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How post\u2010transcriptional methylation contributes to the human disease is currently unknown. By comparing gene expression data with global cytosine\u20105 RNA methylomes in patient fibroblasts and NSun2\u2010deficient mice, we find that loss of cytosine\u20105 RNA methylation increases the angiogenin\u2010mediated endonucleolytic cleavage of transfer RNAs (tRNA) leading to an accumulation of 5\u2032 tRNA\u2010derived small RNA fragments. Accumulation of 5\u2032 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\u2010specific NSun2\u2010mediated methylation and that the presence of 5\u2032 tRNA fragments is sufficient and required to trigger cellular stress responses. Furthermore, the enhanced sensitivity of NSun2\u2010deficient brains to oxidative stress can be rescued through inhibition of angiogenin during embryogenesis. In conclusion, failure in NSun2\u2010mediated tRNA methylation contributes to human diseases via stress\u2010induced RNA cleavage.<\/jats:p>","DOI":"10.15252\/embj.201489282","type":"journal-article","created":{"date-parts":[[2014,7,26]],"date-time":"2014-07-26T00:05:32Z","timestamp":1406333132000},"page":"2020-2039","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":609,"title":["Aberrant methylation of tRNAs links cellular stress to neuro\u2010developmental disorders"],"prefix":"10.1038","volume":"33","author":[{"given":"Sandra","family":"Blanco","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Dietmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana V","family":"Flores","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shobbir","family":"Hussain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Kutter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Humphreys","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margus","family":"Lukk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Lombard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Treps","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martyna","family":"Popis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Kellner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine M","family":"H\u00f6lter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lillian","family":"Garrett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Wurst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lore","family":"Becker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Klopstock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut","family":"Fuchs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Gailus\u2010Durner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Hrab\u0115 de Angelis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ragnhildur T","family":"K\u00e1rad\u00f3ttir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Helm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jernej","family":"Ule","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph G","family":"Gleeson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duncan T","family":"Odom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Frye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,7,25]]},"reference":[{"key":"BFEMBJ201489282_CR1","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/j.ajhg.2012.03.021","volume":"90","author":"L Abbasi\u2010Moheb","year":"2012","unstructured":"Abbasi\u2010Moheb L, Mertel S, Gonsior M, Nouri\u2010Vahid L, Kahrizi K, Cirak S, Wieczorek D, Motazacker MM, Esmaeeli\u2010Nieh S, Cremer K, Weissmann R, Tzschach A, Garshasbi M, Abedini SS, Najmabadi H, Ropers HH, Sigrist SJ, Kuss AW (2012) Mutations in NSUN2 cause autosomal\u2010recessive intellectual disability. 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