Papillomavirus infection causes persistent epithelial lesions, known as papillomas. Papillomavirus infection is also associated with the development of cervical cancer. Our laboratory has established that papillomavirus genomes and the E2 transactivator protein interact with cellular mitotic chromosomes in dividing cells. This ensures that viral genomes are properly segregated to daughter cells and are retained within the nucleus.
Our aim i s to elucidate the mechanisms by which the E2 proteins control the viral life cycle. We have identified persistent and distinctive chromatin binding sites for the E2-Brd4 complex on human chromosomes. These novel sites persist in both interphase and mitotic cells. We propose that the viral DNA is tethered to these sites to maintain and partition the genomes. Understanding how the virus takes advantage of the inherent properties of the Brd4 protein is greatly increasing our understanding of epigenetic regulation and memory of the human genome. Comparative sequence and structural analysis of E2 proteins from different HPVs is providing insight into different mechanisms of persistent viral infection.

Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2013
Total Cost
$422,693
Indirect Cost
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Porter, Samuel S; Stepp, Wesley H; Stamos, James D et al. (2016) Host cell restriction factors that limit transcription and replication of human papillomavirus. Virus Res :
Van Doorslaer, Koenraad; McBride, Alison A (2016) Molecular archeological evidence in support of the repeated loss of a papillomavirus gene. Sci Rep 6:33028
McKinney, Caleb C; Hussmann, Katherine L; McBride, Alison A (2015) The Role of the DNA Damage Response throughout the Papillomavirus Life Cycle. Viruses 7:2450-69
Jang, Moon Kyoo; Anderson, D Eric; van Doorslaer, Koenraad et al. (2015) A proteomic approach to discover and compare interacting partners of papillomavirus E2 proteins from diverse phylogenetic groups. Proteomics 15:2038-50
Jang, Moon Kyoo; Shen, Kui; McBride, Alison A (2014) Papillomavirus genomes associate with BRD4 to replicate at fragile sites in the host genome. PLoS Pathog 10:e1004117
Stepp, Wesley H; Meyers, Jordan M; McBride, Alison A (2013) Sp100 provides intrinsic immunity against human papillomavirus infection. MBio 4:e00845-13
McBride, Alison A (2013) The papillomavirus E2 proteins. Virology 445:57-79
Knipe, David M; Lieberman, Paul M; Jung, Jae U et al. (2013) Snapshots: chromatin control of viral infection. Virology 435:141-56
Sakakibara, Nozomi; Chen, Dan; Jang, Moon Kyoo et al. (2013) Brd4 is displaced from HPV replication factories as they expand and amplify viral DNA. PLoS Pathog 9:e1003777
Gagnon, David; Senechal, Helene; D'Abramo, Claudia M et al. (2013) Genetic analysis of the E2 transactivation domain dimerization interface from bovine papillomavirus type 1. Virology 439:132-9

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