title: BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain.
abstract: The bromodomain protein, BRD4, has been identified recently as a therapeutic 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 metastatic breast cancer. BRD4 also contributes to regulation of both cell cycle and transcription of oncogenes, HIV, and human papilloma 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 (CTD) of RNA polymerase II and directly phosphorylates its serine 2 (Ser2) sites both in vitro and in vivo under conditions where other CTD kinases are inactive. Phosphorylation of the CTD Ser2 is inhibited in vivo by a BRD4 inhibitor that blocks its binding to chromatin. Our finding that BRD4 is an RNA polymerase II CTD Ser2 kinase implicates it as a regulator of eukaryotic transcription.
authors.affiliation: Experimental Immunology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ballachanda N
authors.initials: BN
authors.lastname: Devaiah
authors.forename: Brian A
authors.initials: BA
authors.lastname: Lewis
authors.forename: Natasha
authors.initials: N
authors.lastname: Cherman
authors.forename: Michael C
authors.initials: MC
authors.lastname: Hewitt
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
authors.forename: Pamela G
authors.initials: PG
authors.lastname: Robey
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sims
authors.forename: Dinah S
authors.initials: DS
authors.lastname: Singer
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D012319:RNA Polymerase II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D012319:RNA Polymerase II; D011994:Recombinant Proteins; D012694:Serine; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C486694:Brd4 protein, mouse