Human papillomaviruses (HPV) are the causative agents of cervical, anal and many oral cancers. While prophylactic vaccines to prevent HPV infections have been developed, there is no effective therapeutic treatment for existing HPV lesions. It is therefore of critical importance to understand how the productive life cycle of high-risk HPVs is regulated to identify potential new therapeutic targets. HPVs infect stratified squamous epithelia and link their productive life cycles to the differentiation of the infected cell. My laboratory recently demonstrated that the amplification of HPV genomes in differentiating cells is dependent on activation of the ataxia-telangiectasia mutated (ATM) kinase pathway. In contrast, the ATM pathway has minimal effects on stable maintenance replication in undifferentiated cells. In HPV positive cells, members of the ATM pathway, such as ??H2AX, CHK2, and NBS1, are bound to viral genomes in distinct nuclear replication foci. Our studies have shown that E7 and E1 can activate the DNA damage response in the absence of viral genome replication and that they act through the innate immune regulator, STAT-5 and Tip60 to induce the phosphorylation of ATM. Additional studies using complete viral genomes have indicate that additional viral proteins, such as E5, can also activate the DNA damage pathways. Our experiments specifically implicate homologous recombination factors in mediating HPV amplification. In addition to the ATM pathway, we recently found that both the ataxia telangiectasia and Rad3-related (ATR) pathway, which is important for repair of single strand breaks, along with the p38/MK2 factors are also critical for amplification.. Additional recent studies demonstrate that the cohesin, SMC1, is activated in HPV positive cells as part of the DNA damage response and that it forms complexes with the transcriptional insulator, CTCF, at specific sites on HPV genomes. Knockdown of either SMC1 or CTCF blocks differentiation-dependent HPV genome amplification and mutation of SMC1/CTCF binding sites in HPV 31 interferes with stable maintenance of viral episomes. While we have identified members of the DNA damage pathways that are important for differentiation dependent amplification, the mechanism by which they act is still unclear and investigating this is a major focus of this renewal application. The overall goal of our studies is to understand how members of the DNA damage pathways regulate the differentiation-dependent HPV life cycle. We will address the following questions: 1). How do ATM and ATR regulate HPV genome amplification? Are double strand breaks introduced into HPV genomes? 2). How does the p38/MK2 pathway contribute to amplification? 3). What is the mechanism by which HPV proteins initiate the DNA damage response?

Public Health Relevance

/RELEVANCE Cervical cancer is the second leading killer of women by cancer worldwide. Human papillomaviruses are the etiological agents of these cancers and they regulate their differentiation-dependent life cycles through cellular DNA damage pathways. These studies will determine how HPV manipulates these pathways and so identify new ways to target this important process in women suffering from these malignancies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Read-Connole, Elizabeth Lee
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Northwestern University at Chicago
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Mehta, Kavi; Laimins, Laimonis (2018) Human Papillomaviruses Preferentially Recruit DNA Repair Factors to Viral Genomes for Rapid Repair and Amplification. MBio 9:
Spriggs, Chelsey C; Laimins, Laimonis A (2017) FANCD2 Binds Human Papillomavirus Genomes and Associates with a Distinct Set of DNA Repair Proteins to Regulate Viral Replication. MBio 8:
Hong, Shiyuan; Cheng, Shouqiang; Songock, William et al. (2017) Suppression of MicroRNA 424 Levels by Human Papillomaviruses Is Necessary for Differentiation-Dependent Genome Amplification. J Virol 91:
Spriggs, Chelsey C; Laimins, Laimonis A (2017) Human Papillomavirus and the DNA Damage Response: Exploiting Host Repair Pathways for Viral Replication. Viruses 9:
Hong, Shiyuan; Laimins, Laimonis A (2017) Manipulation of the innate immune response by human papillomaviruses. Virus Res 231:34-40
Langsfeld, Erika; Laimins, Laimonis A (2016) Human papillomaviruses: research priorities for the next decade. Trends Cancer 2:234-240
Mehta, Kavi; Gunasekharan, Vignesh; Satsuka, Ayano et al. (2015) Human papillomaviruses activate and recruit SMC1 cohesin proteins for the differentiation-dependent life cycle through association with CTCF insulators. PLoS Pathog 11:e1004763
Langsfeld, Erika S; Bodily, Jason M; Laimins, Laimonis A (2015) The Deacetylase Sirtuin 1 Regulates Human Papillomavirus Replication by Modulating Histone Acetylation and Recruitment of DNA Damage Factors NBS1 and Rad51 to Viral Genomes. PLoS Pathog 11:e1005181
Galloway, Denise A; Laimins, Laimonis A (2015) Human papillomaviruses: shared and distinct pathways for pathogenesis. Curr Opin Virol 14:87-92
Hong, Shiyuan; Dutta, Anindya; Laimins, Laimonis A (2015) The acetyltransferase Tip60 is a critical regulator of the differentiation-dependent amplification of human papillomaviruses. J Virol 89:4668-75

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