Deficient methylation and formylation of mt-tRNA$^{Met}$ wobble cytosine in a patient carrying mutations in NSUN3
Authors
Van, Haute Lindsey
Dietmann, Sabine
Kremer, Laura
Hussain, Shobbir
Pearce, Sarah F
Powell, Christopher A
Rorbach, Joanna
Blanco Benavente, Sandra
Sauer, Sascha
Kotzaeridou, Urania
Hoffmann, Georg F
Memari, Yasin
Kolb-Kokocinski, Anja
Durbin, Richard
Mayr, Johannes A
Prokisch, Holger
Publication Date
2016-06-30Journal Title
Nature Communications
ISSN
2041-1723
Publisher
Nature Publishing Group
Volume
7
Number
12039
Language
English
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Van, H. L., Dietmann, S., Kremer, L., Hussain, S., Pearce, S. F., Powell, C. A., Rorbach, J., et al. (2016). Deficient methylation and formylation of mt-tRNA$^{Met}$ wobble cytosine in a patient carrying mutations in NSUN3. Nature Communications, 7 (12039)https://doi.org/10.1038/ncomms12039
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.
Sponsorship
This work was funded by the Medical Research Council (MRC; as part of the core funding for the Mitochondrial Biology Unit MC_U105697135 and by the G0801904 grant), the European Research Council (ERC; 310360), Cancer Research UK (CR-UK; C10701/ A15181), European Commission (FP7/2007-2013, under grant agreement number no.262055 (ESGI), as a Transnational Access project of the European Sequencing and Genotyping Infrastructure), core support grant from the Wellcome Trust and MRC to the Wellcome Trust-MRC Cambridge Stem Cell Institute, the European Commission (Horizon2020, under grant agreement number 633974), the Bundesministerium fur Bildung und Forschung (BMBF) (through the German Network for mitochondrial disorders (mitoNET, 01GM1113C) and through the European network for mitochondrial disorders (E-Rare project GENOMIT, 01GM1207)) and by EMBO (ALFT 701-2013).
Funder references
MRC (G0801904)
Cancer Research UK (A7006)
MEDICAL RESEARCH COUNCIL (MR/M01939X/1)
WORLDWIDE CANCER RESEARCH (15-0168)
British Skin Foundation (5010)
Cancer Research UK (15181)
European Research Council (310360)
Cancer Research UK (A16134)
MRC (MC_PC_12009)
MRC (MC_U105697135)
European Commission Horizon 2020 (H2020) Societal Challenges (633974)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1038/ncomms12039
This record's URL: https://www.repository.cam.ac.uk/handle/1810/256905
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International
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