BRD4 facilitates replication stress-induced DNA damage response

Jingwen Zhang, Austin M. Dulak, Maureen M. Hattersley, Brandon S. Willis, Jenni Nikkilä, Anderson Wang, Alan Lau, Corinne Reimer, Michael Zinda, Stephen E. Fawell, Gordon B. Mills, Huawei Chen

    Research output: Contribution to journalArticle

    18 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)3763-3777
    Number of pages15
    JournalOncogene
    Volume37
    Issue number28
    DOIs
    StatePublished - Jul 12 2018

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Cancer Research

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  • Cite this

    Zhang, J., Dulak, A. M., Hattersley, M. M., Willis, B. S., Nikkilä, J., Wang, A., Lau, A., Reimer, C., Zinda, M., Fawell, S. E., Mills, G. B., & Chen, H. (2018). BRD4 facilitates replication stress-induced DNA damage response. Oncogene, 37(28), 3763-3777. https://doi.org/10.1038/s41388-018-0194-3