Abstract
Site-specific DNA methylation plays an important role in epigenetic regulation of gene expression. Chemical methylation of DNA, including the formation of various methylated nitrogenous bases, leads to the formation of genotoxic modifications that impair DNA functions. Despite the fact that different pathways give rise to methyl groups in DNA, the main pathway for their removal is oxidative demethylation, which is catalyzed by nonheme Fe(II)/α-ketoglutarate–dependent DNA dioxygenases. DNA dioxygenases share a common catalytic mechanism of the oxidation of the alkyl groups on nitrogenous bases in nucleic acids. This review presents generalized data on the catalytic mechanism of action of DNA dioxygenases and on the participation of typical representatives of this superfamily, such as prokaryotic enzyme AlkB and eukaryotic enzymes ALKBH1–8 and TET1–3, in both processes of direct repair of alkylated DNA adducts and in the removal of an epigenetic mark (5-methylcytosine).
Highlights
Methylation is one of the most common chemical changes in nucleic acids
We examine the enzymes involved in oxidative demethylation, which is mediated by the class of mononuclear Fe(II)-containing enzymes
DNA and RNA methylation are performed by distinct methyltransferases all three TET enzymes are active toward 5-methyl-ribocytosine (m5 rC) in vitro and in
Summary
Methylation is one of the most common chemical changes in nucleic acids. On the one hand, alkylating agents (extracellular or intracellular) can attack reactive groups in DNA and produce cytotoxic DNA lesions. The DNA damage caused by methylating agents can occur at different positions of nitrogenous bases or of the 20 -deoxyribose-phosphate backbone The outcome depends both on the type of chemical reaction (nucleophilic substitution SN 1 or SN 2) and on the nucleophilic center’s properties. The methylationFe(II)/α-KG–dependent of adenine or cytosine at these positions prevents of Watson–Crick dioxygenases catalyze the theformation direct oxidation of alkyl substit contacts between nitrogenous bases during DNA replication, having toxic effects uents in nitrogenous bases of DNA and RNA The enzymes of this superfamily us on the cell [6]. Embryonic stem cells [19]), when at a certain point, there should be a sharp “reprogramming” and change of methylation sites between DNA replication rounds in the cell Such phenomena obviously require an additional mechanism (i.e., active demethylation of DNA).
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