The research aims to determine the relationship between UV-induced DNA damage and the kinds and location of induced mutations and cancer. These are fundamental questions in carcinogenesis, since mutations in specific genes clearly have a causal role in carcinogenesis, yet the molecular mechanisms by which such mutations occur are poorly understood. For example, a direct link between carcinogen-induced DNA damage and sequence changes has not yet been made in an endogenous gene. The research will focus on determining the sequence location of genetic damage, and the gene- specific and strand-specific repair of UV photoproducts in the HPRT gene and the p53 tumor suppressor gene of human cells that differ in capacity for excision repair. HPRT mutants will be obtained and the mutated HPRT gene will be sequenced. The location of the mutations will be compared with the location of the gene damage present initially and after periods of repair. The location of DNA damage in the p53 gene in skin (human and mouse) will be correlated with mutations in the p53 gene in tumors induced in nude mice skin by UV. The data will provide a direct comparison of the kinds and specific location of gene damage with UV induced mutations and cancer, and will investigate the role of DNA repair in the process.
|McGregor, W G; Wei, D; Chen, R H et al. (1997) Relationship between adduct formation, rates of excision repair and the cytotoxic and mutagenic effects of structurally-related polycyclic aromatic carcinogens. Mutat Res 376:143-52|
|McGregor, W G; Mah, M C; Chen, R W et al. (1995) Lack of correlation between degree of interference with transcription and rate of strand specific repair in the HPRT gene of diploid human fibroblasts. J Biol Chem 270:27222-7|