Brd4, a bromodomain protein that contributes to the regulation of transcription initiation and elongation, has been implicated in regulation of both primary and metastatic tumor growth. However, the molecular mechanism(s) of Brd4 function remains unknown. Since Brd4 binds acetylated histones in chromatin, it has been presumed that it functions to recruit a critical transcriptional regulator (PTEFb) to promoters. We now identify Brd4 as a Pol II CTD Ser2 kinase that phosphorylates the CTD of Pol II independent of other CTD kinases, both in vitro and in vivo, providing a novel function for this tumor regulatory protein, which fundamentally alters our understanding of its mechanism of action.
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