Mutagenic Consequences of the Alteration of DNA by Chemicals and Radiation

Abstract

The induction of mutations in vivo is a process that involves the interaction of exogenous agents, the Biologically Reactive Intermediates (BRIs), with particular nucleotides in the DNA. The finding of “hot spots” (see Hsia et al., 1989) and of “mutator” strains of organisms (Modrich, 1987) indicates that superimposed on the primary interaction of BRIs and nucleotides is an effect of DNA sequence (Burns et al., 1987) and of the proteins involved in replication and in the monitoring of the DNA. Many of the primary interactions of BRIs with DNA result in alterations which block DNA synthesis, at least in vitro. It appears to be a truism that mutation, at least point mutation as a result of damage induced by an agent which inhibits DNA synthesis, requires that the DNA synthetic machinery should bypass the damage by some mechanism. An understanding of the phenomena of mutation therefore requires knowledge of the relationships between the altered DNA bases, the arrest of DNA synthesis, and the location of the damage within the DNA sequence. For example, one might assume that the sites most subject to modification by BRIs are those at which mutation occurs most readily. In fact, it appears that this simplest of hypotheses is not inevitably so, and that other factors may intervene (Brash et al., 1987).