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  • 1
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    The key protein of endosomal mRNP transport Rrm4 binds translational landmark sites of cargo mRNAs (2018)
    Springer Nature
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    Publikationsdatum: 2018
    Beschreibung: Grp1 is a novel accessory component of endosomal mRNA transport and binds preferentially in the 3′ UTR of target mRNAs conjointly with Rrm4. Rrm4 binds distinct targets at landmark sites of translation, suggesting a link between transport and translational regulation. Abstract RNA‐binding proteins (RBPs) determine spatiotemporal gene expression by mediating active transport and local translation of cargo mRNAs. Here, we cast a transcriptome‐wide view on the transported mRNAs and cognate RBP binding sites during endosomal messenger ribonucleoprotein (mRNP) transport in Ustilago maydis. Using individual‐nucleotide resolution UV crosslinking and immunoprecipitation (iCLIP), we compare the key transport RBP Rrm4 and the newly identified endosomal mRNP component Grp1 that is crucial to coordinate hyphal growth. Both RBPs bind predominantly in the 3′ untranslated region of thousands of shared cargo mRNAs, often in close proximity. Intriguingly, Rrm4 precisely binds at stop codons, which constitute landmark sites of translation, suggesting an intimate connection of mRNA transport and translation. Towards uncovering the code of recognition, we identify UAUG as specific binding motif of Rrm4 that is bound by its third RRM domain. Altogether, we provide first insights into the positional organisation of co‐localising RBPs on individual cargo mRNAs.
    Print ISSN: 1469-221X
    Digitale ISSN: 1469-3178
    Thema: Biologie , Medizin
    Publiziert von Springer Nature im Namen von The European Molecular Biology Organization (EMBO).
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  • 2
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    On a Neumann boundary control in a parabolic system (2015)
    Springer
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    Publikationsdatum: 2015-09-18
    Beschreibung: In this paper we have dealt with controlling a boundary condition of a parabolic system in one dimension. This control aims to find the best appropriate right-hand side boundary function which ensures the closeness between the solution of system at final time and the desired target for the solution. Since these types of problems are ill posed, we have used a regularized solution. By numerical examples we have tested the theoretical results.MSC: 35K20, 49J20, 65J20.
    Print ISSN: 1687-2762
    Digitale ISSN: 1687-2770
    Thema: Mathematik
    Publiziert von Springer
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  • 3
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    iCLIP identifies novel roles for SAFB1 in regulating RNA processing and neuronal function (2015)
    BioMed Central
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    Publikationsdatum: 2015-12-24
    Beschreibung: SAFB1 is a RNA binding protein implicated in the regulation of multiple cellular processes such as the regulation of transcription, stress response, DNA repair and RNA processing. To gain further insight into ...
    Digitale ISSN: 1741-7007
    Thema: Biologie
    Publiziert von BioMed Central
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  • 4
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    Intergenic Alu exonisation facilitates the evolution of tissue-specific transcript ends (2015)
    Oxford University Press
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    Publikationsdatum: 2015-12-02
    Beschreibung: The 3' untranslated regions (3' UTRs) of transcripts serve as important hubs for posttranscriptional gene expression regulation. Here, we find that the exonisation of intergenic Alu elements introduced new terminal exons and polyadenylation sites during human genome evolution. While Alu exonisation from introns has been described previously, we shed light on a novel mechanism to create alternative 3' UTRs, thereby opening opportunities for differential posttranscriptional regulation. On the mechanistic level, we show that intergenic Alu exonisation can compete both with alternative splicing and polyadenylation in the upstream gene. Notably, the Alu -derived isoforms are often expressed in a tissue-specific manner, and the Alu -derived 3' UTRs can alter mRNA stability. In summary, we demonstrate that intergenic elements can affect processing of preceding genes, and elucidate how intergenic Alu exonisation can contribute to tissue-specific posttranscriptional regulation by expanding the repertoire of 3' UTRs.
