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

作者：Van Haute Lindsey; Dietmann Sabine; Kremer Laura; Hussain Shobbir; Pearce Sarah F; Powell Christopher A; Rorbach Joanna; Lantaff Rebecca; Blanco Sandra; Sauer Sascha; Kotzaeridou Urania; Hoffmann Georg F; Memari Yasin; Kolb Kokocinski Anja; Durbin Richard; Mayr Johannes A; Frye Michaela^*; Prokisch Holger^*; Minczuk Michal^*

来源：Nature Communications, 2016, 7(1): 12039.

DOI：10.1038/ncomms12039

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-tRNAMet). Further, we demonstrate that m(5)C deficiency in mt-tRNAMet 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.

• 出版日期2016-6
• 单位河北医科大学