DNMT gene

The importance of DNA methylation for normal genome function can also be shown by the finding that homozygous mutation of the DNMT gene results in embryonic lethality [46]. Thus, unwanted activation of certain genes by DNMT inhibitors may pose a risk, for example by derepression of proinvasive genes [47], which puts a caveat to those therapeutical approaches. 

In multicellular eukaryotes, DNA methylation is associated with transcriptional silencing [3]. In these organisms, DNA methylation has been observed exclusively on the C5 position of the cytosine ring and is frequently found in CpG-rich regions. This process is attributed to the action of DNA methyltransferases (DNMTs), which utilize the cofactor, S-adenosyl-L-methionine. Approximately half of all human genes have CpG islands in their promoter regions but these stretches of DNA are typically... 

The covalent trapping of the enzyme leads to a depletion of the cellular pool of DNMTs and subsequent DNA hypomethylation. This in turn results in activation with respect to the reactivation of silenced genes. Additionally, the covalently trapped DNMT may inhibit RNA and DNA polymerases, which leads to an inhibition of protein biosynthesis and DNA strand breaks. This may lead to apoptosis and hence cytotoxicity. Thus, it is not easy to dissect the reasons for the clinical efficacy of these inhibitors in terms of real epigenetic and plain cytotoxic effects [81]. 

DNA methylation is accomplished by DNA methyltransferases (DNMTs), which catalyze the transfer of a methyl group from S-adcnosyl-meth ionine to the 5-position of cytosine in the CpG dinucleotide. DNA hypermethylation within the promoter region of tumor suppressor genes involved in cell proliferation and differentiation is a common phenomenon in numerous solid tumors.4-5... 

CpG islands of tumor-suppressor genes are hypermethylated in cancer cells. Therefore, they recmit multiple repressors that lead to a characteristic histone modification pattern the deacetylation of histones H3 and H4, the methylation of lysine 9 of histone H3, and the demethylation of lysine 4 of histone H3 (52). In addition, it has been shown that the polycomb protein EZH2 associates with DNMTs and that specific methylation of lysine 27 of histone H3 is required to establish DNA methylation in a subset of target genes (6). 

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