Inducible Pathways in Deoxyribonucleic Acid Repair, Mutagenesis and Carcinogenesis

Abstract

The aim of this short review is to summarize our recent knowledge and current ideas about the genetic control and molecular mechanisms of mutagenesis in bacteria, in order to discuss possible mechanisms of malignant transformation in mammalian cells. This review is neither a good source of relevant references nor a critical evaluation of quoted work; these can be found elsewhere (Radman, 1975, 1976; Witkin, 1976; Radman e ta / . , 1977). It is hoped that by studying mutagenesis in bacteria, we may learn something about early steps in the malignant transformation of mammalian cells (Radman, 1976; Radman et al., 1977), the principal arguments being as follows. (1) Not only can bacterial mutagenesis tests efficiently discriminate between carcinogenic and non-carcinogenic chemicals (McCann et al., 1979, but there exists a quantitative correlation between the mutagenic potency in Salmonella tester strains and carcinogenic potency in animals for a heterogeneous group of chemical carcinogens. The respective potencies of these compounds range over five orders of magnitude (Meselson & Russell, 1977). (2) If we accept the hypothesis that carcinogenesis in animals is caused by somatic mutagenesis, and if we trust Meselson & Russell’s (1977) animal carcinogenicitySalmonella mutagenicity correlation, then it appears likely that the basic mechanisms of mutagenesis in both bacteria and animal somatic cells (by these chemical carcinogens) must be very similar. There is growing evidence that somatic mutagenesis is the basis of cancer in man (see Cairns, 1975). Recent studies with cell cultures support this conclusion: the comparison between transformation and mutation frequencies in the same benzo[a]pyrene-treated primary cell culture shows that transformation could be provoked by mutation at a single hypermutable locus (see Huberman et al., 1976). Analogously to forward and backward mutagenesis, the same carcinogen can provoke both induction of transformed-cell clones and their reversion to normal-cell clones, often accompanied by temperaturesensitivity (Bouck & di Majorca, 1976). This is highly suggestive of forward and backward mutagenesis in a gene with a protein product. lnspired by the recent knowledge about pleiotropic gene control in mutagenesis of Escherichia coli (to be summarized below), we have proposed a working model for malignant transformation through mutagenesis of a single locus (Radman et al., 1977; reproduced in Fig. 1) which also includes viral transformation.