DNA methylation and the association between genetic and epigenetic changes: relation to carcinogenesis.
This paper examines the relationship between DNA mutagenic lesions, DNA methylation and the involvement of these changes in the process of carcinogenesis. 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-methyltransferases (DNA-MTases). This can result in altered patterns in the distribution of 5-methylcytosine (5MeC) residues at CpG sites. Methylation of DNA is an epigenetic change that by definition is heritable, can result in changes in chromatin structure, and is often accompanied by modified patterns of gene expression. The presence of 5MeC in DNA, as well as oxidative stress induced by the free radical nitric oxide, can interefere with the repair of alkylation damage, thereby increasing the level of potentially mutagenic lesions. CpG sites in DNA represent mutational hotspots, with both the presence of 5MeC in DNA and the catalytic activity of DNA-MTases being intrinsically mutagenic. The process of carcinogenesis has frequently been associated with an increased expression of DNA-MTase activity, accompanied by either hypermethylation or hypomethylation of target cell (progenitor tumor cell) DNA. In addition, there is evidence that overexpression of DNA-MTase activity could result in increased cytosine methylation at non-CpG sites. A variety of chemicals can alter the extent of DNA methylation in mammalian cells. These include inhibitors of topoisomerase II, as well as inhibitors of DNA synthesis, microtubule formation, histone deacetylation, transmethylation, etc. Genetic and epigenetic changes in DNA have a profound influence on one another and could play a major role in the process of carcinogenesis, by modulating both the extent and the pattern of gene expression.
Wachsman
J T
JT
Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
D044503:5-Methylcytosine; D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004249:DNA Damage; D019175:DNA Methylation / Q000187:drug effects*; D015254:DNA Modification Methylases / Q000378:metabolism*; D004260:DNA Repair; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D018384:Oxidative Stress; D059005:Topoisomerase II Inhibitors
D000477:Alkylating Agents; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D059005:Topoisomerase II Inhibitors; D044503:5-Methylcytosine; D003596:Cytosine; D015254:DNA Modification Methylases