DNA methylation and cancer.
Changes in the pattern of DNA methylation have been a consistent finding in cancer cells. The mostly descriptive nature of these studies and the fact that both hypo- and hypermethylation have been observed at various loci have made it difficult to assess whether these changes are causally involved in the transformation process or whether they reflect the altered physiology of rapidly dividing cancer cells. It is clear, however, that DNA methylation plays an important role in the generation of mutations in human tumors. The high incidence of C-to-T transitions found in the p53 tumor-suppressor gene is attributed to the spontaneous deamination of 5-methylcytosine residues. The multiple observations linking DNA methylation to cancer can be resolved in a model proposing that the high rate of mutation at CpG dinucleotides is due in part to methyltransferase-facilitated deamination. Support for a role of DNA methyltransferase as a mutator enzyme is provided by work with a prokaryotic DNA methyltransferase under S-adenosyl-methionine methyl-donor limiting conditions. Methyl-donor limiting conditions might arise in early stages of tumor development, leading to high rates of methyltransferase-mediated CpG mutagenesis, as seen in human tumors. Such a mechanism is consistent with the frequently reported methionine auxotrophy of cancer cells and with the tumorigenic effects of methyl-deficient diets. Methyl deficiency in tumor cells is also consistent with the commonly observed global hypomethylation of tumor cell DNA, despite normal or even high levels of DNA methyltransferase expression.
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge 02142.
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Laird
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Jaenisch
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D015254:DNA Modification Methylases / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D008745:Methylation; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*
D004273:DNA, Neoplasm; D015254:DNA Modification Methylases