Reversal of alkylation damage by DNA dioxygenases

Reversal of alkylation damage by DNA dioxygenases DNA in cells is susceptible to different types of cytotoxic and mutagenic damage caused by alkylating agents. These genotoxic chemicals generate major lesions like 1-methyladenine, 3-methyladenine, 3-methylcytosine and O6-methylguanine in DNA. Cells have built in repair mechanisms against such toxic molecules. For example, 3-methyladeninie-DNA glycosylases excise some methylated bases while MGMT/hAGT protein transfers alkyl groups from others lesions onto cysteine residues. E.coli AlkB protein has a unique function wherein 1-methyladenine and 3-methylcytosine are demethylated by a combination of oxidative decarboxylation and hydroxylation activities. AlkB and its human orthologs, ALKBH2 (ABH2) and ALKBH3 (ABH3) belong to alpha-ketoglutarate deoxygenase family of enzymes that oxidize chemically inert compounds in the presence of alpha-ketoglutarate, oxygen and ferrous ions. As a byproduct of these chemical reactions, formaldehyde is released in the case of methylated lesions and acetaldehyde in the case 1-ethyladenine in DNA. CO2 and succinate are also released in an intermediate step not shown in the following illustration. Unlike other mechanisms which involve some kind of nuclease activities, this type of repair mechanism leaves the repaired bases intact by just removing the reactive alkyl groups that get bound to the bases thereby effecting accurate restoration of damaged DNA sequences (Trewick et al. 2002, Duncan et al. 2002, Sedgwick 2004).