Epigenetic DNA-(cytosine-5-carbon) modifications: 5-aza-2'-deoxycytidine and DNA-demethylation.
DNA (cytosine-5-carbon) methylation is one of the hallmarks of mammalian chromatin modifications. Distinct methylation pattern can generate synergistic or antagonistic interaction affinities for CpG-islands associated with methylated 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 DNA-methylation 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 5-azacytidine and 5-aza-2'-deoxycytidine (AzadC), in cell culture produces re-expression of certain genes, which otherwise were repressed in association with hypermethylated CpG-rich promoters. Hence the notion developed that AzadC is a demethylating agent. Here we discuss the broad global pictures with the following points: first, chemical definition and recent advances regarding the mechanism of DNA (cytosine-5-carbon) methylation ((Me)CpG-DNA or (Me)CpNpG-DNA formation) and (Me)CpG/(Me)CpNpG-DNA-demethylation, and then with the mechanistic basis of inactivation of DNA-methyltransferase 1 by AzadC. This will clarify that: (i) AzadC has nothing to do with DNA-demethylation; (ii) it cannot prevent even de novo methylation in non-replicating 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 DNA-demethylating agent is a serious misuse of chemistry and chemical terminology.
Patra
S K
SK
Division of Biochemistry, Department of Experimental Medicine, University of Parma, Parma, Italy. skpatra_99@yahoo.com
Bettuzzi
S
S
D044503:5-Methylcytosine / Q000096:biosynthesis*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002453:Cell Cycle / Q000235:genetics; D003596:Cytosine / Q000378:metabolism*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000502:physiology*; D015257:DNA-Cytosine Methylases / Q000378:metabolism; D000077209:Decitabine; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans
D000964:Antimetabolites, Antineoplastic; D044503:5-Methylcytosine; D000077209:Decitabine; D003596:Cytosine; D015257:DNA-Cytosine Methylases; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine