The overall goal of the proposed project is to investigate the induction and repair of DNA damages produced by solar UV radiation under conditions of a simulated sunlight exposure of normal human skin cells and cells derived from individuals which have exhibited enhanced sensitivity to solar UV wavelengths. This represents the primary purpose of this study, because the current state of knowledge as to the photoproducts induced in the DNA by solar UV radiation and the pathways by which human cells repair these lesions is very poor. In addition, the UV component of sunlight, particularly the mid UV region, appears to be responsible for the induction of most skin cancers, which represent the most common form of cancer in the United States. The importance of DNA damage and its subsequent alteration in the causation of carcinogenesis is gaining increasing appreciation with the recent discoveries suggesting that human cancers may result from the conversion of a normal gene (proto-oncogene) to an oncogene as possibly the first step in the formation of a tumor. DNA repair processes certainly play a critical role in this early stage of carcinogenesis either through repair of the lesions and prevention of the initial step, or alternatively DNA repair pathways may exist that actually play a central role in the conversion to an oncogenic state. It is therefore crucial for the understanding of skin carcinogenesis, that the types of DNA lesions induced by solar UV radiation and the mechanisms by which these damages are repaired be elucidated. In this project, normal human cells and human cells hypersensitive to solar UV radiation will be exposed to a solar simulating source consisting essentially of a high-pressure xenon arc lamp with appropriate filters, to create a beam that is nearly identical in spectral composition to sunlight reaching the earth's surface. The induction and repair of specific DNA damages will be measured in solar-irradiated cells, including an analysis of the excision repair pathway(s) by which these lesions are eliminated from the DNA. Also, the pattern of inhibition and recovery of DNA synthesis in cells exposed to solar radiation will be examined and the possibility that synergistic or antagonistic interactions between different wavelength regions in sunlight affecting DNA repair systems will be investigated. Finally, excision repair will be examined in cells treated with a split solar radiation exposure.
