Papillomaviruses (PV) cause benign, slowly proliferating epithelial tumors. HPV types such as -16, -18 and -31 are called high-risk because persistent infections can lead to development of cervical, anogenital, and oropharyngeal cancers. Upon infection, the double stranded circular viral genome is maintained as a low copy episome in basal cells and in upper levels of the epithelial, differentiation cues stimulate its amplification to high copy number. The viral E2 and E1 proteins are thought to be essential for viral replication however their requirement at each stage of replication has not been determined. The host factors that participate in viral replication are also not known. Our hypothesis is that E2 recruits specific and different cellular replication factors during each stag of the viral replicative program. This grant proposes to identify the host replication factors that are in complex with the E2 protein or present at the viral origin of replication. The functions of these factors in viral genome maintenance and amplification stages will then be characterized. In another aim, we will identify post-translational modifications of E2 that regulate its transcription and replication activities during the viral replicative program. We have discovered novel lysine acetylation and tyrosine phosphorylation of specific conserved amino acids. Our unpublished data are consistent with the hypothesis that these modifications to the E2 protein control its activity. Regulation of E2 by lysine acetyltransferases and tyrosine kinase is likely t explain the switch of the mode replication during the viral replicative program in the epithelial environment. These experiments will lead to new insights into the functions of cellular proteins that initiate origin utilization and chromosome replication in a metazoan cell. Only a small subset of HPV infections result in malignancy and these frequently demonstrate loss of E2 expression, leading to viral DNA integration into human chromosomes. We hypothesize that loss of E2 function is critical for oncogenic progression and address how E2 may prevent host cell proliferation in order to usurp this pathway for viral genome amplification. Inhibition of viral genome replication would reduce viral copy number and the capacity of verrucae to produce infectious virus.

Public Health Relevance

Human papillomaviruses (HPV) encode proteins that regulate viral gene expression and viral DNA replication. They accomplish this by interaction with normal cell growth pathways that are subverted for viral purposes. Learning how these viral proteins function will teach us about the viral replicative program and lead to new insights into the mechanism of mammalian DNA replication.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Virology - B Study Section (VIRB)
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Read-Connole, Elizabeth Lee
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Thomas, Yanique; Androphy, Elliot J (2018) Human Papillomavirus Replication Regulation by Acetylation of a Conserved Lysine in the E2 Protein. J Virol 92:
Campos-León, Karen; Wijendra, Kalpanee; Siddiqa, Abida et al. (2017) Association of Human Papillomavirus 16 E2 with Rad50-Interacting Protein 1 Enhances Viral DNA Replication. J Virol 91:
Culleton, Sara P; Kanginakudru, Sriramana; DeSmet, Marsha et al. (2017) Phosphorylation of the Bovine Papillomavirus E2 Protein on Tyrosine Regulates Its Transcription and Replication Functions. J Virol 91:
Xie, Fang; DeSmet, Marsha; Kanginakudru, Sriramana et al. (2017) Kinase Activity of Fibroblast Growth Factor Receptor 3 Regulates Activity of the Papillomavirus E2 Protein. J Virol 91:
DeSmet, Marsha; Kanginakudru, Sriramana; Rietz, Anne et al. (2016) The Replicative Consequences of Papillomavirus E2 Protein Binding to the Origin Replication Factor ORC2. PLoS Pathog 12:e1005934
Kanginakudru, Sriramana; DeSmet, Marsha; Thomas, Yanique et al. (2015) Levels of the E2 interacting protein TopBP1 modulate papillomavirus maintenance stage replication. Virology 478:129-35
Quinlan, Edward J; Culleton, Sara P; Wu, Shwu-Yuan et al. (2013) Acetylation of conserved lysines in bovine papillomavirus E2 by p300. J Virol 87:1497-507
Mallappa, Chandrashekara; Nasipak, Brian T; Etheridge, Letitiah et al. (2010) Myogenic microRNA expression requires ATP-dependent chromatin remodeling enzyme function. Mol Cell Biol 30:3176-86
Wang, Xiaoyu; Naidu, Samisubbu R; Sverdrup, Francis et al. (2009) Tax1BP1 interacts with papillomavirus E2 and regulates E2-dependent transcription and stability. J Virol 83:2274-84
Melanson, Suzanne M; Androphy, Elliot J (2009) Topography of bovine papillomavirus E2 protein on the viral genome during the cell cycle. Virology 393:258-64

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