title: The cellular bromodomain protein Brd4 has multiple functions in E2-mediated papillomavirus transcription activation.
abstract: The cellular bromodomain protein Brd4 functions in multiple processes of the papillomavirus life cycle, including viral replication, genome maintenance, and gene transcription through its interaction with the viral protein, E2. However, the mechanisms by which E2 and Brd4 activate viral transcription are still not completely understood. In this study, we show that recruitment of positive transcription elongation factor b (P-TEFb), a functional interaction partner of Brd4 in transcription activation, is important for E2's transcription activation activity. Furthermore, chromatin immunoprecipitation (ChIP) analyses demonstrate that P-TEFb is recruited to the actual papillomavirus episomes. We also show that E2's interaction with cellular chromatin through Brd4 correlates with its papillomavirus transcription activation function since JQ1(+), a bromodomain inhibitor that efficiently dissociates E2-Brd4 complexes from chromatin, potently reduces papillomavirus transcription. Our study identifies a specific function of Brd4 in papillomavirus gene transcription and highlights the potential use of bromodomain inhibitors as a method to disrupt the human papillomavirus (HPV) life cycle.
authors.affiliation: Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA. chelfer@mail.med.upenn.edu.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Helfer
authors.affiliation: Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA. yanjunpeng1980@hotmail.com.
authors.forename: Junpeng
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA. jianyou@mail.med.upenn.edu.
authors.forename: Jianxin
authors.initials: J
authors.lastname: You
mesh_terms: D018797:Cell Cycle Proteins; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004279:DNA, Viral / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000378:metabolism* / Q000502:physiology*; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D042925:Positive Transcriptional Elongation Factor B; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C054855:E2 protein, Human papillomavirus type 16