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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National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Devaiah, Ballachanda N; Gegonne, Anne; Singer, Dinah S (2016) Bromodomain 4: a cellular Swiss army knife. J Leukoc Biol 100:679-686
Baranello, Laura; Wojtowicz, Damian; Cui, Kairong et al. (2016) RNA Polymerase II Regulates Topoisomerase 1 Activity to Favor Efficient Transcription. Cell 165:357-71
Pradhan, Madhumita A; Blackford Jr, John A; Devaiah, Ballachanda N et al. (2016) Kinetically Defined Mechanisms and Positions of Action of Two New Modulators of Glucocorticoid Receptor-regulated Gene Induction. J Biol Chem 291:342-54
Devaiah, Ballachanda N; Singer, Dinah S (2013) Two faces of brd4: mitotic bookmark and transcriptional lynchpin. Transcription 4:13-7
Devaiah, Ballachanda N; Lewis, Brian A; Cherman, Natasha et al. (2012) BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain. Proc Natl Acad Sci U S A 109:6927-32
Devaiah, Ballachanda N; Singer, Dinah S (2012) Cross-talk among RNA polymerase II kinases modulates C-terminal domain phosphorylation. J Biol Chem 287:38755-66