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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Blanco, Sandra 
Dietmann, Sabine 
Flores, Joana V 
Hussain, Shobbir 
Kutter, Claudia 

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.

Description

Keywords

5‐methylcytidine, Misu, NSun2, RNA modification, Animals, Brain, Gene Expression Profiling, Gene Expression Regulation, Humans, Methylation, Methyltransferases, Mice, Nervous System Diseases, Oxidative Stress, RNA, Transfer, Ribonuclease, Pancreatic

Journal Title

EMBO J

Conference Name

Journal ISSN

0261-4189
1460-2075

Volume Title

33

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (G0801904)
Cancer Research Uk (None)
Medical Research Council (MR/M01939X/1)
Worldwide Cancer Research (None)
British Skin Foundation (5010)
Cancer Research Uk (None)
European Research Council (310360)
Cancer Research Uk (None)
Cancer Research UK (C14303/A17197)
European Research Council (615584)
Cancer Research UK (15603)