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dc.contributor.authorNishi, Ryotaroen
dc.contributor.authorWijnhoven, Paul WGen
dc.contributor.authorKimura, Yusukeen
dc.contributor.authorMatsui, Misakien
dc.contributor.authorKonietzny, Rebeccaen
dc.contributor.authorWu, Qianen
dc.contributor.authorNakamura, Keisukeen
dc.contributor.authorBlundell, Tomen
dc.contributor.authorKessler, Benedikt Men
dc.date.accessioned2019-02-14T14:57:45Z
dc.date.available2019-02-14T14:57:45Z
dc.date.issued2018-12-17en
dc.identifier.issn2045-2322
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/289395
dc.description.abstractNon-homologous end-joining (NHEJ), which can promote genomic instability when dysfunctional, is a major DNA double-strand break (DSB) repair pathway. Although ubiquitylation of the core NHEJ factor, Ku (Ku70-Ku80), which senses broken DNA ends, is important for its removal from sites of damage upon completion of NHEJ, the mechanism regulating Ku ubiquitylation remains elusive. We provide evidence showing that the ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) interacts with and directly deubiquitylates one of the Ku heterodimer subunits, Ku80. Additionally, depleting UCHL3 resulted in reduced Ku80 foci formation, Ku80 binding to chromatin after DSB induction, moderately sensitized cells to ionizing radiation and decreased NHEJ efficiencies. Mechanistically, we show that DNA damage induces UCHL3 phosphorylation, which is dependent on ATM, downstream NHEJ factors and UCHL3 catalytic activity. Furthermore, this phosphorylation destabilizes UCHL3, despite having no effect on its catalytic activity. Collectively, these data suggest that UCHL3 facilitates cellular viability after DSB induction by antagonizing Ku80 ubiquitylation to enhance Ku80 retention at sites of damage.
dc.description.sponsorshipThis work was funded by Grant-in-Aid for Research Activity start-up 15H06738 (R.N.), Grant-in Aid for Young Scientists (A) 16H05888 (R.N.), Daiichi Sankyo Foundation of Life Science (R.N.), Mochida Memorial Foundation for Medical and Pharmaceutical Research (R.N.), Cancer Research UK (CRUK) Grant C6/A11224 and C6/A18796 (P.W.), CRUK Project Grant C6/A14831 (R.N.). T.L.B. and Q.W. are funded by Wellcome Trust Investigator Award (200814_Z_16_Z). Research in the B.M.K. laboratory is supported by a John Fell Fund 133/075, the Wellcome Trust (097813/Z/11/Z) and the Engineering and Physical Sciences Research Council (EP/N034295/1). Research in the S.P.J. laboratory is funded by CRUK Program Grant C6/A18796, and Wellcome Trust Grant WT206388/Z/17/Z. Cancer Research UK Grant C6946/A24843 and Wellcome Trust Grant WT203144 provided core infrastructure funding.
dc.languageengen
dc.publisherNature Publishing Group
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleThe deubiquitylating enzyme UCHL3 regulates Ku80 retention at sites of DNA damage.en
dc.typeArticle
prism.endingPage17891
prism.issueIdentifier1en
prism.publicationDate2018en
prism.publicationNameScientific Reportsen
prism.startingPage17891
prism.volume8en
dc.identifier.doi10.17863/CAM.36643
dcterms.dateAccepted2018-11-16en
rioxxterms.versionofrecord10.1038/s41598-018-36235-0en
rioxxterms.versionVoR*
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2018-12-17en
dc.contributor.orcidBlundell, Tom [0000-0002-2708-8992]
dc.identifier.eissn2045-2322
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (A18796)
pubs.funder-project-idWELLCOME TRUST (200814/Z/16/Z)
pubs.funder-project-idCancer Research UK (C6946/A24843)
pubs.funder-project-idWellcome Trust (203144/Z/16/Z)
dc.identifier.urlhttps://www.nature.com/articles/s41598-018-36235-0#article-infoen


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