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BET Inhibition Induces HEXIM1- and RAD51-Dependent Conflicts between Transcription and Replication

30 Pages Posted: 7 Jan 2019 Publication Status: Published

See all articles by Akhil Bowry

Akhil Bowry

University of Birmingham - Institute of Cancer and Genomic Sciences

Ann Liza Piberger

University of Birmingham - Institute of Cancer and Genomic Sciences

Eva Petermann

University of Birmingham - Institute of Cancer and Genomic Sciences

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Abstract

BET bromodomain proteins are epigenetic readers required for oncogenic transcription activities, and BET inhibitors have been rapidly advanced into clinical trials. Understanding the effects of BET inhibition on other nuclear processes such as DNA replication will be important for future clinical applications. Here we show that BET inhibition causes replication stress in cancer and non-cancer cells due to a rapid burst in global RNA synthesis and interference of transcription with replication. We identify BRD4 as the main BET inhibitor target in this process and provide evidence that BRD4 inhibition causes transcription-replication interference through release of P-TEFb from its inhibitor HEXIM1, promoting RNA Polymerase II phosphorylation. Unusually, BET inhibitor-induced transcription-replication interference does not activate the classic ATM/ATR-dependent DNA damage response. We show however that they promote foci formation of the homologous recombination factor RAD51. Both HEXIM1 and RAD51 are required for BET inhibitor-induced fork slowing, but rescuing fork slowing by HEXIM1 or RAD51 depletion activate a DNA damage response. Our data support a new mechanism where BRD4 inhibition slows replication and suppresses DNA damage through concerted action of transcription and homologous recombination machineries. They shed new light on the roles of DNA replication and recombination in the action of this new class of cancer drugs.

Suggested Citation

Bowry, Akhil and Piberger, Ann Liza and Petermann, Eva, BET Inhibition Induces HEXIM1- and RAD51-Dependent Conflicts between Transcription and Replication (2018). Available at SSRN: https://ssrn.com/abstract=3219270 or http://dx.doi.org/10.2139/ssrn.3219270
This version of the paper has not been formally peer reviewed.

Akhil Bowry

University of Birmingham - Institute of Cancer and Genomic Sciences

Edgbaston, Birmingham B15 2TT
United Kingdom

Ann Liza Piberger

University of Birmingham - Institute of Cancer and Genomic Sciences

Edgbaston, Birmingham B15 2TT
United Kingdom

Eva Petermann (Contact Author)

University of Birmingham - Institute of Cancer and Genomic Sciences ( email )

Edgbaston, Birmingham B15 2TT
United Kingdom

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