HYPOMETHYLATION OF DNA - A POSSIBLE NONGENOTOXIC MECHANISM UNDERLYINGTHE ROLE OF CELL-PROLIFERATION IN CARCINOGENESIS

DNA methylation (i.e., the 5-methylcytosin content of DNA) plays a rol e in the regulation of gene activity. There is a persuasive body of ev idence indicating that differential methylation of DNA (i.e., 5-methyl cytosine versus cytosine) is a determinant of chromatin structure and that the methyl group provides a chemical signal that is recognized by trans-acting factors thar 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 fundamenta l 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 b y 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 me thylation is maintained by the action of a maintenance methylase follo wing DNA replication. Changes in the methylation status of a gene prov ide a mechanism by which its potential for expression can be altered i n an epigenetic heritable manner, and it is expected that modification s in DNA methylation would result from threshold-exhibiting events.