دورية أكاديمية
أعرض في EDS

Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders.

التفاصيل البيبلوغرافية
العنوان: Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders.
المؤلفون: Blanco S; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Dietmann S; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Flores JV; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Hussain S; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Kutter C; Li Ka Shing Centre, CR-UK Cambridge Institute, University of Cambridge, Cambridge, UK., Humphreys P; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Lukk M; Li Ka Shing Centre, CR-UK Cambridge Institute, University of Cambridge, Cambridge, UK., Lombard P; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Treps L; CNRS, UMR8104, Paris, France., Popis M; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Kellner S; Johannes Gutenberg University Mainz, Institute for Pharmacy and Biochemistry, Mainz, Germany., Hölter SM; German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany., Garrett L; German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany., Wurst W; German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Center for Vertigo and Balance Disorders, Munich, Germany., Becker L; German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Institute for Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany., Klopstock T; German Center for Vertigo and Balance Disorders, Munich, Germany Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany., Fuchs H; German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Institute for Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany., Gailus-Durner V; German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Institute for Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany., Hrabĕ de Angelis M; German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Institute for Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany., Káradóttir RT; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Helm M; Johannes Gutenberg University Mainz, Institute for Pharmacy and Biochemistry, Mainz, Germany., Ule J; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK., Gleeson JG; Laboratory of Pediatric Brain Diseases, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA., Odom DT; Li Ka Shing Centre, CR-UK Cambridge Institute, University of Cambridge, Cambridge, UK., Frye M; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK Michaela.Frye@cancer.org.uk mf364@cam.ac.uk.
المصدر: The EMBO journal [EMBO J] 2014 Sep 17; Vol. 33 (18), pp. 2020-39. Date of Electronic Publication: 2014 Jul 25.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8208664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2075 (Electronic) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE
أسماء مطبوعة: Publication: 2024- : [London] : Nature Publishing Group
Original Publication: Eynsham, Oxford, England : Published for the European Molecular Biology Organization by IRL Press, [c1982-
مواضيع طبية MeSH: Gene Expression Regulation*, Methyltransferases/*metabolism , Nervous System Diseases/*congenital , Nervous System Diseases/*pathology , RNA, Transfer/*metabolism, Animals ; Brain/pathology ; Gene Expression Profiling ; Humans ; Methylation ; Methyltransferases/genetics ; Mice ; Oxidative Stress ; Ribonuclease, Pancreatic/metabolism
مستخلص: Mutations in the cytosine-5 RNA methyltransferase NSun2 cause microcephaly and other neurological abnormalities in mice and human. How post-transcriptional methylation contributes to the human disease is currently unknown. By comparing gene expression data with global cytosine-5 RNA methylomes in patient fibroblasts and NSun2-deficient mice, we find that loss of cytosine-5 RNA methylation increases the angiogenin-mediated endonucleolytic cleavage of transfer RNAs (tRNA) leading to an accumulation of 5' tRNA-derived small RNA fragments. Accumulation of 5' tRNA fragments in the absence of NSun2 reduces protein translation rates and activates stress pathways leading to reduced cell size and increased apoptosis of cortical, hippocampal and striatal neurons. Mechanistically, we demonstrate that angiogenin binds with higher affinity to tRNAs lacking site-specific NSun2-mediated methylation and that the presence of 5' tRNA fragments is sufficient and required to trigger cellular stress responses. Furthermore, the enhanced sensitivity of NSun2-deficient brains to oxidative stress can be rescued through inhibition of angiogenin during embryogenesis. In conclusion, failure in NSun2-mediated tRNA methylation contributes to human diseases via stress-induced RNA cleavage.
(© 2014 The Authors. Published under the terms of the CC BY 4.0 license.)
التعليقات: Comment in: EMBO J. 2014 Sep 17;33(18):1981-3. (PMID: 25216676)
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معلومات مُعتمدة: 089701 United Kingdom WT_ Wellcome Trust; 15181 United Kingdom CRUK_ Cancer Research UK; G0801904 United Kingdom MRC_ Medical Research Council; 16134 United Kingdom CRUK_ Cancer Research UK; 15603 United Kingdom CRUK_ Cancer Research UK; MC_U105185858 United Kingdom MRC_ Medical Research Council
فهرسة مساهمة: Keywords: 5‐methylcytidine; Misu; NSun2; RNA modification
سلسلة جزيئية: GEO GSE44746
المشرفين على المادة: 9014-25-9 (RNA, Transfer)
EC 2.1.1.- (Methyltransferases)
EC 2.1.1.- (Misu protein, mouse)
EC 2.1.1.- (NSUN2 protein, human)
EC 3.1.27.- (angiogenin)
EC 3.1.27.5 (Ribonuclease, Pancreatic)
تواريخ الأحداث: Date Created: 20140727 Date Completed: 20141107 Latest Revision: 20240513
رمز التحديث: 20240513
مُعرف محوري في PubMed: PMC4195770
DOI: 10.15252/embj.201489282
PMID: 25063673
قاعدة البيانات: MEDLINE
الوصف
تدمد:1460-2075
DOI:10.15252/embj.201489282