Deficient methylation and formylation of mt-tRNAMet wobble cytosine in a patient carrying mutations in NSUN3

Lindsey Van Haute, Sabine Dietmann, Laura Kremer, Shobbir Hussain, Sarah F. Pearce, Christopher A. Powell, Joanna Rorbach, Rebecca Lantaff, Sandra Blanco, Sascha Sauer, Urania Kotzaeridou, Georg F. Hoffmann, Yasin Memari, Anja Kolb-Kokocinski, Richard Durbin, Johannes A. Mayr, Michaela Frye (), Holger Prokisch () and Michal Minczuk ()
Additional contact information
Lindsey Van Haute: MRC Mitochondrial Biology Unit
Sabine Dietmann: Wellcome Trust—Medical Research Council Cambridge Stem Cell Institute, Genetics, University of Cambridge
Laura Kremer: Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Institute of Human Genetics
Shobbir Hussain: University of Bath, Claverton Down
Sarah F. Pearce: MRC Mitochondrial Biology Unit
Christopher A. Powell: MRC Mitochondrial Biology Unit
Joanna Rorbach: MRC Mitochondrial Biology Unit
Rebecca Lantaff: University of Cambridge
Sandra Blanco: Wellcome Trust—Medical Research Council Cambridge Stem Cell Institute, Genetics, University of Cambridge
Sascha Sauer: Max-Planck-Institute for Molecular Genetics, Otto-Warburg Laboratory
Urania Kotzaeridou: University Children's Hospital
Georg F. Hoffmann: University Children's Hospital
Yasin Memari: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Anja Kolb-Kokocinski: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Richard Durbin: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Johannes A. Mayr: Paracelsus Medical University
Michaela Frye: Wellcome Trust—Medical Research Council Cambridge Stem Cell Institute, Genetics, University of Cambridge
Holger Prokisch: Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Institute of Human Genetics
Michal Minczuk: MRC Mitochondrial Biology Unit

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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 (m5C) methyltransferase NSun3 and link m5C 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 m5C at the anticodon loop in the mitochondrially encoded transfer RNA methionine (mt-tRNAMet). Further, we demonstrate that m5C deficiency in mt-tRNAMet results in the lack of 5-formylcytosine (f5C) at the same tRNA position. Our findings demonstrate that NSUN3 is necessary for efficient mitochondrial translation and reveal that f5C in human mitochondrial RNA is generated by oxidative processing of m5C.

Date: 2016
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DOI: 10.1038/ncomms12039

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