Chromatin adaptor Brd4 modulates E2 transcription activity and protein stability.
Brd4 is a chromatin adaptor containing tandem bromodomains binding to acetylated histone H3 and H4. Although Brd4 has been implicated in the transcriptional control of papillomavirus-encoded E2 protein, it is unclear how Brd4 regulates E2 function and whether the involvement of Brd4 in transactivation and transrepression is common to different types of E2 proteins. Using DNase I footprinting performed with in vitro reconstituted human papillomavirus (HPV) chromatin and nucleosome-free DNA templates, we found that Brd4 facilitates E2 binding to its cognate sequences in chromatin depending on bromodomains and the E2-interacting region of Brd4. Moreover, the coactivator and corepressor function of Brd4 requires at least one intact bromodomain and is mediated by its direct association with E2 proteins encoded by cancer-inducing high risk HPV-16 and HPV-18, wart-causing low risk HPV-11, and bovine papillomavirus type 1, in part through enhancing the protein stability of E2 that is normally degraded via the ubiquitin-dependent proteasome pathway. Our findings indicate that a chromatin adaptor can bridge and 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.
Lee
A-Young
AY
Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8807.
Chiang
Cheng-Ming
CM
Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8807; Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8807; Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8807. Electronic address: cheng-ming.chiang@utsouthwestern.edu.
D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002843:Chromatin / Q000378:metabolism; D017931:DNA Primers; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology*; D027383:Papillomaviridae / Q000378:metabolism*; D011485:Protein Binding; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
D018797:Cell Cycle Proteins; D002843:Chromatin; D017931:DNA Primers; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014764:Viral Proteins; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins