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.

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 methylmethanesulfonate 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 methylmethanesulfonate 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.