.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20010689" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions/*genetics ; Alleles ; Animals ; Cells, Cultured ; Chromosome Breakpoints ; Gene Rearrangement, B-Lymphocyte/*genetics ; Genes, Immunoglobulin Heavy Chain/*genetics ; Genes, myc/*genetics ; Immunoglobulin Class Switching/genetics ; Lymphoma, B-Cell/*genetics/pathology ; Mice ; Mice, Transgenic ; Regulatory Sequences, Nucleic Acid/*genetics ; Translocation, Genetic/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Mechanisms promoting translocations in editing and switching peripheral B cells (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-07-10
    Description: Variable, diversity and joining gene segment (V(D)J) recombination assembles immunoglobulin heavy or light chain (IgH or IgL) variable region exons in developing bone marrow B cells, whereas class switch recombination (CSR) exchanges IgH constant region exons in peripheral B cells. Both processes use directed DNA double-strand breaks (DSBs) repaired by non-homologous end-joining (NHEJ). Errors in either V(D)J recombination or CSR can initiate chromosomal translocations, including oncogenic IgH locus (Igh) to c-myc (also known as Myc) translocations of peripheral B cell lymphomas. Collaboration between these processes has also been proposed to initiate translocations. However, the occurrence of V(D)J recombination in peripheral B cells is controversial. Here we show that activated NHEJ-deficient splenic B cells accumulate V(D)J-recombination-associated breaks at the lambda IgL locus (Igl), as well as CSR-associated Igh breaks, often in the same cell. Moreover, Igl and Igh breaks are frequently joined to form translocations, a phenomenon associated with specific Igh-Igl co-localization. Igh and c-myc also co-localize in these cells; correspondingly, the introduction of frequent c-myc DSBs robustly promotes Igh-c-myc translocations. Our studies show peripheral B cells that attempt secondary V(D)J recombination, and determine a role for mechanistic factors in promoting recurrent translocations in tumours.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907259/" 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/PMC2907259/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Jing H -- Gostissa, Monica -- Yan, Catherine T -- Goff, Peter -- Hickernell, Thomas -- Hansen, Erica -- Difilippantonio, Simone -- Wesemann, Duane R -- Zarrin, Ali A -- Rajewsky, Klaus -- Nussenzweig, Andre -- Alt, Frederick W -- 5P01CA92625/CA/NCI NIH HHS/ -- P01 CA092625/CA/NCI NIH HHS/ -- P01 CA092625-010001/CA/NCI NIH HHS/ -- P01 CA092625-020001/CA/NCI NIH HHS/ -- P01 CA092625-060006/CA/NCI NIH HHS/ -- P01 CA092625-070006/CA/NCI NIH HHS/ -- P01 CA092625-080006/CA/NCI NIH HHS/ -- P01 CA092625-090006/CA/NCI NIH HHS/ -- R01 AI077595/AI/NIAID NIH HHS/ -- R01 AI077595-02/AI/NIAID NIH HHS/ -- T32 CA009382/CA/NCI NIH HHS/ -- T32 CA009382-27/CA/NCI NIH HHS/ -- T32 CA009382-28/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2009 Jul 9;460(7252):231-6. doi: 10.1038/nature08159.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19587764" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/*metabolism ; Cytidine Deaminase/deficiency/genetics/metabolism ; DNA Breaks, Double-Stranded ; DNA-Binding Proteins/deficiency/metabolism ; Female ; Gene Rearrangement, B-Lymphocyte/*genetics ; Genes, Immunoglobulin/*genetics ; Genes, myc/genetics ; Homeodomain Proteins/metabolism ; Immunoglobulin Class Switching/*genetics ; Immunoglobulin Heavy Chains/genetics ; Immunoglobulin kappa-Chains/genetics ; Immunoglobulin lambda-Chains/genetics ; Integrases/genetics/metabolism ; Interphase ; Lymphocyte Activation ; Male ; Mice ; Receptors, Complement 3d/genetics ; Recombination, Genetic/genetics ; Spleen/cytology/immunology ; Translocation, Genetic/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-03-06