    Print ISSN: 0305-1048
    Digitale ISSN: 1362-4962
    Thema: Biologie
    Publiziert von Oxford University Press
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  • 5
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    The origin of neural microexons (2019)
    Springer Nature
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    Publikationsdatum: 2019
    Digitale ISSN: 2397-334X
    Thema: Biologie
    Publiziert von Springer Nature
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  • 6
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    Orthogonal matrix factorization enables integrative analysis of multiple RNA binding proteins (2016)
    Oxford University Press
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    Publikationsdatum: 2016-05-14
    Beschreibung: Motivation: RNA binding proteins (RBPs) play important roles in post-transcriptional control of gene expression, including splicing, transport, polyadenylation and RNA stability. To model protein–RNA interactions by considering all available sources of information, it is necessary to integrate the rapidly growing RBP experimental data with the latest genome annotation, gene function, RNA sequence and structure. Such integration is possible by matrix factorization, where current approaches have an undesired tendency to identify only a small number of the strongest patterns with overlapping features. Because protein–RNA interactions are orchestrated by multiple factors, methods that identify discriminative patterns of varying strengths are needed. Results: We have developed an integrative orthogonality-regularized nonnegative matrix factorization (iONMF) to integrate multiple data sources and discover non-overlapping, class-specific RNA binding patterns of varying strengths. The orthogonality constraint halves the effective size of the factor model and outperforms other NMF models in predicting RBP interaction sites on RNA. We have integrated the largest data compendium to date, which includes 31 CLIP experiments on 19 RBPs involved in splicing (such as hnRNPs, U2AF2, ELAVL1, TDP-43 and FUS) and processing of 3’UTR (Ago, IGF2BP). We show that the integration of multiple data sources improves the predictive accuracy of retrieval of RNA binding sites. In our study the key predictive factors of protein–RNA interactions were the position of RNA structure and sequence motifs, RBP co-binding and gene region type. We report on a number of protein-specific patterns, many of which are consistent with experimentally determined properties of RBPs. Availability and implementation: The iONMF implementation and example datasets are available at https://github.com/mstrazar/ionmf . Contact : tomaz.curk@fri.uni-lj.si Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Digitale ISSN: 1460-2059
    Thema: Biologie , Informatik , Medizin
    Publiziert von Oxford University Press
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  • 7
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    hiCLIP reveals the in vivo atlas of mRNA secondary structures recognized by Staufen 1 (2015)
    Nature Publishing Group (NPG)
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    Publikationsdatum: 2015-03-25
    Beschreibung: The structure of messenger RNA is important for post-transcriptional regulation, mainly because it affects binding of trans-acting factors. However, little is known about the in vivo structure of full-length mRNAs. Here we present hiCLIP, a biochemical technique for transcriptome-wide identification of RNA secondary structures interacting with RNA-binding proteins (RBPs). Using this technique to investigate RNA structures bound by Staufen 1 (STAU1) in human cells, we uncover a dominance of intra-molecular RNA duplexes, a depletion of duplexes from coding regions of highly translated mRNAs, an unexpected prevalence of long-range duplexes in 3' untranslated regions (UTRs), and a decreased incidence of single nucleotide polymorphisms in duplex-forming regions. We also discover a duplex spanning 858 nucleotides in the 3' UTR of the X-box binding protein 1 (XBP1) mRNA that regulates its cytoplasmic splicing and stability. Our study reveals the fundamental role of mRNA secondary structures in gene expression and introduces hiCLIP as a widely applicable method for discovering new, especially long-range, RNA duplexes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376666/" 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/PMC4376666/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sugimoto, Yoichiro -- Vigilante, Alessandra -- Darbo, Elodie -- Zirra, Alexandra -- Militti, Cristina -- D'Ambrogio, Andrea -- Luscombe, Nicholas M -- Ule, Jernej -- 103760/Wellcome Trust/United Kingdom -- 103760/Z/14/Z/Wellcome Trust/United Kingdom -- 206726/European Research Council/International -- 617837/European Research Council/International -- A16358/Cancer Research UK/United Kingdom -- MC_U105185858/Medical Research Council/United Kingdom -- U105185858/Medical Research Council/United Kingdom -- England -- Nature. 