BRD4 facilitates replication stress-induced DNA damage response.
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Date
2018-07-12ICR Author
Author
Zhang, J
Dulak, AM
Hattersley, MM
Willis, BS
Nikkilä, J
Wang, A
Lau, A
Reimer, C
Zinda, M
Fawell, SE
Mills, GB
Chen, H
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
Animals
Humans
Mice
Mice, SCID
DNA Damage
Sulfoxides
Piperazines
Pyrimidines
Heterocyclic Compounds, 2-Ring
Nuclear Proteins
Transcription Factors
Xenograft Model Antitumor Assays
Signal Transduction
DNA Replication
Gene Expression Regulation, Neoplastic
Phosphorylation
Female
Research team
Target Biology and Genomic Instability
Language
eng
Date accepted
2018-02-05
License start date
2018-07
Citation
Oncogene, 2018, 37 (28), pp. 3763 - 3777
Publisher
NATURE PUBLISHING GROUP