Effect of guanine alkylation on mispairing

Abstract

ALKYLATING agents, such as nitrosamines, nitrosoureas, dimethylsulphate, and so on, are known to cause mutations and cancerous growth^1–3. Since nitrosamines can be produced by the reaction of amines and nitrous acid, the presence of nitrites and nitrous acid in many food items as well as in the urban environment has become a source of concern^4,5. Recent evidence⁶ has indicated that carcinogenesis and mutagenesis bear a strong relationship to each other, although agreement is not unanimous⁷. In vivo alkylation of DNA occurs mainly at the N7 position of guanine (G)^1–2. Minor alkylation of G at the O6 and N3 positions is also known to occur^8–9. Whether alkylation at any one of these sites is mainly responsible for mutagenesis and carcinogenesis is still an open question, although O6 alkylation seems to be favoured^3,8–11. We have investigated the effect of methylation at each of these three sites on the ability of G to mispair with a thymine (or uracil), which may lead to a mutation, and the mechanism involved in such mispairing, using the CNDO/2 method of calculation. The calculations are carried out for the 9-methyl purines and 1-methyl pyrimidines to simulate the bases in the DNA helix. The details of the calculations are published elsewhere¹². The magnitudes reported are particular to the geometrical parameters used here¹³. Since we were only interested in the relative effect of various G methylations, the qualitative trends observed here are expected to hold; no attempt at a full minimisation of the geometric parameters was therefore made; (a horrendous task for molecules of such sizes).