DNA METHYLATION AND THE ASSOCIATION BETWEEN GENETIC AND EPIGENETIC CHANGES - RELATION TO CARCINOGENESIS

This paper examines the relationship between DNA mutagenic lesions, DN A methylation and the involvement of these changes in the process of c arcinogenesis. Many types of DNA damage (oxidative lesions, alkylation of bases, abasic sites, photodimers, etc.) interfere with the ability of mammalian cell DNA to be methylated at CpG dinucleotides by DNA-me thyltransferases (DNA-MTases). This can result in altered patterns in the distribution of 5-methylcytosine (5MeC) residues at CpG sites. Met hylation of DNA is an epigenetic change that by definition is heritabl e, can result in changes in chromatin structure, and is often accompan ied by modified patterns of gene expression. The presence of 5MeC in D NA, as well as oxidative stress induced by the free radical nitric oxi de, can interefere with the repair of alkylation damage, thereby incre asing the level of potentially mutagenic lesions. CpG sites in DNA rep resent mutational hotspots, with both the presence of 5MeC in DNA and the catalytic activity of DNA-MTases being intrinsically mutagenic. Th e process of carcinogenesis has frequently been associated with an inc reased expression of DNA-MTase activity, accompanied by either hyperme thylation or hypomethylation of target cell (progenitor tumor cell) DN A. In addition, there is evidence that overexpression of DNA-MTase act ivity could result in increased cytosine methylation at non-CpG sites. A variety of chemicals can alter the extent of DNA methylation in mam malian cells. These include inhibitors of topoisomerase II, as well as inhibitors of DNA synthesis, microtubule formation, histone deacetyla tion, transmethylation, etc. Genetic and epigenetic changes in DNA hav e a profound influence on one another and could play a major role in t he process of carcinogenesis, by modulating both the extent and the pa ttern of gene expression.