Mutational specificity of alkylating agents and the influence of DNA repair

Abstract

Abstract Alkylating treatments predominantly induce G: C = > A: T transitions, consistent with the predicted significance of the miscoding potential of the O 6 ‐alG lesion. However, the frequency and distribution of these events induced by any one compound may be diagnostic. S N 1 agents that act via an alkyldiazonium cation, such as the N‐nitroso compounds, preferentially generate G:C = > A : T transitions at 5′‐RG‐3′ sites, while the more S N 2 alkylsulfates and alkylalkane‐sulfonates do not. The precise nature of this site bias and the possibility of strand bias are target dependent. The extent of this site bias and the contribution of other base substitutions are substituent size dependent. A similar 5′‐RT‐3′ effect is seen for A:T = > G:C transitions, presumably directed by O 4 ‐alT lesions. The 5′‐RG‐3′ effect, at least, likely reflects a deposition specificity arising from some aspect of helix geometry, although it may be further exaggerated by alkylation‐specific repair. Excision repair appears to preferentially reduce the occurrence of ethylation‐induced G:C = > A:T and A:T = > G:C transitions at sites flanked by A:T base pairs. This may be due to an enhancement of the helical distortion imposed by damage at such positions. A similar effect is not seen for methylation‐induced mutations and in the case of propyl adducts, the influence of excision repair on the ultimate distribution of mutation cannot be as easily defined with respect to neighbouring sequence.

Keywords

Affiliated Institutions

• Cancer Research UK Scotland Institute GB
• York University CA

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