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Blanco, S.* ; Dietmann, S.* ; Flores, J.V.* ; Hussain, S.* ; Kutter, C.* ; Humphreys, P.* ; Lukk, M.* ; Lombard, P.* ; Treps, L.* ; Popis, M.* ; Kellner, S.* ; Hölter, S.M. ; Garrett, L. ; Wurst, W. ; Becker, L. ; Klopstock, T.* ; Fuchs, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Káradóttir, R.T.* ; Helm, M.* ; Ule, J.* ; Gleeson, J.G.* ; Odom, D.T.* ; Frye, M.*

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

EMBO J. 33, 2020-2039 (2014)
Publ. Version/Full Text DOI PMC
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords 5‐methylcytidine ; Misu ; Nsun2 ; Rna Modification; Amyotrophic-lateral-sclerosis; Recessive Intellectual Disability; Methyltransferase Misu Nsun2; Phenylalanine Transfer-rna; Deep-sequencing Data; Saccharomyces-cerevisiae; Protein-synthesis; Oxidative Stress; Translational Regulation; Binding Proteins
Language english
Publication Year 2014
HGF-reported in Year 2014
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Journal EMBO Journal, The
Quellenangaben Volume: 33, Issue: 18, Pages: 2020-2039 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Heidelberg, Germany
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)
Institute of Developmental Genetics (IDG)
POF-Topic(s) 30201 - Metabolic Health
30204 - Cell Programming and Repair
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500600-001
G-500600-003
G-500500-001
PubMed ID 25063673
DOI 10.15252/embj.201489282
WOS ID WOS:000342503000006
Scopus ID 84908153517
Erfassungsdatum 2014-07-28
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