    Description: Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins. Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841477/" 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/PMC2841477/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hirschey, Matthew D -- Shimazu, Tadahiro -- Goetzman, Eric -- Jing, Enxuan -- Schwer, Bjoern -- Lombard, David B -- Grueter, Carrie A -- Harris, Charles -- Biddinger, Sudha -- Ilkayeva, Olga R -- Stevens, Robert D -- Li, Yu -- Saha, Asish K -- Ruderman, Neil B -- Bain, James R -- Newgard, Christopher B -- Farese, Robert V Jr -- Alt, Frederick W -- Kahn, C Ronald -- Verdin, Eric -- DK019514-29/DK/NIDDK NIH HHS/ -- DK59637/DK/NIDDK NIH HHS/ -- K01 DK076573/DK/NIDDK NIH HHS/ -- K08 AG022325/AG/NIA NIH HHS/ -- K08 AG022325-01A1/AG/NIA NIH HHS/ -- P01 HL068758/HL/NHLBI NIH HHS/ -- P01 HL068758-06A1/HL/NHLBI NIH HHS/ -- P30 DK026743/DK/NIDDK NIH HHS/ -- P30 DK026743-26A1/DK/NIDDK NIH HHS/ -- R01 DK019514/DK/NIDDK NIH HHS/ -- R01 DK019514-29/DK/NIDDK NIH HHS/ -- R01 DK067509/DK/NIDDK NIH HHS/ -- R01 DK067509-04/DK/NIDDK NIH HHS/ -- U24 DK059637/DK/NIDDK NIH HHS/ -- U24 DK059637-01/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Mar 4;464(7285):121-5. doi: 10.1038/nature08778.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gladstone Institute of Virology and Immunology, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20203611" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Acyl-CoA Dehydrogenase, Long-Chain/chemistry/*metabolism ; Adenosine Triphosphate/biosynthesis/metabolism ; Adipose Tissue, Brown/enzymology/metabolism ; Animals ; Body Temperature Regulation ; Caloric Restriction ; Carnitine/analogs & derivatives/metabolism ; Cell Line ; Cold Temperature ; Fasting/metabolism ; Fatty Acids/*metabolism ; Humans ; Hypoglycemia/metabolism ; Liver/enzymology/metabolism ; Male ; Mass Spectrometry ; Mice ; Mitochondria/*enzymology/*metabolism ; Oxidation-Reduction ; Sirtuin 3/deficiency/genetics/*metabolism ; Triglycerides/metabolism ; Up-Regulation
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Orientation-specific joining of AID-initiated DNA breaks promotes antibody class switching (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-08-27
    Description: During B-cell development, RAG endonuclease cleaves immunoglobulin heavy chain (IgH) V, D, and J gene segments and orchestrates their fusion as deletional events that assemble a V(D)J exon in the same transcriptional orientation as adjacent Cmu constant region exons. In mice, six additional sets of constant region exons (CHs) lie 100-200 kilobases downstream in the same transcriptional orientation as V(D)J and Cmu exons. Long repetitive switch (S) regions precede Cmu and downstream CHs. In mature B cells, class switch recombination (CSR) generates different antibody classes by replacing Cmu with a downstream CH (ref. 2). Activation-induced cytidine deaminase (AID) initiates CSR by promoting deamination lesions within Smu and a downstream acceptor S region; these lesions are converted into DNA double-strand breaks (DSBs) by general DNA repair factors. Productive CSR must occur in a deletional orientation by joining the upstream end of an Smu DSB to the downstream end of an acceptor S-region DSB. However, the relative frequency of deletional to inversional CSR junctions has not been measured. Thus, whether orientation-specific joining is a programmed mechanistic feature of CSR as it is for V(D)J recombination and, if so, how this is achieved is unknown. To address this question, we adapt high-throughput genome-wide translocation sequencing into a highly sensitive DSB end-joining assay and apply it to endogenous AID-initiated S-region DSBs in mouse B cells. We show that CSR is programmed to occur in a productive deletional orientation and does so via an unprecedented mechanism that involves in cis Igh organizational features in combination with frequent S-region DSBs initiated by AID. We further implicate ATM-dependent DSB-response factors in enforcing this mechanism and provide an explanation of why CSR is so reliant on the 53BP1 DSB-response factor.