Hypomethylation of DNA: a possible nongenotoxic mechanism underlying the role of cell proliferation in carcinogenesis.

DNA methylation (i.e., the 5-methylcytosin content of DNA) plays a role in the regulation of gene activity. There is a persuasive body of evidence indicating that differential methylation of DNA (i.e., 5-methylcytosine versus cytosine) is a determinant of chromatin structure and that the methyl group provides a chemical signal that is recognized by trans-acting factors that regulate transcription. Hypomethylation (i.e., low levels of DNA 5-methylcytosine) of a gene is necessary but not sufficient for its expression, and, therefore, a hypomethylated gene can be considered to possess an increased potential for expression as compared to a hypermethylated gene. Cell proliferation is a fundamental component of carcinogenesis. It plays a key role in expanding clones of initiated cells and, in addition, cell replication may contribute to carcinogenesis by facilitating mutagenesis. This can occur either by causing the fixation of promutagenic DNA-damage before repair or as a consequence of a "normal" error occurring during DNA replication. During periods of cell proliferation the established pattern of DNA methylation is maintained by the action of a maintenance methylase following DNA replication. Changes in the methylation status of a gene provide a mechanism by which its potential for expression can be altered in an epigenetic heritable manner, and it is expected that modifications in DNA methylation would result from threshold-exhibiting events.