BRD4 facilitates replication stress-induced DNA damage response.
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Embargo End Date
ICR Authors
Authors
Zhang, J
Dulak, AM
Hattersley, MM
Willis, BS
Nikkilä, J
Wang, A
Lau, A
Reimer, C
Zinda, M
Fawell, SE
Mills, GB
Chen, H
Dulak, AM
Hattersley, MM
Willis, BS
Nikkilä, J
Wang, A
Lau, A
Reimer, C
Zinda, M
Fawell, SE
Mills, GB
Chen, H
Document Type
Journal Article
Date
2018-07-12
Date Accepted
2018-02-05
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.
Citation
Oncogene, 2018, 37 (28), pp. 3763 - 3777
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
0950-9232
eISSN
1476-5594
Collections
Research Team
Target Biology and Genomic Instability