The incidence of skin cancer, the most common type of human cancer, is increasing at an alarming rate in the United States and worldwide. The damage of DNA bases by ultraviolet (UV) radiation causes mutations and UV light is strongly implicated in the development of human basal and squamous cell carcinoma as well as the less common but more lethal melanoma. To understand UV carcinogenesis, a more detailed knowledge of the molecular mechanisms of UV damage formation, DNA repair processes and mutation induction is necessary. We will apply uniquely sensitive, mostly PCR-based techniques, to map UV-induced lesions and their repair rates as well as the mutations they produce at the DNA sequence level in human genes. We propose to investigate the molecular mechanisms of selective UV damage formation in vivo, and to analyze DNA sequence-specific repair rates in several human genes. Possible molecular mechanisms of sequence- specific repair of UV-induced lesions will be elucidated by comparative analysis of chromatin structure and protein-DNA interactions at sequences showing differential repair rates. Variations of the ligation-mediated PCR technique will be used to search for in vivo processing intermediates of UV photoproducts. We will attempt to develop new methodology to study repair of (6-4) photoproducts at the DNA sequence level. The relationship between high UV damage frequency, slow repair rates and mutagenesis at specific sites will be determined by using an allele-specific PCR assay for-mutation detection. Finally, we will investigate whether genetic defects in human DNA repair deficiency and cancer-prone syndromes are related to alterations in sequence-specific DNA repair.
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