2015 Mar 26;519(7544):491-4. doi: 10.1038/nature14280. Epub 2015 Mar 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. ; 1] Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK [2] UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, Gower Street, London WC1E 6BT, UK. ; Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. ; Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. ; 1] MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK [2] Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. ; 1] Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK [2] UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, Gower Street, London WC1E 6BT, UK [3] Okinawa Institute of Science &Technology, 1919-1 Tancha, Onna-son, Kunigami-gun, Okinawa 904-0495, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25799984" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): 3' Untranslated Regions/genetics ; Base Sequence ; Cytoplasm/genetics/metabolism ; Cytoskeletal Proteins/*metabolism ; DNA-Binding Proteins/genetics ; Humans ; *Nucleic Acid Conformation ; Polymorphism, Single Nucleotide/genetics ; RNA Splicing ; RNA Stability ; RNA, Messenger/*chemistry/genetics/*metabolism ; RNA-Binding Proteins/*metabolism ; Transcription Factors/genetics
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
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  • 8
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    HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease (2015)
    Nature Publishing Group (NPG)
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    Publikationsdatum: 2015-06-18
    Beschreibung: Fructose is a major component of dietary sugar and its overconsumption exacerbates key pathological features of metabolic syndrome. The central fructose-metabolising enzyme is ketohexokinase (KHK), which exists in two isoforms: KHK-A and KHK-C, generated through mutually exclusive alternative splicing of KHK pre-mRNAs. KHK-C displays superior affinity for fructose compared with KHK-A and is produced primarily in the liver, thus restricting fructose metabolism almost exclusively to this organ. Here we show that myocardial hypoxia actuates fructose metabolism in human and mouse models of pathological cardiac hypertrophy through hypoxia-inducible factor 1alpha (HIF1alpha) activation of SF3B1 and SF3B1-mediated splice switching of KHK-A to KHK-C. Heart-specific depletion of SF3B1 or genetic ablation of Khk, but not Khk-A alone, in mice, suppresses pathological stress-induced fructose metabolism, growth and contractile dysfunction, thus defining signalling components and molecular underpinnings of a fructose metabolism regulatory system crucial for pathological growth.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mirtschink, Peter -- Krishnan, Jaya -- Grimm, Fiona -- Sarre, Alexandre -- Horl, Manuel -- Kayikci, Melis -- Fankhauser, Niklaus -- Christinat, Yann -- Cortijo, Cedric -- Feehan, Owen -- Vukolic, Ana -- Sossalla, Samuel -- Stehr, Sebastian N -- Ule, Jernej -- Zamboni, Nicola -- Pedrazzini, Thierry -- Krek, Wilhelm -- England -- Nature. 2015 Jun 25;522(7557):444-9. doi: 10.1038/nature14508. Epub 2015 Jun 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland. ; Department of Medicine, University of Lausanne, 1011 Lausanne, Switzerland. ; Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland. ; MRC-Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK. ; Universitatsmedizin Gottingen, Klinik fur Kardiologie und Pneumologie, D-37075 Gottingen, and DZHK (German Centre for Cardiovascular Research), Partner Site Gottingen, Germany. ; Department of Anesthesiology and Critical Care Medicine, University Hospital Jena, 07747 Jena, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26083752" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Alternative Splicing ; Animals ; Cardiomyopathy, Hypertrophic/genetics/*metabolism/pathology/physiopathology ; Disease Models, Animal ; Fructokinases/deficiency/genetics/*metabolism ; Fructose/*metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism ; Isoenzymes/deficiency/genetics/metabolism ; Male ; Metabolic Syndrome X/metabolism ; Mice ; Phosphoproteins/deficiency/genetics/*metabolism ; Ribonucleoprotein, U2 Small Nuclear/deficiency/genetics/*metabolism
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
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  • 9
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    Tia1 dependent regulation of mRNA subcellular location and translation controls p53 expression in B cells (2017)
    Springer Nature
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    Publikationsdatum: 2017-09-14
    Beschreibung: Tia1 dependent regulation of mRNA subcellular location and translation controls p53 expression in B cells Nature Communications, Published online: 13 September 2017; doi:10.1038/s41467-017-00454-2 Sequestering mRNA in cytoplasmic stress granules is a mechanism for translational repression. Here the authors find that p53 mRNA, present in stress granules in activated B lymphocytes, is released upon DNA damage and is translated in a CAP-independent manner.
