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.author Abreu, Carla Manuela
dc.contributor.author Kumar, Ramesh
dc.contributor.author Hamilton, Danielle
dc.contributor.author Dawdy, Andrew William
dc.contributor.author Creavin, Kevin
dc.contributor.author Eivers, Sarah
dc.contributor.author Finn, Karen
dc.contributor.author Balsbaugh, Jeremy Lynn
dc.contributor.author O'Connor, Rosemary
dc.contributor.author Kiely, Patrick A.
dc.contributor.author Shabanowitz, Jeffrey
dc.contributor.author Hunt, Donald F.
dc.contributor.author Grenon, Muriel
dc.contributor.author Lowndes, Noel Francis
dc.date.accessioned 2016-02-17T11:46:19Z
dc.date.available 2016-02-17T11:46:19Z
dc.date.issued 2013
dc.identifier.citation Abreu 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.1003310 en
dc.identifier.volume 9 en
dc.identifier.issued 4 en
dc.identifier.issn 1553-7404
dc.identifier.uri http://hdl.handle.net/10468/2384
dc.identifier.doi 10.1371/journal.pgen.1003310
dc.description.abstract The 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.sponsorship Science 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.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Public Library of Science en
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.uri http://creativecommons.org/licenses/by/4.0/ en
dc.subject Double strand breaks en
dc.subject Budding yeast Rad9 en
dc.subject Saccharomyces cerevisiae Rad9 en
dc.subject Cell cycle en
dc.subject Homologous recombination en
dc.subject Replication checkpoint en
dc.subject Signaling pathways en
dc.subject Protein kinases en
dc.subject End resection en
dc.subject In vivo en
dc.title Site-specific phosphorylation of the DNA damage response mediator Rad9 by cyclin-dependent kinases regulates activation of checkpoint kinase 1 en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Rosemary O'Connor, Biochemistry and Cell Biology, University College Cork, Cork, Ireland. +353-21-490-3000 Email: r.oconnor@ucc.ie en
dc.internal.availability Full text available en
dc.description.version Published Version en
dc.internal.wokid WOS:000318073300001
dc.contributor.funder Science Foundation Ireland en
dc.contributor.funder European Commission en
dc.contributor.funder Health Research Board en
dc.contributor.funder Irish Research Council for Science Engineering and Technology en
dc.contributor.funder National University of Ireland Galway en
dc.contributor.funder Fundação para a Ciência e a Tecnologia, Portugal
dc.contributor.funder Irish Cancer Society en
dc.contributor.funder National Institutes of Health, United States en
dc.description.status Peer reviewed en
dc.identifier.journaltitle PLOS GENETICS en
dc.internal.IRISemailaddress r.oconnor@ucc.ie en
dc.identifier.articleid e1003310


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© 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. Except where otherwise noted, this item's license is described as © 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.
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