Influence of DNA Conformation on DNA Methylation and the Direct Binding of N-Methyl-N-Nitroso-N¹-Nitroguanidine

Abstract

One of the attractive mechanisms by which chemicals can cause cancer is through somatic mutation. The theory of somatic mutation speculates that mutations relatable to carcinogenesis are induced by the presence of carcinogen modified base residue in an appropriate gene sequence during cell proliferation. This theory implies that the availability of base residues at specific genomic sites to the carcinogen for interaction is critical for the initiation of carcinogenic process. It is logical to presume that one of the major determinants for the exposition of gene sequence to the carcinogen may be the conformation of DNA. In order to gain an insight into whether DNA conformation and/or sequence can influence carcinogen-DNA interaction, we designed several studies on the effect of modulation of DNA conformation on DNA methylation by potent carcinogens. This study is concerned with the demonstration that (a) DNA structure and/or sequence affects DNA methylation by N-methyl-N-nitroso-N¹-nitroguanidine (MNNG) and (b) MNNG interacts directly with rat liver DNA forming DNA-MNNG complex prior to the transfer of its methyl group to DNA.

This study was supported by grants from Medical Research Council, Canada.