Journal
EMBO JOURNAL
Volume 33, Issue 18, Pages 2020-2039Publisher
WILEY
DOI: 10.15252/embj.201489282
Keywords
5-methylcytidine; Misu; NSun2; RNA modification
Categories
Funding
- Cambridge Stem Cell Initiative
- Cancer Research UK (CR-UK)
- Medical Research Council (MRC)
- European Research Council (ERC)
- EMBO
- German Federal Ministry of Education and Research [01GS0850, 01GS0851, 01KX1012]
- German Center for Diabetes Research
- German Center for Vertigo and Balance Disorders [01 EO 0901]
- Helmholtz Alliance for Mental Health in an Ageing Society [HA-215]
- MRC [G0801904, MC_U105185858] Funding Source: UKRI
- British Skin Foundation [5010] Funding Source: researchfish
- Cancer Research UK [15603, 15181, 16134] Funding Source: researchfish
- Medical Research Council [G0801904, MC_U105185858] Funding Source: researchfish
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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 50 tRNA-derived small RNA fragments. Accumulation of 50 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 50 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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