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| Item Type: | Article |
|---|---|
| Title: | Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3 |
| Creators Name: | Van Haute, L., Dietmann, S., Kremer, L., Hussain, S., Pearce, S.F., Powell, C.A., Rorbach, J., Lantaff, R., Blanco, S., Sauer, S., Kotzaeridou, U., Hoffmann, G.F., Memari, Y., Kolb-Kokocinski, A., Durbin, R., Mayr, J.A., Frye, M., Prokisch, H. and Minczuk, M. |
| Abstract: | Epitranscriptome modifications are required for structure and function of RNA and defects in these pathways have been associated with human disease. Here we identify the RNA target for the previously uncharacterized 5-methylcytosine (m(5)C) methyltransferase NSun3 and link m(5)C RNA modifications with energy metabolism. Using whole-exome sequencing, we identified loss-of-function mutations in NSUN3 in a patient presenting with combined mitochondrial respiratory chain complex deficiency. Patient-derived fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of NSun3. We show that NSun3 is required for deposition of m(5)C at the anticodon loop in the mitochondrially encoded transfer RNA methionine (mt-tRNA(Met)). Further, we demonstrate that m(5)C deficiency in mt-tRNA(Met) results in the lack of 5-formylcytosine (f(5)C) at the same tRNA position. Our findings demonstrate that NSUN3 is necessary for efficient mitochondrial translation and reveal that f(5)C in human mitochondrial RNA is generated by oxidative processing of m(5)C. |
| Keywords: | Gene Expression Regulation, HEK293 Cells, HeLa Cells, Methylation, Methyltransferases, Mitochondria, Mitochondrial Diseases, Mutation, Transfer RNA |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 7 |
| Page Range: | 12039 |
| Date: | 30 June 2016 |
| Official Publication: | https://doi.org/10.1038/ncomms12039 |
| PubMed: | View item in PubMed |
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