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

Sandra Blanco, Sabine Dietmann, Joana V. Flores, Shobbir Hussain, Claudia Kutter, Peter Humphreys, Margus Lukk, Patrick Lombard, Lucas Treps, Martyna Popis, Stefanie Kellner, Sabine M. Hölter, Lillian Garrett, Wolfgang Wurst, Lore Becker, Thomas Klopstock, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabě De Angelis, Ragnhildur T. KáradõttirMark Helm, Jernej Ule, Joseph G. Gleeson, Duncan T. Odom, Michaela Frye

Research output: Contribution to journalArticlepeer-review

314 Scopus citations

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. Synopsis This study causally links post-transcriptional methylation-controlled tRNA identity and their stability to neurological disorders in human. NSun2-mediated tRNA methylation protects from endonucleolytic cleavage into small RNA fragments. tRNA-derived small RNA fragments are sufficient and required to induce cellular stress responses. Loss of cytosine-5 methylation in tRNAs contributes to neuro-developmental disease through accumulation of tRNA-derived small RNA fragments. This study causally links post-transcriptional methylation-controlled tRNA identity and their stability to neurological disorders in human.

Original languageEnglish
Pages (from-to)2020-2039
Number of pages20
JournalEMBO Journal
Volume33
Issue number18
DOIs
StatePublished - Sep 17 2014

Keywords

  • 5-methylcytidine
  • Misu
  • NSun2
  • RNA modification

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