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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. [Display omitted] • Unlike BETi (JQ1), BRD4 degradation causes profound Pol II pausing genome wide • The bromodomains of BRD4 are dispensable for Pol II pause release in living cells • A BET-less C-terminal BRD4 fragment interacts with PTEFb and releases paused Pol II • The C-terminal disordered region of BRD4 secures cyclin T1 in the BRD4-PTEFb complex Zheng et al. demonstrate that while the regulation of Pol II pause release by BRD4 does not require bromodomain-mediated BRD4 binding to acetylated histones, a bromodomain-less, C-terminal fragment of BRD4 is both necessary and sufficient to drive the release of paused Pol II into productive elongation. [ABSTRACT FROM AUTHOR]