Distinct layers of BRD4-PTEFb reveal bromodomain-independent function in transcriptional regulation

Bin Zheng, Sarah Gold, Marta Iwanaszko, Benjamin Charles Howard, Lu Wang*, Ali Shilatifard*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

The BET family protein BRD4, which forms the CDK9-containing BRD4-PTEFb complex, is considered to be a master regulator of RNA polymerase II (Pol II) pause release. Because its tandem bromodomains interact with acetylated histone lysine residues, it has long been thought that BRD4 requires these bromodomains for its recruitment to chromatin and transcriptional regulatory function. Here, using rapid depletion and genetic complementation with domain deletion mutants, we demonstrate that BRD4 bromodomains are dispensable for Pol II pause release. A minimal, bromodomain-less C-terminal BRD4 fragment containing the PTEFb-interacting C-terminal motif (CTM) is instead both necessary and sufficient to mediate Pol II pause release in the absence of full-length BRD4. Although BRD4-PTEFb can associate with chromatin through acetyl recognition, our results indicate that a distinct, active BRD4-PTEFb population functions to regulate transcription independently of bromodomain-mediated chromatin association. These findings may enable more effective pharmaceutical modulation of BRD4-PTEFb activity.

Original languageEnglish (US)
Pages (from-to)2896-2910.e4
JournalMolecular cell
Volume83
Issue number16
DOIs
StatePublished - Aug 17 2023

Keywords

  • BRD4
  • JQ1
  • PTEFb
  • Pol II
  • bromodomains
  • dBET6
  • elongation
  • pause release
  • rapid depletion

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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