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dc.contributor.authorZhang, Jen_US
dc.contributor.authorDulak, AMen_US
dc.contributor.authorHattersley, MMen_US
dc.contributor.authorWillis, BSen_US
dc.contributor.authorNikkilä, Jen_US
dc.contributor.authorWang, Aen_US
dc.contributor.authorLau, Aen_US
dc.contributor.authorReimer, Cen_US
dc.contributor.authorZinda, Men_US
dc.contributor.authorFawell, SEen_US
dc.contributor.authorMills, GBen_US
dc.contributor.authorChen, Hen_US
dc.date.accessioned2020-05-19T13:40:55Z
dc.date.issued2018-07en_US
dc.identifier.citationOncogene, 2018, 37 (28), pp. 3763 - 3777en_US
dc.identifier.issn0950-9232en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3617
dc.identifier.eissn1476-5594en_US
dc.identifier.doi10.1038/s41388-018-0194-3en_US
dc.description.abstractPrevious reports have demonstrated that select cancers depend on BRD4 to regulate oncogenic gene transcriptional programs. Here we describe a novel role for BRD4 in DNA damage response (DDR). BRD4 associates with and regulates the function of pre-replication factor CDC6 and plays an indispensable part in DNA replication checkpoint signaling. Inhibition of BRD4 by JQ1 or AZD5153 resulted in a rapid, time-dependent reduction in CHK1 phosphorylation and aberrant DNA replication re-initiation. Furthermore, BRD4 inhibition sensitized cancer cells to various replication stress-inducing agents, and synergized with ATR inhibitor AZD6738 to induce cell killing across a number of cancer cell lines. The synergistic interaction between AZD5153 and AZD6738 is translatable to in vivo ovarian cell-line and patient-derived xenograft models. Taken together, our study uncovers a new biological function of BRD4 and provides mechanistic rationale for combining BET inhibitors with DDR-targeted agents for cancer therapy.en_US
dc.formatPrint-Electronicen_US
dc.format.extent3763 - 3777en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserveden_US
dc.subjectCell Line, Tumoren_US
dc.subjectAnimalsen_US
dc.subjectHumansen_US
dc.subjectMiceen_US
dc.subjectMice, SCIDen_US
dc.subjectDNA Damageen_US
dc.subjectSulfoxidesen_US
dc.subjectPiperazinesen_US
dc.subjectPyrimidinesen_US
dc.subjectHeterocyclic Compounds, 2-Ringen_US
dc.subjectNuclear Proteinsen_US
dc.subjectTranscription Factorsen_US
dc.subjectXenograft Model Antitumor Assaysen_US
dc.subjectSignal Transductionen_US
dc.subjectDNA Replicationen_US
dc.subjectGene Expression Regulation, Neoplasticen_US
dc.subjectPhosphorylationen_US
dc.subjectFemaleen_US
dc.titleBRD4 facilitates replication stress-induced DNA damage response.en_US
dc.typeJournal Article
dcterms.dateAccepted2018-02-05en_US
rioxxterms.versionofrecord10.1038/s41388-018-0194-3en_US
rioxxterms.licenseref.startdate2018-07en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfOncogeneen_US
pubs.issue28en_US
pubs.notesNot knownen_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 Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Biology and Genomic Instability
pubs.publication-statusPublisheden_US
pubs.volume37en_US
pubs.embargo.termsNot knownen_US
icr.researchteamTarget Biology and Genomic Instabilityen_US
dc.contributor.icrauthorWang, Andersonen_US


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