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Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3

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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. and Dietmann, S. and Kremer, L. and Hussain, S. and Pearce, S.F. and Powell, C.A. and Rorbach, J. and Lantaff, R. and Blanco, S. and Sauer, S. and Kotzaeridou, U. and Hoffmann, G.F. and Memari, Y. and Kolb-Kokocinski, A. and Durbin, R. and Mayr, J.A. and Frye, M. and 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.
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group (U.K.)
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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