dc.contributor.author | Zhang, J | |
dc.contributor.author | Dulak, AM | |
dc.contributor.author | Hattersley, MM | |
dc.contributor.author | Willis, BS | |
dc.contributor.author | Nikkilä, J | |
dc.contributor.author | Wang, A | |
dc.contributor.author | Lau, A | |
dc.contributor.author | Reimer, C | |
dc.contributor.author | Zinda, M | |
dc.contributor.author | Fawell, SE | |
dc.contributor.author | Mills, GB | |
dc.contributor.author | Chen, H | |
dc.date.accessioned | 2020-05-19T13:40:55Z | |
dc.date.issued | 2018-07-12 | |
dc.identifier.citation | Oncogene, 2018, 37 (28), pp. 3763 - 3777 | |
dc.identifier.issn | 0950-9232 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3617 | |
dc.identifier.eissn | 1476-5594 | |
dc.identifier.doi | 10.1038/s41388-018-0194-3 | |
dc.description.abstract | Previous 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. | |
dc.format | Print-Electronic | |
dc.format.extent | 3763 - 3777 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Mice, SCID | |
dc.subject | DNA Damage | |
dc.subject | Sulfoxides | |
dc.subject | Piperazines | |
dc.subject | Pyrimidines | |
dc.subject | Heterocyclic Compounds, 2-Ring | |
dc.subject | Nuclear Proteins | |
dc.subject | Transcription Factors | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Signal Transduction | |
dc.subject | DNA Replication | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Phosphorylation | |
dc.subject | Female | |
dc.title | BRD4 facilitates replication stress-induced DNA damage response. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-02-05 | |
rioxxterms.versionofrecord | 10.1038/s41388-018-0194-3 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2018-07 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Oncogene | |
pubs.issue | 28 | |
pubs.notes | Not known | |
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.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-status | Published | |
pubs.volume | 37 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Target Biology and Genomic Instability | |
dc.contributor.icrauthor | Wang, Anderson | |