See also: G Stoecklin & S Diederichs (September 2014)
Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders
Article first published online: 25 JUL 2014
© 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
The EMBO Journal
Volume 33, Issue 18, pages 2020–2039, 17 September 2014
How to Cite
The EMBO Journal (2014) 33: 2020–2039
- Issue published online: 17 SEP 2014
- Article first published online: 25 JUL 2014
- Manuscript Accepted: 23 JUN 2014
- Manuscript Received: 16 JUN 2014
- Cancer Research UK
- Medical Research Council
- European Research Council
- German Federal Ministry of Education and Research. Grant Numbers: 01GS0850, 01GS0851, 01KX1012
- German Center for Diabetes Research
- German Center for Vertigo and Balance Disorders. Grant Number: 01 EO 0901
- Helmholtz Alliance for Mental Health in an Ageing Society. Grant Number: HA-215
- RNA modification
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.
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.