BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer.
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Date
2018-01-16Author
Li, X
Baek, G
Ramanand, SG
Sharp, A
Gao, Y
Yuan, W
Welti, J
Rodrigues, DN
Dolling, D
Figueiredo, I
Sumanasuriya, S
Crespo, M
Aslam, A
Li, R
Yin, Y
Mukherjee, B
Kanchwala, M
Hughes, AM
Halsey, WS
Chiang, C-M
Xing, C
Raj, GV
Burma, S
de Bono, J
Mani, RS
Type
Journal Article
Metadata
Show full item recordAbstract
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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Subject
Cell Line, Tumor
Chromatin
Humans
Prostatic Neoplasms
DNA Damage
Cell Cycle Proteins
Oncogene Proteins, Fusion
Nuclear Proteins
Histones
Transcription Factors
Gene Fusion
Gene Rearrangement
Acetylation
Male
DNA End-Joining Repair
Research team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Language
eng
Date accepted
2017-12-21
License start date
2018-01
Citation
Cell reports, 2018, 22 (3), pp. 796 - 808
Publisher
CELL PRESS