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592165/" 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/PMC4592165/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dong, Junchao -- Panchakshari, Rohit A -- Zhang, Tingting -- Zhang, Yu -- Hu, Jiazhi -- Volpi, Sabrina A -- Meyers, Robin M -- Ho, Yu-Jui -- Du, Zhou -- Robbiani, Davide F -- Meng, Feilong -- Gostissa, Monica -- Nussenzweig, Michel C -- Manis, John P -- Alt, Frederick W -- AI037526/AI/NIAID NIH HHS/ -- AI072529/AI/NIAID NIH HHS/ -- AI077595/AI/NIAID NIH HHS/ -- AI112602/AI/NIAID NIH HHS/ -- CA133781/CA/NCI NIH HHS/ -- R01 AI077595/AI/NIAID NIH HHS/ -- R21 AI088510/AI/NIAID NIH HHS/ -- R21 CA133781/CA/NCI NIH HHS/ -- T32HL066987/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Sep 3;525(7567):134-9. doi: 10.1038/nature14970. Epub 2015 Aug 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Boston Children's Hospital and Joint Program in Transfusion Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Howard Hughes Medical Institute, Laboratory of Molecular Immunology, 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/26308889" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Ataxia Telangiectasia Mutated Proteins/metabolism ; B-Lymphocytes/enzymology/immunology/*metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Cytidine Deaminase/*metabolism ; *DNA Breaks, Double-Stranded ; DNA Repair/*genetics ; DNA-Binding Proteins/metabolism ; Deamination ; Immunoglobulin Class Switching/*genetics ; Immunoglobulin Constant Regions/*genetics ; Immunoglobulin Heavy Chains/*genetics ; Mice ; Sequence Deletion/genetics ; VDJ Exons/genetics
    Print ISSN: 0028-0836
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  • 5
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    ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-12-17
    Description: Classical non-homologous DNA end-joining (NHEJ) is a major mammalian DNA double-strand-break (DSB) repair pathway. Deficiencies for classical NHEJ factors, such as XRCC4, abrogate lymphocyte development, owing to a strict requirement for classical NHEJ to join V(D)J recombination DSB intermediates. The XRCC4-like factor (XLF; also called NHEJ1) is mutated in certain immunodeficient human patients and has been implicated in classical NHEJ; however, XLF-deficient mice have relatively normal lymphocyte development and their lymphocytes support normal V(D)J recombination. The ataxia telangiectasia-mutated protein (ATM) detects DSBs and activates DSB responses by phosphorylating substrates including histone H2AX. However, ATM deficiency causes only modest V(D)J recombination and lymphocyte developmental defects, and H2AX deficiency does not have a measurable impact on these processes. Here we show that XLF, ATM and H2AX all have fundamental roles in processing and joining DNA ends during V(D)J recombination, but that these roles have been masked by unanticipated functional redundancies. Thus, combined deficiency of ATM and XLF nearly blocks mouse lymphocyte development due to an inability to process and join chromosomal V(D)J recombination DSB intermediates. Combined XLF and ATM deficiency also severely impairs classical NHEJ, but not alternative end-joining, during IgH class switch recombination. Redundant ATM and XLF functions in classical NHEJ are mediated by ATM kinase activity and are not required for extra-chromosomal V(D)J recombination, indicating a role for chromatin-associated ATM substrates. Correspondingly, conditional H2AX inactivation in XLF-deficient pro-B lines leads to V(D)J recombination defects associated with marked degradation of unjoined V(D)J ends, revealing that H2AX has a role in this process.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058373/" 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/PMC3058373/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zha, Shan -- Guo, Chunguang -- Boboila, Cristian -- Oksenych, Valentyn -- Cheng, Hwei-Ling -- Zhang, Yu -- Wesemann, Duane R -- Yuen, Grace -- Patel, Harin -- Goff, Peter H -- Dubois, Richard L -- Alt, Frederick W -- AI007376/AI/NIAID NIH HHS/ -- AI020047/AI/NIAID NIH HHS/ -- AI076210/AI/NIAID NIH HHS/ -- K08 AI089972/AI/NIAID NIH HHS/ -- K08 AI089972-01/AI/NIAID NIH HHS/ -- P01 AI076210/AI/NIAID NIH HHS/ -- P01 AI076210-03/AI/NIAID NIH HHS/ -- R01 AI020047/AI/NIAID NIH HHS/ -- R01 AI020047-28/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jan 13;469(7329):250-4. doi: 10.1038/nature09604. Epub 2010 Dec 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, The Children's Hospital, the Immune Disease Institute and the Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21160472" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/*metabolism ; Cell Line, Transformed ; Chromatin/metabolism ; Chromosomes, Mammalian/genetics/metabolism ; *DNA Breaks, Double-Stranded ; *DNA Repair ; DNA-Binding Proteins/deficiency/genetics/*metabolism ; Embryo, Mammalian/embryology/metabolism ; *Gene Rearrangement, B-Lymphocyte/genetics ; Histones/*metabolism ; Mice ; Precursor Cells, B-Lymphoid/cytology/metabolism ; Protein-Serine-Threonine Kinases/deficiency/genetics/*metabolism ; *Recombination, Genetic ; Tumor Suppressor Proteins/deficiency/genetics/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    CTCF-binding elements mediate control of V(D)J recombination (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-09-13
