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dc.contributor.authorHeldt, FSen_US
dc.contributor.authorBarr, ARen_US
dc.contributor.authorCooper, Sen_US
dc.contributor.authorBakal, Cen_US
dc.contributor.authorNovák, Ben_US
dc.date.accessioned2018-03-16T11:55:44Z
dc.date.issued2018-03en_US
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2018, 115 (10), pp. 2532 - 2537en_US
dc.identifier.issn0027-8424en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1601
dc.identifier.eissn1091-6490en_US
dc.identifier.doi10.1073/pnas.1715345115en_US
dc.description.abstractHuman cells that suffer mild DNA damage can enter a reversible state of growth arrest known as quiescence. This decision to temporarily exit the cell cycle is essential to prevent the propagation of mutations, and most cancer cells harbor defects in the underlying control system. Here we present a mechanistic mathematical model to study the proliferation-quiescence decision in nontransformed human cells. We show that two bistable switches, the restriction point (RP) and the G1/S transition, mediate this decision by integrating DNA damage and mitogen signals. In particular, our data suggest that the cyclin-dependent kinase inhibitor p21 (Cip1/Waf1), which is expressed in response to DNA damage, promotes quiescence by blocking positive feedback loops that facilitate G1 progression downstream of serum stimulation. Intriguingly, cells exploit bistability in the RP to convert graded p21 and mitogen signals into an all-or-nothing cell-cycle response. The same mechanism creates a window of opportunity where G1 cells that have passed the RP can revert to quiescence if exposed to DNA damage. We present experimental evidence that cells gradually lose this ability to revert to quiescence as they progress through G1 and that the onset of rapid p21 degradation at the G1/S transition prevents this response altogether, insulating S phase from mild, endogenous DNA damage. Thus, two bistable switches conspire in the early cell cycle to provide both sensitivity and robustness to external stimuli.en_US
dc.formatPrint-Electronicen_US
dc.format.extent2532 - 2537en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden_US
dc.subjectCells, Cultureden_US
dc.subjectHumansen_US
dc.subjectDNA Damageen_US
dc.subjectMitogensen_US
dc.subjectCell Cycleen_US
dc.subjectCell Proliferationen_US
dc.subjectModels, Biologicalen_US
dc.subjectCyclin-Dependent Kinase Inhibitor p21en_US
dc.subjectGene Knockout Techniquesen_US
dc.subjectSingle-Cell Analysisen_US
dc.titleA comprehensive model for the proliferation-quiescence decision in response to endogenous DNA damage in human cells.en_US
dc.typeJournal Article
rioxxterms.versionofrecord10.1073/pnas.1715345115en_US
rioxxterms.licenseref.startdate2018-03en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfProceedings of the National Academy of Sciences of the United States of Americaen_US
pubs.issue10en_US
pubs.notesNo embargoen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Dynamical Cell Systems
pubs.publication-statusPublisheden_US
pubs.volume115en_US
pubs.embargo.termsNo embargoen_US
icr.researchteamDynamical Cell Systemsen_US
dc.contributor.icrauthorBakal, Christopheren_US


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