Transcriptional Regulation and DNA Replication in Human Papillomaviruses (HPVs)
HPVs induce many human diseases, including skin warts, genital warts, cervical cancer, anal cancer, and head-and-neck cancer.
We are interested in understanding the mechanisms by which virus-encoded E2 and E6 proteins activate or repress HPV transcription in the context of both DNA and chromatin templates.
Using in vitro-reconstituted HPV minichromosome that faithfully recapitulates in vivo phasing of HPV chromatin, we first identified bromodomain-containing protein 4 (BRD4) as the cellular adaptor mediating the repressing activity of HPV E2 that controls E6 and E7 gene transcription.
We have elucidated the repression mechanisms employed by the E2-BRD4 silencing complex and defined the role of SMC5 and SMC6 proteins in regulating E2 function in transcription, cell cycle checkpoint control, viral DNA replication, and HPV genome maintenance and segregation.
HPV-encoded E6 inhibits p53 target gene transcription by inducing p53 degradation through ubiquitin-dependent proteosome pathway or by epigenetic mechanisms through suppressing of p300/CBP histone acetyltransferase (HAT) activity independent of p53 degradation pathway.