    Description: Immunoglobulin heavy chain (IgH) variable region exons are assembled from V(H), D and J(H) gene segments in developing B lymphocytes. Within the 2.7-megabase mouse Igh locus, V(D)J recombination is regulated to ensure specific and diverse antibody repertoires. Here we report in mice a key Igh V(D)J recombination regulatory region, termed intergenic control region 1 (IGCR1), which lies between the V(H) and D clusters. Functionally, IGCR1 uses CTCF looping/insulator factor-binding elements and, correspondingly, mediates Igh loops containing distant enhancers. IGCR1 promotes normal B-cell development and balances antibody repertoires by inhibiting transcription and rearrangement of D(H)-proximal V(H) gene segments and promoting rearrangement of distal V(H) segments. IGCR1 maintains ordered and lineage-specific V(H)(D)J(H) recombination by suppressing V(H) joining to D segments not joined to J(H) segments, and V(H) to DJ(H) joins in thymocytes, respectively. IGCR1 is also required for feedback regulation and allelic exclusion of proximal V(H)-to-DJ(H) recombination. Our studies elucidate a long-sought Igh V(D)J recombination control region and indicate a new role for the generally expressed CTCF protein.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342812/" 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/PMC3342812/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Chunguang -- Yoon, Hye Suk -- Franklin, Andrew -- Jain, Suvi -- Ebert, Anja -- Cheng, Hwei-Ling -- Hansen, Erica -- Despo, Orion -- Bossen, Claudia -- Vettermann, Christian -- Bates, Jamie G -- Richards, Nicholas -- Myers, Darienne -- Patel, Harin -- Gallagher, Michael -- Schlissel, Mark S -- Murre, Cornelis -- Busslinger, Meinrad -- Giallourakis, Cosmas C -- Alt, Frederick W -- AI40227/AI/NIAID NIH HHS/ -- CA054198-20/CA/NCI NIH HHS/ -- K08 AI070839/AI/NIAID NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- R01 AI020047/AI/NIAID NIH HHS/ -- R01 AI020047-27/AI/NIAID NIH HHS/ -- R01 AI020047-28/AI/NIAID NIH HHS/ -- R01 AI020047-29/AI/NIAID NIH HHS/ -- R01 AI20047/AI/NIAID NIH HHS/ -- R01 HL48702/HL/NHLBI NIH HHS/ -- R37 AI040227/AI/NIAID NIH HHS/ -- T32 CA009151/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Sep 11;477(7365):424-30. doi: 10.1038/nature10495.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, The Children's Hospital, The Immune Disease Institute, Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21909113" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/cytology/metabolism ; Cell Lineage/genetics ; Chromosomes, Mammalian/genetics/metabolism ; DNA, Intergenic/*genetics ; Enhancer Elements, Genetic/genetics ; Feedback, Physiological ; Gene Rearrangement, B-Lymphocyte, Heavy Chain/*genetics ; Germ Cells/metabolism ; Immunoglobulin Heavy Chains/genetics ; Immunoglobulin Variable Region/genetics ; Mice ; Mutation/genetics ; Recombination, Genetic/*genetics ; Regulatory Sequences, Nucleic Acid/*genetics ; Repressor Proteins/*metabolism ; Thymus Gland/cytology ; Transcription, Genetic/genetics ; VDJ Exons/*genetics
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  • 7
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    Microbial colonization influences early B-lineage development in the gut lamina propria (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-08-24
