BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer
Open accessAbstract
BRD4 belongs to the bromodomain and extraterminal (BET) family of chromatin reader proteins that bind acetylated histones and regulate gene expression. Pharmacological inhibition of BRD4 by BET inhibitors (BETi) has indicated antitumor activity against multiple cancer types. We show that BRD4 is essential for the repair of DNA double-strand breaks (DSBs) and mediates the formation of oncogenic gene rearrangements by engaging the non-homologous end joining (NHEJ) pathway. Mechanistically, genome-wide DNA breaks are associated with enhanced acetylation of histone H4, leading to BRD4 recruitment, and stable establishment of the DNA repair complex. In support of this, we also show that, in clinical tumor samples, BRD4 protein levels are negatively associated with outcome after prostate cancer (PCa) radiation therapy. Thus, in addition to regulating gene expression, BRD4 is also a central player in the repair of DNA DSBs, with significant implications for cancer therapy.
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BRD4 can bind 53BP1 and recruit it to DNA double-strand break sites, thereby facilitating NHEJ in a transcriptionally independent manner.
“BRD4 has the potential to bind 53BP1, a DNA damage response protein serving as an adaptor for the assembly and activation of the DNA repair machinery, and recruit it to DSB sites, thereby facilitating NHEJ in a transcriptionally independent manner32,33.”
From A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells (2020) · cites this paper as [33]
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References 48 · Cited by 148
- Authors
- Li, X., Baek, G., Ramanand, S. G., Sharp, A., Gao, Y., Yuan, W., Welti, J., Rodrigues, D. N., Dolling, D., Figueiredo, I., Sumanasuriya, S., Crespo, M., Aslam, A., Li, R., Yin, Y., Mukherjee, B., Kanchwala, M., Hughes, A. M., Halsey, W. S., Chiang, C.-M., Xing, C., Raj, G. V., Burma, S., de Bono, J., & Mani, R. S.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Royal Marsden NHS Foundation Trust (GB)
- Institute of Cancer Research (GB)
- GlaxoSmithKline (United States) (US)
- Harold C. Simmons Comprehensive Cancer Center (US)
- Corresponding author
- Mani, Ram S.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 22
- Issue
- 3
- Pages
- 796-808
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5843368
- OpenAlex
- W2784159027
- Cited by
- 148
- References
- 48
- Citations by year
- 2026: 12 · 2025: 21 · 2024: 16 · 2023: 25 · 2022: 22 · 2021: 17 · 2020: 12 · 2019: 17 · 2018: 6
- FWCI
- 4.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Prostate Cancer UK
- DOD Prostate Cancer Research Program
- Welch Foundation (UL1TR001105, I-1805)
- Institute of Cancer Research
- Academy of Medical Sciences
- National Cancer Institute (1P30 CA142543-01, R00CA160640)
- National Aeronautics and Space Administration (CA103867, NNX16AD78G)
- Cancer Research UK
- Stand Up To Cancer
- National Institute on Handicapped Research
- Medical Research Council
- Cancer Prevention and Research Institute of Texas (RP140367)
- Prostate Cancer Foundation
- National Institutes of Health (R21CA202403, RO1CA197796, RO1CA149461)
- Movember Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- BRD4, BET proteins, DNA double-strand break repair, non-homologous end joining, TMPRSS2-ERG fusion, prostate cancer, histone H4 acetylation, chromatin reader proteins, BET inhibitors, radiotherapy
- MeSH terms
- Bromodomain Containing Proteins, Acetylation, Chromatin, DNA Damage, Histones, Humans, Male, Nuclear Proteins, Prostatic Neoplasms, Transcription Factors, Gene Rearrangement, Oncogene Proteins, Fusion, Cell Cycle Proteins, Cell Line, Tumor, Gene Fusion, DNA End-Joining Repair
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