Altered DNA methylation and genome instability: A new pathway to cancer?

DNA methylation is a mechanism for changing the base sequence of DNA without altering its coding function. As a heritable, yet reversible, epigenetic change, it has the potential of altering gene expression and has profound developmental and genetic consequences. The methylation reaction itself is mechanistically complex and involves the flipping of the target cytosine out of the intact double helix, so that the transfer of the methyl group from S-adenosylmethionine can occur in a cleft in the enzyme (1). Cytosine methylation is inherently mutagenic, which presumably has led to the 80% suppression of the CpG methyl acceptor site in eukaryotic organisms, which methylate their genomes. It contributes strongly to the generation of polymorphisms and germ-line mutations, and to transition mutations that inactivate tumor-suppressor genes (2). Despite a 10- to 40-fold increase in the rate of transitions at methylated versus unmethylated cytosines (3), methylation is not only tolerated in several eukaryotes, but is actually required for the embryonic development of mammals (4). The reasons 5-methylcytosine is essential for development remain obscure, but most probably relate to the well documented ability of methylation, particularly the methylation of CpG-rich promoters, to block transcriptional activation. Indeed, there is growing evidence that methylation plays a pivotal role in key developmental processes such as genomic imprinting and stabilization of X-chromosome inactivation. It therefore is not surprising that alterations in this essential epigenetic system might play a role in carcinogenesis (see Fig. 1 for examples).