Abstract: 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. Viral infections are known to cause 15- 20% of cancers. For example, persistent genus β human papillomavirus (β-HPV) infections cause non- melanoma skin cancers. β-HPV’s role in these malignancies is through a novel mechanism that could be shared with emerging pathogens. Specifically, β-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 β-HPV. In addition to abundant supportive epidemiological, animal model, and cell culture evidence from other labs, we have established the ability of a β-HPV gene (β-HPV E6) to attenuate the expression of four cellular DNA repair factors. β-HPV E6’s inhibition of repair stem primarily from the viral protein’s degradation of a cellular transcription factor, p300. However, β-HPV E6 simultaneously disrupts DNA repair through p300- independent mechanisms. This leaves uncertainty as to the extent that p300 disruption alone hinders DNA repair. This results in a critical need to define the role of p300 in DNA repair in a cleaner, complementary system. This proposal uses a small molecule p300 inhibitor (CCS1477) to address this need and advance towards our long-term goal of understanding the genotoxic/oncogenic potential of viral proteins that destabilize p300. Overall objective in this proposal is to define the extent that p300 inhibition by CCS1477 (i) hinders DDR signaling, (ii) increases the cytotoxicity associated with DNA damage, and (iii) exacerbates the frequency of mutations associated with DNA damage. It is an even split between two independent research groups (Chung and Wallace labs) and represents a burgeoning collaboration. Our research teams will use a combination of cutting edge techniques as well as traditional molecular biology and biochemical approaches to test our central hypothesis is that inhibition of p300 activity by CCS1477 will impede activation of three essential DDR kinases (ATM, ATR, and DNA-PKcs) reducing the cellular response to DNA damage. In the process of testing our hypothesis, we will provide excellent training opportunities for undergraduate researchers at our home institutions (Kansas State University and Pittsburg State University) and improve the overall research environment in the state of Kansas.