Regulation of the DNA methylation machinery and its role in cellular transformation.

DNA methylation, a covalent modification of the genome, is emerging as an important player in the regulation of gene expression. This review discusses the different components of the DNA methylation machinery responsible for replicating the DNA methylation pattern. Recent data have changed our basic understanding of the DNA methylation machinery. A number of DNA methyltransferases (DNMT) have been identified and a demethylase has recently been reported. Because the DNA methylation pattern is critical for gene expression programs, the cell possesses a number of mechanisms to coordinate DNA replication and methylation. DNMT1 levels are regulated with the cell cycle and are induced upon entry into the S phase of the cell cycle. DNMT1 also regulates expression of cell-cycle proteins by its other regulatory functions and not through its DNA methylation activity. Once the mechanisms that coordinate DNMT1 and the cell cycle are disrupted, DNMT1 exerts an oncogenic activity. Tumor suppressor genes are frequently methylated in cancer but the mechanisms responsible are unclear. Overexpression of DNMT1 is probably not responsible for the aberrant methylation of tumor suppressor genes. Unraveling how the different components of the DNA methylation machinery interact to replicate the DNA methylation pattern, and how they are disrupted in cancer, is critical for understanding the molecular mechanisms of cancer.