BRD4 is an atypical kinase that phosphorylates Serine2 of the RNA~ Polymerase II carboxy-terminal domain.

The btomodomain protein. BRD4, has been identified recently as a therapeusic target in acute myeloid leukemia, multiple myeloma, Burkitt's lymphoma. NUT midline carcinoma, colon cancer, and inflammatory disease; its loss is a prognostic signature for meta- static breast cancer. BRD4 also contributes to regulation of both cell cycle and transcription of oncogenes. HIV, and human papil- loma virus (HPV). Despite its role in a broad range of biological processes, the precise molecular mechanism of BRD4 function remains unknown. We report that BRD4 is an atypical kinase that binds to the carboxyl-terminal domain (GD) of RNA polymerase II and directly phosphorylates its serine 2 (Ser2) sites both in vitro and in vivo under conditions where other GD kinases are inactive. Phosphorylation of the GD Ser2 is inhibited in vivo by a BRD4 inhibitor that blocks its binding to chromatin. Our finding that BRD4 is an RNA polymerase II GD Ser2 kinase implicates it as a regulator of eukaryotic transcription. [ABSTRACT FROM AUTHOR]