Carcinogen–DNA interaction: Differential effects of distamycin‐A and spermine on the formation of 7‐methylguanine in DNA by N‐methyl‐N‐nitrosourea, methylmethanesulfonate, and dimethylsulfate

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Abstract
Experiments were designed to determine whether DNA conformation and sequence play any role in its methylation by N‐methyl‐N‐nitrosourea, methylmethanesulfonate, and dimethylsulfate, agents that are known to methylate DNA by different mechanisms but yield 7‐methylguanine as the major product. The approach taken was to bind ligands to DNA that interact with it stereospecifically and to study their effect on the formation of 7‐ methylguanine by the three methylating agents. The results indicate that both distamycin A and spermine shielded the formation of 7‐methylguanine in vitro in rat liver DNA by N‐methyl‐N‐nitrosourea but not by methylmethane‐sulfonate or dimethylsulfate; they did not, however, protect 2‐deoxyguanylic acid against methylation by N‐methyl‐N‐nitrosourea. Based on the mechanism by which the methylating agents and the ligands react with DNA, these results are interpreted to suggest that (1) guanines methylatable at the N‐7 position by N‐methyl‐N‐nitrosourea are located at, or close to, the binding sites of the ligands, probably the A‐T‐rich regions, and those methylatable by methyl‐ methanesulfonate and dimethylsulfate are distal to these regions, and/or (2) the conformation DNA assumes in the presence of distamycin A or spermine permits methylation by methylmethanesulfonate and dimethylsulfate but not by N‐methyl‐N‐nitrosourea. The study implicates DNA structure and/or its sequences in carcinogen‐DNA interaction.