DNA (cytosine5carbon) methylation is one of the hallmarks of mammalian chromatin modifications. Distinct methylation pattern can generate synergistic or antagonistic interaction affinities for CpGislands associated with methy lated or unmethylated cytosine binding proteins, which also may dictate histone modifications and dynamic transition between transcriptionally silent or transcriptionally active chromatin states. The enzymes and cofactors associated with DNAmethylation reactions are convincing in terms of chemistry and chemical thermodynamics. The mechanism of demethylation, the candidate enzyme(s) exhibiting direct demethylase activity, and associated cofactors are not firmly established. Use of azanucleosides, such as 5azacytidine and 5aza2′deoxycytidine (AzadC), in cell culture produces re expression of certain genes, which otherwise were repressed in association with hypermethylated CpGrich promoters. Hence the notion developed that AzadC is a demethylating agent. Here we discuss the broad global pictures with the fol lowing points: first, chemical definition and recent advances regarding the mechanism of DNA (cytosine5carbon) methy lation (MeCpGDNA or MeCpNpGDNA formation) and MeCpG/MeCpNpGDNAdemethylation, and then with the mechanistic basis of inactivation of DNAmethyltransferase 1 by AzadC. This will clarify that: (i) AzadC has nothing to do with DNAdemethylation; (ii) it cannot prevent even de novo methylation in nonreplicating cells; (iii) it can only prevent replication coupled maintenance as well as de novo methylations. Finally, we would like to suggest that terming/designating AzadC as DNAdemethylating agent is a serious misuse of chemistry and chemical terminology.
Epigenetic DNA-(Cytosine-5-Carbon) Modifications: 5-Aza-2'-Deoxycytidine and DNA-Demethylation / PATRA S. K; BETTUZZI S.. - In: BIOCHEMISTRY. - ISSN 0006-2979. - 74(2009), pp. 613-619. [10.1134/S0006297909060042]