    Digitale ISSN: 2041-1723
    Thema: Biologie , Chemie und Pharmazie , Allgemeine Naturwissenschaft , Physik
    Publiziert von Springer Nature
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  • 10
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    Recursive splicing in long vertebrate genes (2015)
    Nature Publishing Group (NPG)
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    Publikationsdatum: 2015-05-15
    Beschreibung: It is generally believed that splicing removes introns as single units from precursor messenger RNA transcripts. However, some long Drosophila melanogaster introns contain a cryptic site, known as a recursive splice site (RS-site), that enables a multi-step process of intron removal termed recursive splicing. The extent to which recursive splicing occurs in other species and its mechanistic basis have not been examined. Here we identify highly conserved RS-sites in genes expressed in the mammalian brain that encode proteins functioning in neuronal development. Moreover, the RS-sites are found in some of the longest introns across vertebrates. We find that vertebrate recursive splicing requires initial definition of an 'RS-exon' that follows the RS-site. The RS-exon is then excluded from the dominant mRNA isoform owing to competition with a reconstituted 5' splice site formed at the RS-site after the first splicing step. Conversely, the RS-exon is included when preceded by cryptic promoters or exons that fail to reconstitute an efficient 5' splice site. Most RS-exons contain a premature stop codon such that their inclusion can decrease mRNA stability. Thus, by establishing a binary splicing switch, RS-sites demarcate different mRNA isoforms emerging from long genes by coupling cryptic elements with inclusion of RS-exons.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471124/" 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/PMC4471124/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sibley, Christopher R -- Emmett, Warren -- Blazquez, Lorea -- Faro, Ana -- Haberman, Nejc -- Briese, Michael -- Trabzuni, Daniah -- Ryten, Mina -- Weale, Michael E -- Hardy, John -- Modic, Miha -- Curk, Tomaz -- Wilson, Stephen W -- Plagnol, Vincent -- Ule, Jernej -- 104682/Wellcome Trust/United Kingdom -- 206726/European Research Council/International -- 617837/European Research Council/International -- G0802462/Medical Research Council/United Kingdom -- G0901254/Medical Research Council/United Kingdom -- MC_U105185858/Medical Research Council/United Kingdom -- U105185858/Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2015 May 21;521(7552):371-5. doi: 10.1038/nature14466. Epub 2015 May 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK [2] MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. ; University College London Genetics Institute, Gower Street, London WC1E 6BT, UK. ; Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. ; Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. ; 1] MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK [2] Institute for Clinical Neurobiology, University of Wurzburg, Versbacherstr. 5, 97078, Wurzburg, Germany. ; 1] Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK [2] Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia. ; 1] Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK [2] Department of Medical &Molecular Genetics, King's College London, Guy's Hospital, London SE1 9RT, UK. ; Department of Medical &Molecular Genetics, King's College London, Guy's Hospital, London SE1 9RT, UK. ; 1] MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK [2] Institute of Stem Cell Research, German Research Center for Environmental Health, Helmholtz Center Munich, 85764 Neuherberg, Germany. ; Faculty of Computer and Information Science, University of Ljubljana, 1000 Ljubljana, Slovenia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25970246" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Ankyrins/genetics ; Base Sequence ; Brain/cytology/metabolism ; Cell Adhesion Molecules/genetics ; Codon, Terminator/genetics ; Drosophila melanogaster/genetics ; Exons/genetics ; Female ; Frontal Lobe/cytology/metabolism ; Humans ; Immunoglobulins/genetics ; Introns/genetics ; Male ; Promoter Regions, Genetic/genetics ; RNA Isoforms/genetics/metabolism ; RNA Splice Sites/genetics ; RNA Splicing/*genetics ; RNA Stability/genetics ; Vertebrates/*genetics ; Zebrafish/embryology/genetics ; Zebrafish Proteins/genetics
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
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