DNA alteration and repair

Abstract

DNA alteration and repair is undoubtedly as essential stage in the mechanism of chemical carcinogenesis. Present knowledge has in fact shown, and in a rather convincing manner, that the majority of known chemical carcinogens, in addition to radiations and viruses, are also mutagens in the widest sense of the word and usually induce alteration of the genome. Proof that carcinogenic or procarcinogenic chemical agents display muta.genic action is based on the recent experiments by McCann and Ames (4), who demonstrated a close relationship betneen carcinogenicity and mutagenicity in 9OcTo of the tested products (157/ 173, whereas the percentage of non-carcinogenic substances which were also non-mutagenic was 8770 (94/108) (Fig. 1). Initial experimental data allso confirm that failure of DNA repair could result in the appearance of tumours: for example, the potentiation of the oncogenic action of ultraviolet radiations in patients suffering from Xeroderma Pigmentosum who show a defect in DNA repair, in the same way as Cleaver (1) has ascertained recently for Ataxia Telangiectasia and Cokayne’s syndrome. At this point it is perhaps necessary to try to understand why alterations in nuclear DNA should be considered as the basic mechanism of carcinogenesis induced by chemical agents, when interaction has certainly been observed between the latter and other molecules involved in gene expression, such as RNA or regulating proteins. The possibility of chemical interactions between damaging agents and other target molecules has in fact already been shown in the literature. Two examples can be quoted: Wunderlich et al. (9. 10) observed a mcthylation of the mitochondrial DNA by methylnitrosourea (MNU) or dimethylnitrosamine (DMN); and the experiments by Sarma et al. (5) on the relationship between carcinogens like 2-AAF, MNU and ethionine and some types of RNA. In our view.