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

Akhil Bowry1, Ann Liza Piberger1, Patricia Rojas1

  • 1Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.

Cell Reports
|November 22, 2018
PubMed

Insights

BET inhibitors, particularly BRD4 inhibitors, induce replication stress by increasing RNA synthesis. This process involves transcription-replication conflicts that recruit RAD51, influencing DNA replication fork dynamics in cancer drug development.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • BET bromodomain proteins are crucial for oncogenic transcription.
  • BET inhibitors are emerging as a promising class of cancer therapeutics.
  • Understanding BET inhibition's impact on DNA replication is vital for clinical use.

Purpose of the Study:

  • To investigate the effects of BET inhibition on DNA replication.
  • To elucidate the molecular mechanisms underlying BET inhibitor-induced replication stress.

Main Methods:

  • Assessed the impact of BET inhibition, specifically BRD4 inhibition, on cellular processes.
  • Investigated the role of P-TEFb, HEXIM1, and RAD51 in response to BET inhibition.
  • Analyzed the activation of DNA damage response pathways (ATM/ATR) and homologous recombination.

Main Results:

  • BET inhibition, particularly of BRD4, triggers replication stress via increased RNA synthesis.
  • BET inhibition releases P-TEFb from HEXIM1, leading to transcription-replication conflicts.
  • These conflicts recruit RAD51, slowing replication forks without activating ATM/ATR DNA damage response.

Conclusions:

  • BET inhibitors induce replication fork slowing through coordinated transcription and recombination.
  • HEXIM1 and RAD51 play protective roles, preventing a DNA damage response during BET inhibition.
  • Replication stress is a key mechanism in the action of BET inhibitors as experimental cancer drugs.
Keywords:
BRD4DNA damageI-BET151JQ1P-TEFbcancerhomologous recombinationreplication forkreplication stress

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