The Role of DNA Repair in Preventing the Cytotoxic and Mutagenic Effects of Carcinogens in Human Cells

Abstract

We compared excision repair-proficient and repair-deficient diploid human fibroblasts, derived from normal individuals or xeroderma pigmentosum patients, for their response to the mutagenic and/or cytotoxic effect of ultraviolet radiation, or reactive derivatives of aromatic amines or polycyclic aromatic hydrocarbons. Each of these carcinogens forms DNA helix-distorting photo- products or adducts. The results indicated that excision repair processes in these human cells act to prevent cell killing and the induction of mutations; that is, they decrease the potentially cytotoxic or mutagenic effect of such agents. The rate of removal of radioactively-labeled carcinogen adducts from cellular DNA was found to be highly correlated with the rate of increase in percent survival and rate of decrease in the frequency of mutations to 6-thioguanine resistance induced by these carcinogens. The data indicate that the observed mutations are not the result of “error-prone” excision repair but arise, directly or indirectly, from semi-conservative DNA synthesis on templates containing unexcised lesions. The ultimate biological consequences of exposure to these agents, i.e., the probability of a cell not being able to form a colony and the probability of mutations being introduced, appear to be determined by the rate of excision repair and the amount of time available between the introduction of the lesions and the onset of the “critical event responsible for cell killing” or the “critical event responsible for mutations.” The data suggest that the latter is semi- conservative DNA synthesis.