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

• Sandra Blanco ^[3] ; Sabine Dietmann ^[3] ; Joana V Flores ^[3] ; Shobbir Hussain ^[3] ; Claudia Kutter ^[4] ; Peter Humphreys ^[3] ; Margus Lukk ^[4] ; Patrick Lombard ^[3] ; Lucas Treps ^[5] ; Martyna Popis ^[3] ; Stefanie Kellner ^[6] ; Sabine M Hölter ^[1] ; Lillian Garrett ^[1] ; Wolfgang Wurst ^[1] ; Lore Becker ^[1] ; Thomas Klopstock ^[7] ; Helmut Fuchs ^[1] ; Valerie Gailus-Durner ^[1] ; Martin Hrabĕ de Angelis ^[1] ; Ragnhildur T Káradóttir ^[3] ; Mark Helm ^[6] ; Jernej Ule ^[8] ; Joseph G Gleeson ^[2] ; Duncan T Odom ^[4] ; Michaela Frye ^[3]
  1. [1] Helmholtz Zentrum München

     Helmholtz Zentrum München

     Kreisfreie Stadt München, Alemania

     
  2. [2] Howard Hughes Medical Institute

     Howard Hughes Medical Institute

     Estados Unidos

     
  3. [3] 1 Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute, University of Cambridge Cambridge, UK
  4. [4] 2 Li Ka Shing Centre, CR-UK Cambridge Institute, University of Cambridge Cambridge, UK
  5. [5] 3 CNRS, UMR8104 Paris, France
  6. [6] 4 Johannes Gutenberg University Mainz, Institute for Pharmacy and Biochemistry Mainz, Germany
  7. [7] 7 German Center for Vertigo and Balance Disorders Munich, Germany; 9 Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University Munich, Germany
  8. [8] 10 Department of Molecular Neuroscience, UCL Institute of Neurology London, UK

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 33, Nº. 18, 2014, págs. 2020-2039
• Idioma: inglés
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• Resumen

  • 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.