MUTAGENIC AND EPIGENETIC EFFECTS OF DNA METHYLATION

Tumorigenesis begins with the disregulated growth of an abnormal cell that has acquired the ability to divide more rapidly than its normal c ounterparts (Nowell, P.C. (1976) Science, 194, 23-28 [1]). Alterations in global levels and regional changes in the patterns of DNA methylat ion are among the earliest and most frequent events known to occur in human cancers (Feinberg and Vogelstein (1983) Nature, 301, 89-92 ([2]) , Gama-Sosa, M.A. et al. (1983) Nucleic Acids Res., 11, 6883-6894 ([3] ); Jones, P.A. (1986) Cancer Res., 46, 461-466 [4]). These changes in methylation may impair the proper expression and/or function of cell-c ycle regulatory genes and thus confer a selective growth advantage to affected cells. Developments in the field of cancer research over the past few years have led to an increased understanding of the role DNA methylation may play in tumorigenesis. Many of these studies have inve stigated two major mechanisms by which DNA methylation may lead to abe rrant cell cycle control: (1) through the generation of transition mut ations via deamination-driven events resulting in the inactivation of tumor suppressor genes, or (2) by altering levels of gene expression t hrough epigenetic effects at CpG islands. The mechanisms by which the normal function of growth regulatory genes may become affected by the mutagenic and epigenetic properties of DNA methylation will be discuss ed in the framework of recent discoveries in the field.