title: Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders.
abstract: 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.
authors: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors: Sandra
authors: S
authors: Blanco
authors: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors: Sabine
authors: S
authors: Dietmann
authors: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors: Joana V
authors: JV
authors: Flores
authors: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors: Shobbir
authors: S
authors: Hussain
authors: Li Ka Shing Centre, CR-UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Claudia
authors: C
authors: Kutter
authors: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors: Peter
authors: P
authors: Humphreys
authors: Li Ka Shing Centre, CR-UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Margus
authors: M
authors: Lukk
authors: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors: Patrick
authors: P
authors: Lombard
authors: CNRS, UMR8104, Paris, France.
authors: Lucas
authors: L
authors: Treps
authors: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors: Martyna
authors: M
authors: Popis
authors: Johannes Gutenberg University Mainz, Institute for Pharmacy and Biochemistry, Mainz, Germany.
authors: Stefanie
authors: S
authors: Kellner
authors: German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors: Sabine M
authors: SM
authors: Hölter
authors: German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors: Lillian
authors: L
authors: Garrett
authors: 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.
authors: Wolfgang
authors: W
authors: Wurst
authors: German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Institute for Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors: Lore
authors: L
authors: Becker
authors: German Center for Vertigo and Balance Disorders, Munich, Germany Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany.
authors: Thomas
authors: T
authors: Klopstock
authors: German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Institute for Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors: Helmut
authors: H
authors: Fuchs
authors: German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Institute for Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors: Valerie
authors: V
authors: Gailus-Durner
authors: German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Institute for Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors: Martin
authors: M
authors: Hrabĕ de Angelis
authors: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors: Ragnhildur T
authors: RT
authors: Káradóttir
authors: Johannes Gutenberg University Mainz, Institute for Pharmacy and Biochemistry, Mainz, Germany.
authors: Mark
authors: M
authors: Helm
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors: Jernej
authors: J
authors: Ule
authors: Laboratory of Pediatric Brain Diseases, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
authors: Joseph G
authors: JG
authors: Gleeson
authors: Li Ka Shing Centre, CR-UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Duncan T
authors: DT
authors: Odom
authors: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK Michaela.Frye@cancer.org.uk mf364@cam.ac.uk.
authors: Michaela
authors: M
authors: Frye
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009422:Nervous System Diseases / Q000151:congenital* / Q000473:pathology*; D018384:Oxidative Stress; D012343:RNA, Transfer / Q000378:metabolism*; D012259:Ribonuclease, Pancreatic / Q000378:metabolism
chemical_list: D012343:RNA, Transfer; D008780:Methyltransferases; C513146:Misu protein, mouse; C515610:NSUN2 protein, human; C046366:angiogenin; D012259:Ribonuclease, Pancreatic
keywords: 5‐methylcytidine; Misu; NSun2; RNA modification