Emerging infectious diseases account for at least 12% of all human pathogens. Increased globalization among other factors led the World Health Organization to predict that novel infectious agents will continue to appear at an unprecedented rate. To protect society against these pathogens, it is essential to know all of the potential mechanisms by which infectious agents can cause disease. While viral infections are known to cause 15-20% of cancers, persistent genus ? human papillomavirus (?-HPV) infections cause non-melanoma skin cancers. ?- HPV's role in these malignancies is through a novel mechanism that could be shared with emerging pathogens. Specifically, ?-HPV infections act as co-factor that along with UV, blocks DNA repair and reduces host genome fidelity. The resulting mutations can drive tumorigenesis without continued exposure to UV or ?-HPV. In addition to abundant supportive epidemiological, animal model, and cell culture evidence from other labs, the PI and his group have established the ability of a ?-HPV gene (?-HPV E6) to attenuate the expression of four cellular DNA repair factors. ?-HPV E6's inhibition of repair stem primarily from the viral protein's degradation of a cellular transcription factor, p300. This proposal defines the extent that the p300 loss prevents cells from mitigating genome destabilizing events, particularly events occurring during S-phase.
AIM1 interrogates ?-HPV E6's inhibition of signaling events triggered by DNA crosslinks.
AIM2 defines the mechanisms of ?-HPV E6's impairment of double strand DNA break repair.
AIM3 determines how ?-HPV E6 attenuates the regulation of centrosome duplication. The research team uses a combination of cutting edge techniques as well as traditional molecular biology and biochemical approaches. Virus-free systems confirm all mechanisms. The selective forces (dependence on host replication factors and a tropism for sun-exposed cells) that make it advantageous for ?- HPV to disrupt cell cycle regulation and DNA repair are not unique to ?-HPV. Thus, p300 inactivation by other novel cutaneous viruses would be a good marker of oncogenic potential. The overall goal of this study is to understand the mutagenic potential of p300 destabilization to improve risk assessment of emerging viruses. More specific to ?-HPV, the expected results have preventative implications as the current FDA-approved HPV vaccine technology could be adapted to target ?-HPV and ?-HPV specific inhibitors could be developed and added to formulations used to block UV light (e.g. sunscreen).
To best respond to emerging viruses, all potential pathogenic mechanisms must be appreciated. Inhibition/degradation of p53 and pRB are established ways that viruses can be oncogenic, but others likely exist. This project examines the mutagenic and oncogenic potential of p300 inactivation using cutaneous human papillomaviruses as a model.
