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 counterparts (Nowell, P.C. (1976) Science, 194, 23-28 [1]). Alterations in global levels and regional changes in the patterns of DNA methylation 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-cycle 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 investigated two major mechanisms by which DNA methylation may lead to aberrant cell cycle control: (1) through the generation of transition mutations via deamination-driven events resulting in the inactivation of tumor suppressor genes, or (2) by altering levels of gene expression through 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 discussed in the framework of recent discoveries in the field.
Gonzalgo
M L
ML
Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, University of Southern California, School of Medicine, Los Angeles 90033, USA.
Jones
P A
PA
D044503:5-Methylcytosine; D000818:Animals; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D019175:DNA Methylation; D004798:Enzymes / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014498:Uracil / Q000378:metabolism
D004798:Enzymes; D014498:Uracil; D044503:5-Methylcytosine; D003596:Cytosine