Site-specific phosphorylation of the DNA damage response mediator Rad9 by cyclin-dependent kinases regulates activation of checkpoint kinase 1

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dc.contributor.authorAbreu, Carla Manuela
dc.contributor.authorKumar, Ramesh
dc.contributor.authorHamilton, Danielle
dc.contributor.authorDawdy, Andrew William
dc.contributor.authorCreavin, Kevin
dc.contributor.authorEivers, Sarah
dc.contributor.authorFinn, Karen
dc.contributor.authorBalsbaugh, Jeremy Lynn
dc.contributor.authorO'Connor, Rosemary
dc.contributor.authorKiely, Patrick A.
dc.contributor.authorShabanowitz, Jeffrey
dc.contributor.authorHunt, Donald F.
dc.contributor.authorGrenon, Muriel
dc.contributor.authorLowndes, Noel Francis
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderEuropean Commissionen
dc.contributor.funderHealth Research Boarden
dc.contributor.funderIrish Research Council for Science Engineering and Technologyen
dc.contributor.funderNational University of Ireland Galwayen
dc.contributor.funderFundação para a Ciência e a Tecnologia, Portugal
dc.contributor.funderIrish Cancer Societyen
dc.contributor.funderNational Institutes of Health, United Statesen
dc.date.accessioned2016-02-17T11:46:19Z
dc.date.available2016-02-17T11:46:19Z
dc.date.issued2013
dc.description.abstractThe mediators of the DNA damage response (DDR) are highly phosphorylated by kinases that control cell proliferation, but little is known about the role of this regulation. Here we show that cell cycle phosphorylation of the prototypical DDR mediator Saccharomyces cerevisiae Rad9 depends on cyclin-dependent kinase (CDK) complexes. We find that a specific G2/M form of Cdc28 can phosphorylate in vitro the N-terminal region of Rad9 on nine consensus CDK phosphorylation sites. We show that the integrity of CDK consensus sites and the activity of Cdc28 are required for both the activation of the Chk1 checkpoint kinase and its interaction with Rad9. We have identified T125 and T143 as important residues in Rad9 for this Rad9/Chk1 interaction. Phosphorylation of T143 is the most important feature promoting Rad9/Chk1 interaction, while the much more abundant phosphorylation of the neighbouring T125 residue impedes the Rad9/Chk1 interaction. We suggest a novel model for Chk1 activation where Cdc28 regulates the constitutive interaction of Rad9 and Chk1. The Rad9/Chk1 complex is then recruited at sites of DNA damage where activation of Chk1 requires additional DDR-specific protein kinases.en
dc.description.sponsorshipScience Foundation Ireland (SFI Principal Investigator awards (06/IN.1/B107) (07/IN1/B958)); European Commission (European Union DNA repair FP6 Integrated Project (512113)); Health Research Board Programme Award (PR001/2001); Irish Cancer Society (Cancer Research Ireland grants CR105GRE, CRF09KIE); National University of Ireland Galway College (fellowship); Fundação para a Ciência e a Tecnologia, Portugal (Fellowship, SFRH/BD/42128/2007); Irish Research Council for Science Engineering and Technology; National Institutes of Health award (GM037537);en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleide1003310
dc.identifier.citationAbreu CM, Kumar R, Hamilton D, Dawdy AW, Creavin K, Eivers S, et al. (2013) Site-Specific Phosphorylation of the DNA Damage Response Mediator Rad9 by Cyclin-Dependent Kinases Regulates Activation of Checkpoint Kinase 1. PLoS Genet 9(4): e1003310. doi:10.1371/journal.pgen.1003310en
dc.identifier.doi10.1371/journal.pgen.1003310
dc.identifier.issn1553-7404
dc.identifier.issued4en
dc.identifier.journaltitlePLOS GENETICSen
dc.identifier.urihttps://hdl.handle.net/10468/2384
dc.identifier.volume9en
dc.language.isoenen
dc.publisherPublic Library of Scienceen
dc.rights© 2013 Abreu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectDouble strand breaksen
dc.subjectBudding yeast Rad9en
dc.subjectSaccharomyces cerevisiae Rad9en
dc.subjectCell cycleen
dc.subjectHomologous recombinationen
dc.subjectReplication checkpointen
dc.subjectSignaling pathwaysen
dc.subjectProtein kinasesen
dc.subjectEnd resectionen
dc.subjectIn vivoen
dc.titleSite-specific phosphorylation of the DNA damage response mediator Rad9 by cyclin-dependent kinases regulates activation of checkpoint kinase 1en
dc.typeArticle (peer-reviewed)en
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