BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer

Xiangyi Li, Guem Hee Baek, Susmita G. Ramanand, Adam Sharp, Yunpeng Gao, Wei Yuan, Jon Welti, Daniel N. Rodrigues, David Dolling, Ines Figueiredo, Semini Sumanasuriya, Mateus Crespo, Adam Aslam, Rui Li, Yi Yin, Bipasha Mukherjee, Mohammed Kanchwala, Ashley M. Hughes, Wendy S. Halsey, Cheng Ming ChiangChao Xing, Ganesh V. Raj, Sandeep Burma, Johann de Bono, Ram S. Mani

Research output: Contribution to journalArticle

16 Citations (Scopus)

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. The classic function of BRD4 is to regulate gene expression. Li et al. present experimental and clinical data to suggest that BRD4 is also a key player in DNA repair and is associated with the development of CRPC after radiation therapy.

Original languageEnglish (US)
Pages (from-to)796-808
Number of pages13
JournalCell Reports
Volume22
Issue number3
DOIs
StatePublished - Jan 16 2018

Fingerprint

Gene Rearrangement
DNA Repair
Prostatic Neoplasms
Repair
Double-Stranded DNA Breaks
Genes
Gene Expression
Histones
Gene expression
DNA
Radiotherapy
Neoplasms
DNA Breaks
Acetylation
Chromatin
Proteins
Genome
Pharmacology
Joining
Tumors

Keywords

  • BRD2
  • BRD4
  • CRPC
  • DNA repair
  • gene fusion
  • genomic rearrangements
  • NHEJ
  • non-homologous end joining
  • prostate cancer
  • TMPRSS2-ERG

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer. / Li, Xiangyi; Baek, Guem Hee; Ramanand, Susmita G.; Sharp, Adam; Gao, Yunpeng; Yuan, Wei; Welti, Jon; Rodrigues, Daniel N.; Dolling, David; Figueiredo, Ines; Sumanasuriya, Semini; Crespo, Mateus; Aslam, Adam; Li, Rui; Yin, Yi; Mukherjee, Bipasha; Kanchwala, Mohammed; Hughes, Ashley M.; Halsey, Wendy S.; Chiang, Cheng Ming; Xing, Chao; Raj, Ganesh V.; Burma, Sandeep; de Bono, Johann; Mani, Ram S.

In: Cell Reports, Vol. 22, No. 3, 16.01.2018, p. 796-808.

Research output: Contribution to journalArticle

Li, X, Baek, GH, 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, CM, Xing, C, Raj, GV, Burma, S, de Bono, J & Mani, RS 2018, 'BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer', Cell Reports, vol. 22, no. 3, pp. 796-808. https://doi.org/10.1016/j.celrep.2017.12.078
Li, Xiangyi ; Baek, Guem Hee ; Ramanand, Susmita G. ; Sharp, Adam ; Gao, Yunpeng ; Yuan, Wei ; Welti, Jon ; Rodrigues, Daniel N. ; Dolling, David ; Figueiredo, Ines ; Sumanasuriya, Semini ; Crespo, Mateus ; Aslam, Adam ; Li, Rui ; Yin, Yi ; Mukherjee, Bipasha ; Kanchwala, Mohammed ; Hughes, Ashley M. ; Halsey, Wendy S. ; Chiang, Cheng Ming ; Xing, Chao ; Raj, Ganesh V. ; Burma, Sandeep ; de Bono, Johann ; Mani, Ram S. / BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer. In: Cell Reports. 2018 ; Vol. 22, No. 3. pp. 796-808.
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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. The classic function of BRD4 is to regulate gene expression. Li et al. present experimental and clinical data to suggest that BRD4 is also a key player in DNA repair and is associated with the development of CRPC after radiation therapy.",
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T1 - BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer

AU - Li, Xiangyi

AU - Baek, Guem Hee

AU - Ramanand, Susmita G.

AU - Sharp, Adam

AU - Gao, Yunpeng

AU - Yuan, Wei

AU - Welti, Jon

AU - Rodrigues, Daniel N.

AU - Dolling, David

AU - Figueiredo, Ines

AU - Sumanasuriya, Semini

AU - Crespo, Mateus

AU - Aslam, Adam

AU - Li, Rui

AU - Yin, Yi

AU - Mukherjee, Bipasha

AU - Kanchwala, Mohammed

AU - Hughes, Ashley M.

AU - Halsey, Wendy S.

AU - Chiang, Cheng Ming

AU - Xing, Chao

AU - Raj, Ganesh V.

AU - Burma, Sandeep

AU - de Bono, Johann

AU - Mani, Ram S.

PY - 2018/1/16

Y1 - 2018/1/16

N2 - 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. The classic function of BRD4 is to regulate gene expression. Li et al. present experimental and clinical data to suggest that BRD4 is also a key player in DNA repair and is associated with the development of CRPC after radiation therapy.

AB - 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. The classic function of BRD4 is to regulate gene expression. Li et al. present experimental and clinical data to suggest that BRD4 is also a key player in DNA repair and is associated with the development of CRPC after radiation therapy.

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KW - non-homologous end joining

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KW - TMPRSS2-ERG

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