    Description: The RAG1/RAG2 endonuclease (RAG) initiates the V(D)J recombination reaction that assembles immunoglobulin heavy (IgH) and light (IgL) chain variable region exons from germline gene segments to generate primary antibody repertoires. IgH V(D)J assembly occurs in progenitor (pro-) B cells followed by that of IgL in precursor (pre-) B cells. Expression of IgH mu and IgL (Igkappa or Iglambda) chains generates IgM, which is expressed on immature B cells as the B-cell antigen-binding receptor (BCR). Rag expression can continue in immature B cells, allowing continued Igkappa V(D)J recombination that replaces the initial VkappaJkappa exon with one that generates a new specificity. This 'receptor editing' process, which can also lead to Iglambda V(D)J recombination and expression, provides a mechanism whereby antigen encounter at the Rag-expressing immature B-cell stage helps shape pre-immune BCR repertoires. As the major site of postnatal B-cell development, the bone marrow is the principal location of primary immunoglobulin repertoire diversification in mice. Here we report that early B-cell development also occurs within the mouse intestinal lamina propria (LP), where the associated V(D)J recombination/receptor editing processes modulate primary LP immunoglobulin repertoires. At weanling age in normally housed mice, the LP contains a population of Rag-expressing B-lineage cells that harbour intermediates indicative of ongoing V(D)J recombination and which contain cells with pro-B, pre-B and editing phenotypes. Consistent with LP-specific receptor editing, Rag-expressing LP B-lineage cells have similar VH repertoires, but significantly different Vkappa repertoires, compared to those of Rag2-expressing bone marrow counterparts. Moreover, colonization of germ-free mice leads to an increased ratio of Iglambda-expressing versus Igkappa-expressing B cells specifically in the LP. We conclude that B-cell development occurs in the intestinal mucosa, where it is regulated by extracellular signals from commensal microbes that influence gut immunoglobulin repertoires.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807868/" 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/PMC3807868/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wesemann, Duane R -- Portuguese, Andrew J -- Meyers, Robin M -- Gallagher, Michael P -- Cluff-Jones, Kendra -- Magee, Jennifer M -- Panchakshari, Rohit A -- Rodig, Scott J -- Kepler, Thomas B -- Alt, Frederick W -- AI020047/AI/NIAID NIH HHS/ -- AI89972/AI/NIAID NIH HHS/ -- HHSN272201000053C/PHS HHS/ -- K08 AI089972/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Sep 5;501(7465):112-5. doi: 10.1038/nature12496. Epub 2013 Aug 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Cellular and Molecular Medicine and Department of Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA. dwesemann@research.bwh.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23965619" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/*cytology/*immunology/metabolism ; Bone Marrow Cells/cytology/immunology ; *Cell Lineage ; DNA-Binding Proteins/genetics/metabolism ; Gene Rearrangement, B-Lymphocyte/genetics ; Germ-Free Life ; Immunoglobulins/genetics/immunology ; Intestinal Mucosa/*cytology/*immunology ; Mice ; Precursor Cells, B-Lymphoid/cytology/metabolism ; Symbiosis ; Weaning
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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    Antigen-specific B-cell receptor sensitizes B cells to infection by influenza virus (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-10-22
    Description: Influenza A virus-specific B lymphocytes and the antibodies they produce protect against infection. However, the outcome of interactions between an influenza haemagglutinin-specific B cell via its receptor (BCR) and virus is unclear. Through somatic cell nuclear transfer we generated mice that harbour B cells with a BCR specific for the haemagglutinin of influenza A/WSN/33 virus (FluBI mice). Their B cells secrete an immunoglobulin gamma 2b that neutralizes infectious virus. Whereas B cells from FluBI and control mice bind equivalent amounts of virus through interaction of haemagglutinin with surface-disposed sialic acids, the A/WSN/33 virus infects only the haemagglutinin-specific B cells. Mere binding of virus is not sufficient for infection of B cells: this requires interactions of the BCR with haemagglutinin, causing both disruption of antibody secretion and FluBI B-cell death within 18 h. In mice infected with A/WSN/33, lung-resident FluBI B cells are infected by the virus, thus delaying the onset of protective antibody release into the lungs, whereas FluBI cells in the draining lymph node are not infected and