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BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer.
- Source :
-
Cell reports [Cell Rep] 2018 Jan 16; Vol. 22 (3), pp. 796-808. - Publication Year :
- 2018
-
Abstract
- 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.<br /> (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Acetylation
Cell Cycle Proteins
Cell Line, Tumor
Chromatin genetics
Chromatin metabolism
DNA Damage
Gene Fusion
Gene Rearrangement
Histones genetics
Histones metabolism
Humans
Male
Nuclear Proteins metabolism
Oncogene Proteins, Fusion metabolism
Prostatic Neoplasms metabolism
Prostatic Neoplasms pathology
Transcription Factors metabolism
DNA End-Joining Repair
Nuclear Proteins genetics
Oncogene Proteins, Fusion genetics
Prostatic Neoplasms genetics
Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 22
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 29346775
- Full Text :
- https://doi.org/10.1016/j.celrep.2017.12.078