Abstract
Changes in DNA methylation patterns is a prominent characteristic of human tumors. Tumor cells display reduced levels of genomic DNA methylation and site-specific CpG island hypermethylation. Methylation of CpG dinucleotides is catalyzed by the enzyme family of DNA methyltransferases (DNMTs). In this review, the role of DNA methylation and DNMTs as key determinants of carcinogenesis is further elucidated. The chromatin modifying proteins that are known to interact with DNMTs are also described. Finally, the role of DNMTs as potential therapeutic targets is addressed.
Highlights
Cancer has long been viewed as a set of diseases caused by progressive genetic and epigenetic alterations
Robert et al [85] demonstrated that DNMT1 was necessary and sufficient to maintain CpG island methylation and aberrant gene silencing in human cancer cells
Aberrant epigenetic silencing of tumor suppressor genes by CpG island promoter hypermethylation plays an important role in the pathogenesis of cancer
Summary
Cancer has long been viewed as a set of diseases caused by progressive genetic and epigenetic alterations. A large and expanding body of evidence suggests that the initiation and progression of several cancer types is controlled by epigenetic modifications-heritable changes in gene expression patterns that are mediated by mechanisms other than changes in the primary DNA sequence. Aberrant DNA methylation is the most prominent form of epigenetic modification in cancer [1,2,3]. Aberrant CpG methylation patterns are accompanied by genome-wide hypomethylation and gene-specific hypermethylation [3, 5]. The aberrant CpG methylation patterns in human cancer cells are inscribed by the de novo DNA cytosine-5 methyltransferases (DNMTs), DNMT3a and DNMT3b, and transmitted in the subsequent cell generations by the maintenance DNMT1 [4, 6]. The DNA methylation mechanism and the DNA methylation machinery are described in detail along with the associations between DNMTs and chromatin modifying protein complexes
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