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dc.contributor.authorvan Vugt, MATM
dc.contributor.authorGardino, AK
dc.contributor.authorLinding, R
dc.contributor.authorOstheimer, GJ
dc.contributor.authorReinhardt, HC
dc.contributor.authorOng, S-E
dc.contributor.authorTan, CS
dc.contributor.authorMiao, H
dc.contributor.authorKeezer, SM
dc.contributor.authorLi, J
dc.contributor.authorPawson, T
dc.contributor.authorLewis, TA
dc.contributor.authorCarr, SA
dc.contributor.authorSmerdon, SJ
dc.contributor.authorBrummelkamp, TR
dc.contributor.authorYaffe, MB
dc.date.accessioned2018-08-24T08:24:58Z
dc.date.issued2010-01
dc.identifier1
dc.identifier.citationPLOS BIOLOGY, 2010, 8
dc.identifier.issn1545-7885
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2375
dc.identifier.doi10.1371/journal.pbio.1000287
dc.description.abstractDNA damage checkpoints arrest cell cycle progression to facilitate DNA repair. The ability to survive genotoxic insults depends not only on the initiation of cell cycle checkpoints but also on checkpoint maintenance. While activation of DNA damage checkpoints has been studied extensively, molecular mechanisms involved in sustaining and ultimately inactivating cell cycle checkpoints are largely unknown. Here, we explored feedback mechanisms that control the maintenance and termination of checkpoint function by computationally identifying an evolutionary conserved mitotic phosphorylation network within the DNA damage response. We demonstrate that the non-enzymatic checkpoint adaptor protein 53BP1 is an in vivo target of the cell cycle kinases Cyclin-dependent kinase-1 and Polo-like kinase-1 (Plk1). We show that Plk1 binds 53BP1 during mitosis and that this interaction is required for proper inactivation of the DNA damage checkpoint. 53BP1 mutants that are unable to bind Plk1 fail to restart the cell cycle after ionizing radiation-mediated cell cycle arrest. Importantly, we show that Plk1 also phosphorylates the 53BP1-binding checkpoint kinase Chk2 to inactivate its FHA domain and inhibit its kinase activity in mammalian cells. Thus, a mitotic kinase-mediated negative feedback loop regulates the ATM-Chk2 branch of the DNA damage signaling network by phosphorylating conserved sites in 53BP1 and Chk2 to inactivate checkpoint signaling and control checkpoint duration.
dc.languageeng
dc.language.isoeng
dc.publisherPUBLIC LIBRARY SCIENCE
dc.titleA Mitotic Phosphorylation Feedback Network Connects Cdk1, Plk1, 53BP1, and Chk2 to Inactivate the G2/M DNA Damage Checkpoint
dc.typeJournal Article
rioxxterms.versionofrecord10.1371/journal.pbio.1000287
rioxxterms.licenseref.startdate2010-01
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfPLOS BIOLOGY
pubs.notesaffiliation: van Vugt, MATM (Reprint Author), Univ Groningen, Univ Med Ctr Groningen, Dept Med Oncol, NL-9713 AV Groningen, Netherlands. van Vugt, Marcel A. T. M.; Gardino, Alexandra K.; Ostheimer, Gerard J.; Reinhardt, H. Christian; Yaffe, Michael B., MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. Linding, Rune, Inst Canc Res, Cellular & Mol Log Team Integrat Network Biol Ini, Sect Cell & Mol Biol, London SW3 6JB, England. Ostheimer, Gerard J.; Yaffe, Michael B., MIT, Dept Biol Engn, Cambridge, MA 02139 USA. Ostheimer, Gerard J.; Yaffe, Michael B., MIT, Dept Biol, Cambridge, MA 02139 USA. Ong, Shao-En; Miao, Hua; Pawson, Tony; Lewis, Timothy A.; Carr, Steven A.; Yaffe, Michael B., Broad Inst Harvard & MIT, Cambridge, MA USA. Tan, Chris S., Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. Keezer, Susan M., Cell Signaling Technol, Danvers, MA USA. Li, Jeijin; Smerdon, Stephen J., Natl Inst Med Res, MRC, Div Mol Struct, London NW7 1AA, England. Brummelkamp, Thijn R., MIT, Whitehead Inst, Cambridge, MA 02139 USA. article-number: e1000287 keywords-plus: DOUBLE-STRAND BREAKS; POLO-LIKE KINASE-1; CELL-CYCLE CHECKPOINTS; IONIZING-RADIATION; IN-VIVO; PROTEIN-PHOSPHORYLATION; GENOMIC INSTABILITY; GENOTOXIC STRESS; REPAIR PROTEINS; ACTIVATES ATM research-areas: Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics web-of-science-categories: Biochemistry & Molecular Biology; Biology author-email: [email protected] researcherid-numbers: Li, Jiejin/G-4980-2010 Pawson, Tony/E-4578-2013 Tan, Soon Heng/C-1177-2009 orcid-numbers: Li, Jiejin/0000-0003-1525-7768 funding-acknowledgement: National Institutes of Health [GM68762, CA112967, ES015339]; National Cancer Institute’s Initiative for Chemical Genetics, National Institutes of Health [N01-CO-12400]; Netherlands Organization for Scientific Research (NWO-ZonMW); American Cancer Society [PF-06-286-01-CCG]; Genome Canada through Ontario Genomics Institute; Deutsche Forschungsgemeinschaft [RE2246/1-1]; Deutsche Nierenstiftung; David H. Koch Fund; Medical Research Council [MC_U117584228] funding-text: This work was funded by National Institutes of Health grants GM68762, CA112967, and ES015339 to MBY, and by the National Cancer Institute’s Initiative for Chemical Genetics, National Institutes of Health, under contract no. N01-CO-12400. MVV was supported by a VENI award from the Netherlands Organization for Scientific Research (NWO-ZonMW). AG was supported by a grant from the American Cancer Society # PF-06-286-01-CCG, and RL is supported by Genome Canada through Ontario Genomics Institute and was a Human Frontiers Fellow. HCR was supported by the Deutsche Forschungsgemeinschaft (RE2246/1-1), the Deutsche Nierenstiftung, and the David H. Koch Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. number-of-cited-references: 109 times-cited: 98 usage-count-last-180-days: 0 usage-count-since-2013: 4 journal-iso: PLoS. Biol. doc-delivery-number: 564ZH unique-id: ISI:000275256800017 oa: gold da: 2018-08-23
pubs.notesNot known
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pubs.organisational-group/ICR
pubs.volume8
pubs.embargo.termsNot known
dc.contributor.icrauthorLinding, Runeen


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