The papillomaviruses (PVs) are a group of small DNA viruses that induce benign lesions in variety of higher vertebrates, including humans. Certain papillomaviruses, including the human papillomaviruses (HPVs) such as HPV16 and 18, are also associated with the pathogenesis of cervical cancer and other human tumors. Papillomaviruses establish persistent infections in which the viral genomes are maintained as autonomous replicating plasmids at a low copy number in the nuclei of proliferating host cells. In bovine papillomavirus (BPV1) transformed mouse cells, the viral genomes also replicate as multicopy nuclear plasmids that can persist over long periods of time to maintain the transformation status of the cells. To ensure persistence in both infected and transformed cells, the replicated viral genomes must be partitioned and maintained in the nuclei of daughter cells following mitosis. Without a mechanism to ensure the localization of the viral genome within the nuclear envelope following nuclear reassembly, the viral genome could be left behind in the cytoplasm and lost either through degradation or dilution after cell division. The papillomavirus E2 protein, which is an important regulatory protein that plays critical roles in viral transcriptional and viral DNA replication, is also required for viral genome maintenance in dividing cells. E2, as well as the PV genomes, are closely associated with mitotic chromosomes in dividing cells. Utilizing a proteomic approach to systematically characterize cellular proteins that associate with E2 in vivo, we recently identified Brd4 (bromodomain-containing protein 4) as an E2 interacting protein and showed that it functions as the mitotic chromosome receptor for BPV1 E2. The focus of this research grant is to extend these studies on the PV E2 proteins and to examine the functional significance of the interaction of E2 with Brd4 to other aspects of the viral life cycle. Disruption of the binding of E2 to Brd4 can block the transformation of cells by BPV1 and the association of E2 and the viral DNA with mitotic chromosomes. Chemical genetic screens will be conducted to identify small molecule inhibitors of E2/Brd4 binding as potential lead molecules for novel therapeutic antiviral compounds. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Virology - B Study Section (VIRB)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Schools of Medicine
United States
Zip Code
Howley, Peter M; Pfister, Herbert J (2015) Beta genus papillomaviruses and skin cancer. Virology 479-480:290-6
French, Christopher A; Rahman, Shaila; Walsh, Erica M et al. (2014) NSD3-NUT fusion oncoprotein in NUT midline carcinoma: implications for a novel oncogenic mechanism. Cancer Discov 4:928-41
Smith, Jennifer A; Haberstroh, Friederike S; White, Elizabeth A et al. (2014) SMCX and components of the TIP60 complex contribute to E2 regulation of the HPV E6/E7 promoter. Virology 468-470:311-21
Rahman, Shaila; Sowa, Mathew E; Ottinger, Matthias et al. (2011) The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Mol Cell Biol 31:2641-52
Smith, Jennifer A; White, Elizabeth A; Sowa, Mathew E et al. (2010) Genome-wide siRNA screen identifies SMCX, EP400, and Brd4 as E2-dependent regulators of human papillomavirus oncogene expression. Proc Natl Acad Sci U S A 107:3752-7
Zheng, Gang; Schweiger, Michal-Ruth; Martinez-Noel, Gustavo et al. (2009) Brd4 regulation of papillomavirus protein E2 stability. J Virol 83:8683-92
You, Jianxin; Li, Qing; Wu, Chong et al. (2009) Regulation of aurora B expression by the bromodomain protein Brd4. Mol Cell Biol 29:5094-103
Ottinger, Matthias; Smith, Jennifer A; Schweiger, Michal-Ruth et al. (2009) Cell-type specific transcriptional activities among different papillomavirus long control regions and their regulation by E2. Virology 395:161-71
Ottinger, Matthias; Pliquet, Daniel; Christalla, Thomas et al. (2009) The interaction of the gammaherpesvirus 68 orf73 protein with cellular BET proteins affects the activation of cell cycle promoters. J Virol 83:4423-34
Schweiger, Michal-Ruth; Ottinger, Matthias; You, Jianxin et al. (2007) Brd4-independent transcriptional repression function of the papillomavirus e2 proteins. J Virol 81:9612-22

Showing the most recent 10 out of 13 publications