The primary goal of the research proposal is to engineer and characterize cellular and mouse models of the human skin cancer susceptibility syndrome xeroderma pigmentosum variant (XP-V). XP-V individuals are deficient in a novel DNA polymerase (PolH). I will analyze the mechanism of replication fork arrest and signal transduction in human XP-V (PolH-null) cells following irradiation. I will develop mouse models of XP-V that overexpress the human PolH protein or underexpress or knockout for mouse polH. I will characterize the murine XP-V phenotype for potential roles of Pol H in skin pathology and UV responses. Taken together, these experiments are expected to reveal novel mechanisms of carcinogenesis in models of human hereditary disease.
