Abstract
SummaryBET bromodomain proteins are required for oncogenic transcription activities, and BET inhibitors have been rapidly advanced into clinical trials. Understanding the effects of BET inhibition on processes such as DNA replication will be important for future clinical applications. Here, we show that BET inhibition, and specifically inhibition of BRD4, causes replication stress through a rapid overall increase in RNA synthesis. We provide evidence that BET inhibition acts by releasing P-TEFb from its inhibitor HEXIM1, promoting interference between transcription and replication. Unusually, these transcription-replication conflicts do not activate the ATM/ATR-dependent DNA damage response but recruit the homologous recombination factor RAD51. Both HEXIM1 and RAD51 promote BET inhibitor-induced fork slowing but also prevent a DNA damage response. Our data suggest that BET inhibitors slow replication through concerted action of transcription and recombination machineries and shed light on the importance of replication stress in the action of this class of experimental cancer drugs.
Highlights
Members of the BET bromodomain-containing protein family bind to lysine-acetylated histone tails and regulate transcription by recruiting and activating positive transcription elongation factor b (P-TEFb)
P-TEFb can occur in two active complexes with BET protein BRD4 or the super elongation complex (SEC) and an inactive complex with 7SK-snRP (7SK RNA, HEXIM1, LARP7, and MEPCE)
We show that BET inhibition and loss of BRD4 cause rapid upregulation of RNA synthesis and transcription-dependent replication fork slowing in a pathway that depends on HEXIM1 and RAD51
Summary
Members of the BET bromodomain-containing protein family bind to lysine-acetylated histone tails and regulate transcription by recruiting and activating positive transcription elongation factor b (P-TEFb). P-TEFb can occur in two active complexes with BET protein BRD4 or the super elongation complex (SEC) and an inactive complex with 7SK-snRP (7SK RNA, HEXIM1, LARP7, and MEPCE). BRD4 activates P-TEFb by releasing it from 7SK-snRP and recruits active P-TEFb to gene promoters (Quaresma et al, 2016). BET proteins promote oncogenic transcription programs, and specific small-molecule inhibitors of BET bromodomains promise a targeted cancer treatment (Delmore et al, 2011). BET inhibition downregulates MYC protein levels and kills tumor cells independently of p53 (Da Costa et al, 2013). BET inhibitor responses can be MYC independent (Lockwood et al, 2012). The molecular mechanisms surrounding BET inhibitor action are still poorly understood, BET inhibitors are already undergoing clinical trials in a wide range of cancers (Andrieu et al, 2016; Fujisawa and Filippakopoulos, 2017)
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