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dc.contributor.authorVan Haute, Lindseyen
dc.contributor.authorLee, Song-Yien
dc.contributor.authorMcCann, Beverly Jen
dc.contributor.authorPowell, Christopher Aen
dc.contributor.authorBansal, Dhiruen
dc.contributor.authorVasiliauskaitė, Linaen
dc.contributor.authorGarone, Caterinaen
dc.contributor.authorShin, Sangheeen
dc.contributor.authorKim, Jong-Seoen
dc.contributor.authorFrye, Michaelaen
dc.contributor.authorGleeson, Joseph Gen
dc.contributor.authorMiska, Ericen
dc.contributor.authorRhee, Hyun-Wooen
dc.contributor.authorMinczuk, Michalen
dc.date.accessioned2019-08-22T23:31:14Z
dc.date.available2019-08-22T23:31:14Z
dc.date.issued2019-09en
dc.identifier.issn0305-1048
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/296162
dc.description.abstractExpression of human mitochondrial DNA is indispensable for proper function of the oxidative phosphorylation machinery. The mitochondrial genome encodes 22 tRNAs, 2 rRNAs and 11 mRNAs and their post-transcriptional modification constitutes one of the key regulatory steps during mitochondrial gene expression. Cytosine-5 methylation (m5C) has been detected in mitochondrial transcriptome, however its biogenesis has not been investigated in details. Mammalian NOP2/Sun RNA Methyltransferase Family Member 2 (NSUN2) has been characterized as an RNA methyltransferase introducing m5C in nuclear-encoded tRNAs, mRNAs and microRNAs and associated with cell proliferation and differentiation, with pathogenic variants in NSUN2 being linked to neurodevelopmental disorders. Here we employ spatially restricted proximity labelling and immunodetection to demonstrate that NSUN2 is imported into the matrix of mammalian mitochondria. Using three genetic models for NSUN2 inactivation-knockout mice, patient-derived fibroblasts and CRISPR/Cas9 knockout in human cells-we show that NSUN2 is necessary for the generation of m5C at positions 48, 49 and 50 of several mammalian mitochondrial tRNAs. Finally, we show that inactivation of NSUN2 does not have a profound effect on mitochondrial tRNA stability and oxidative phosphorylation in differentiated cells. We discuss the importance of the newly discovered function of NSUN2 in the context of human disease.
dc.description.sponsorshipMedical Research Council, UK [MC_UU_00015/4 to M.M.]; EMBO [ALFT 701-2013 to L.V.H.]; National Research Foundation of Korea [NRF-2019R1A2C3008463 to S.Y.L and H.W.R.]; Cancer Research UK [C13474/A18583, C6946/A14492 to E.A.M.]; Wellcome Trust [104640/Z/14/Z, 092096/Z/10/Z to E.A.M.]. Funding for open access charge: MRC.
dc.format.mediumPrinten
dc.languageengen
dc.publisherOxford University Press
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectMitochondriaen
dc.subjectFibroblastsen
dc.subjectAnimalsen
dc.subjectMice, Knockouten
dc.subjectHumansen
dc.subjectMiceen
dc.subjectMicrocephalyen
dc.subjectEczemaen
dc.subjectFaciesen
dc.subjectGrowth Disordersen
dc.subject5-Methylcytosineen
dc.subjectMethyltransferasesen
dc.subjectRNA, Messengeren
dc.subjectRNA, Transferen
dc.subjectRNA Processing, Post-Transcriptionalen
dc.subjectNucleic Acid Conformationen
dc.subjectMethylationen
dc.subjectProtein Transporten
dc.subjectOxidative Phosphorylationen
dc.subjectGene Knockout Techniquesen
dc.subjectHEK293 Cellsen
dc.subjectIntellectual Disabilityen
dc.subjectPrimary Cell Cultureen
dc.subjectCRISPR-Cas Systemsen
dc.subjectGene Editingen
dc.subjectRNA, Mitochondrialen
dc.titleNSUN2 introduces 5-methylcytosines in mammalian mitochondrial tRNAs.en
dc.typeArticle
prism.endingPage8733
prism.issueIdentifier16en
prism.publicationDate2019en
prism.publicationNameNucleic acids researchen
prism.startingPage8720
prism.volume47en
dc.identifier.doi10.17863/CAM.43210
dcterms.dateAccepted2019-07-02en
rioxxterms.versionofrecord10.1093/nar/gkz559en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-09en
dc.contributor.orcidLee, Song-Yi [0000-0001-9091-8242]
dc.contributor.orcidKim, Jong-Seo [0000-0002-8909-8440]
dc.contributor.orcidFrye, Michaela [0000-0002-5636-6840]
dc.contributor.orcidMiska, Eric [0000-0002-4450-576X]
dc.contributor.orcidMinczuk, Michal [0000-0001-8242-1420]
dc.identifier.eissn1362-4962
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (721757)
pubs.funder-project-idMRC (MC_U105697135)
pubs.funder-project-idMRC (MC_UU_00015/4)
pubs.funder-project-idWellcome Trust (092096/Z/10/Z)
pubs.funder-project-idWELLCOME TRUST (104640/Z/14/Z)
pubs.funder-project-idCancer Research UK (18583)
pubs.funder-project-idCancer Research UK (A14492)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International