Multiple Functions of BRD4 in E2 Mediated HPV Transciptional Regulation




Lee, A-Young

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Human papillomaviruses (HPVs) are DNA viruses that cause benign and malignant tumors of epithelial origins. Expression of HPV-encoded E6 and E7 oncoproteins is controlled by the viral E2 protein, which plays a dual role in gene activation and repression. Recently, we identified bromodomain-containing protein 4 (Brd4) as a cellular corepressor for E2-mediated inhibition of HPV transcription. Brd4 contains two bromodomains which function as acetyl-lysine-binding modules that facilitate chromatin targeting via their interactions with acetylated histones. Although Brd4 has been known to be involved in E2-mediated transcriptional regulation, it was unclear how Brd4 regulates E2 function and whether the involvement of Brd4 in transactivation and transrepression is common to different types of E2 proteins. Here, we show that Brd4 enhances E2 binding to its cognate sequences through Brd4's bromodomains and the E2-interacting region in chromatin. We further demonstrate that the corepressor function of Brd4 is common to E2 proteins encoded by cancer-inducing high-risk HPV, wart-causing low-risk HPV, and bovine papillomavirus type 1. The general cofactor function of Brd4 on E2-mediated transcription is in part controlled by enhancing the protein stability of E2, which is normally degraded via the ubiquitin-dependent proteasome pathway. These findings indicate that a chromatin adaptor can enhance the binding of a sequence-specific transcription factor to chromatin and further promote the stability of a labile transcription factor via direct protein-protein interaction. Also, we identify two additional E2-interacting regions of Brd4: the E2-interacting domain (E2ID) and phosphorylation-dependent interacting domain (PDID). While E2ID binds to all different types of E2 proteins, PDID interacts only with high risk E2 (HRE2) in a casein kinase 2 (CK2) phosphorylation-dependent manner. In addition to HRE2-specific interaction, the phosphorylation of PDID also induces intramolecular interaction between PDID and E2ID, which blocks the E2-interaction of E2ID. Finally, we show that the PDID-HRE2 interaction is important for the HRE2-mediated transcriptional activation. Collectively, our data show that the posttranslational modification of the cellular protein Brd4 confers selective recognition of HRE2, thereby providing a unique regulation mechanism for the protein encoded by cancer-inducing HPV.

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