proliferate. We propose that influenza targets and kills influenza-specific B cells in the lung, thus allowing the virus to gain purchase before the initiation of an effective adaptive response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863936/" 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/PMC3863936/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dougan, Stephanie K -- Ashour, Joseph -- Karssemeijer, Roos A -- Popp, Maximilian W -- Avalos, Ana M -- Barisa, Marta -- Altenburg, Arwen F -- Ingram, Jessica R -- Cragnolini, Juan Jose -- Guo, Chunguang -- Alt, Frederick W -- Jaenisch, Rudolf -- Ploegh, Hidde L -- DP1 GM106409/GM/NIGMS NIH HHS/ -- R01 AI033456/AI/NIAID NIH HHS/ -- R01 AI087879/AI/NIAID NIH HHS/ -- R01 GM100518/GM/NIGMS NIH HHS/ -- R01 HD045022/HD/NICHD NIH HHS/ -- R37 HD045022/HD/NICHD NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 21;503(7476):406-9. doi: 10.1038/nature12637. Epub 2013 Oct 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24141948" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies/immunology/metabolism ; Antibody Specificity/immunology ; B-Lymphocytes/*immunology/pathology/secretion/*virology ; Cell Death ; Female ; Hemagglutinin Glycoproteins, Influenza Virus/immunology/metabolism ; Immunoglobulin G/immunology/metabolism ; Lung/cytology/immunology/secretion/virology ; Lymph Nodes/cytology/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Neutralization Tests ; Nuclear Transfer Techniques ; Orthomyxoviridae/pathogenicity/*physiology ; Receptors, Antigen, B-Cell/*immunology/metabolism ; Virus Replication
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 9
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    The NAD-dependent deacetylase SIRT2 is required for programmed necrosis (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-12-04
    Description: Although initially viewed as unregulated, increasing evidence suggests that cellular necrosis often proceeds through a specific molecular program. In particular, death ligands such as tumour necrosis factor (TNF)-alpha activate necrosis by stimulating the formation of a complex containing receptor-interacting protein 1 (RIP1) and receptor-interacting protein 3 (RIP3). Relatively little is known regarding how this complex formation is regulated. Here, we show that the NAD-dependent deacetylase SIRT2 binds constitutively to RIP3 and that deletion or knockdown of SIRT2 prevents formation of the RIP1-RIP3 complex in mice. Furthermore, genetic or pharmacological inhibition of SIRT2 blocks cellular necrosis induced by TNF-alpha. We further demonstrate that RIP1 is a critical target of SIRT2-dependent deacetylation. Using gain- and loss-of-function mutants, we demonstrate that acetylation of RIP1 lysine 530 modulates RIP1-RIP3 complex formation and TNF-alpha-stimulated necrosis. In the setting of ischaemia-reperfusion injury, RIP1 is deacetylated in a SIRT2-dependent fashion. Furthermore, the hearts of Sirt2(-/-) mice, or wild-type mice treated with a specific pharmacological inhibitor of SIRT2, show marked protection from ischaemic injury. Taken together, these results implicate SIRT2 as an important regulator of programmed necrosis and indicate that inhibitors of this deacetylase may constitute a novel approach to protect against necrotic injuries, including ischaemic stroke and myocardial infarction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Narayan, Nisha -- Lee, In Hye -- Borenstein, Ronen -- Sun, Junhui -- Wong, Renee -- Tong, Guang -- Fergusson, Maria M -- Liu, Jie -- Rovira, Ilsa I -- Cheng, Hwei-Ling -- Wang, Guanghui -- Gucek, Marjan -- Lombard, David -- Alt, Fredrick W -- Sack, Michael N -- Murphy, Elizabeth -- Cao, Liu -- Finkel, Toren -- Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Dec 13;492(7428):199-204. doi: 10.1038/nature11700. Epub 2012 Nov 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23201684" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Cell Line ; Female ; HEK293 Cells ; HeLa Cells ; Humans ; Jurkat Cells ; Male ; Mice ; Necrosis/*enzymology ; Nuclear Pore Complex Proteins/metabolism ; Protein Binding ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Sirtuin 2/*genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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