Manipulation of the Host Cell DNA Damage Pathways by Human Papillomavirus
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Anacker, Daniel. Manipulation of the Host Cell Dna Damage Pathways by Human Papillomavirus. 2016. https://doi.org/10.17615/94p6-y908APA
Anacker, D. (2016). Manipulation of the Host Cell DNA Damage Pathways by Human Papillomavirus. https://doi.org/10.17615/94p6-y908Chicago
Anacker, Daniel. 2016. Manipulation of the Host Cell Dna Damage Pathways by Human Papillomavirus. https://doi.org/10.17615/94p6-y908- Last Modified
- March 20, 2019
- Creator
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Anacker, Daniel
- Affiliation: School of Medicine, Department of Microbiology and Immunology
- Abstract
- Human papilloma virus (HPV) is thought to be the most common sexually transmitted viral infection in the United States. It poses a major public health risk since persistent infection with certain types of HPV is a major risk factor for several cancers. HPV is highly adapted for immune evasion and follows a strictly regimented life cycle in order to evade immune detection. The HPV life cycle is closely tied to host cell differentiation with late viral events, such as structural gene expression and viral genome amplification taking place in the differentiating upper layers of the epithelia, removed from immune detection. The virus accomplishes this through a complex system of host cell manipulation, and tight control of its own gene expression and genome replication This dissertation addresses how the virus, with its very limited coding capacity, has managed to commandeer the many host factors required to successfully replicate the viral genome. I specifically investigated how the virus, especially the viral oncogenes E6 and E7 interface with the ATM and ATR dependent DNA damage response (DDR), in order to create an atmosphere conducive to productive viral replication in a differentiating keratinocyte. First, we expanded on previous work that indicated the ATM DDR response was constitutively activated in HPV positive cells and necessary for successful productive viral genome replication. We determined that Nbs1, a protein involved in the ATM DDR pathway, known to be recruited to sites of HPV replication, was required for productive viral genome replication. However, we found that Nbs1 plays a role in viral genome amplification outside of its ability to activate ATM. Our evidence suggests that Nbs1 may recruit other proteins, involved in homologous repair (HR), that may be needed for productive viral replication. We next investigated how the virus may be activating the ATR DDR in order to provide other factors necessary for viral genome synthesis. Previous research has shown that the ATR DDR is activated in HPV positive cells and that levels of the ribonucleotide reductase (RNR) small subunit M2 (RRM2) are upregulated. In this dissertation we show that levels of deoxyribonucleotide triphosphates (dNTPs) are elevated in HPV positive cells, both prior to and post differentiation. We have found that RRM2 levels in these cells are upregulated in an ATR/Chk1/E2F1 dependent manner and that RRM2 is necessary for viral genome replication, especially upon differentiation.
- Date of publication
- August 2016
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- Resource type
- Rights statement
- In Copyright
- Advisor
- Raab-Traub, Nancy
- Damania, Blossom
- Heise, Mark
- Moody, Cary
- Moorman, Nathaniel
- Degree
- Doctor of Philosophy
- Degree granting institution
- University of North Carolina at Chapel Hill Graduate School
- Graduation year
- 2016
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