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

TitleDeficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3.
Publication TypeJournal Article
Year of Publication2016
AuthorsVan Haute, L, Dietmann, S, Kremer, L, Hussain, S, Pearce, SF, Powell, CA, Rorbach, J, Lantaff, R, Blanco, S, Sauer, S, Kotzaeridou, U, Hoffmann, GF, Memari, Y, Kolb-Kokocinski, A, Durbin, R, Mayr, JA, Frye, M, Prokisch, H, Minczuk, MA
JournalNature Communications
Volume7
Pagination12039
Date Published2016
ISSN2041-1723
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.

DOI10.1038/ncomms12039
Alternate JournalNat Commun
Citation Key10.1038/ncomms12039
PubMed ID27356879
PubMed Central IDPMC4931328
Grant List310360 / / European Research Council / International