Reversal of Alkylation Damage By DNA Dioxygenases

Stable Identifier
Reaction [transition]
Gallus gallus
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Cellular DNA is susceptible to different types of cytotoxic and mutagenic damage caused by alkylating agents. These genotoxic chemicals generate significant levels of such lesions as 1-methyladenine and 3-methylcytosine in single stranded DNA and 3-methyladenine and O-6-methylguanine in double stranded DNA. A variety of cellular repair mechanisms guard against such toxic molecules. For example, 3-methyladenine DNA glycosylases excise certain methylated bases while tbe MGMT/hAGT protein transfers alkyl groups from particular lesions onto a cysteine residue on the enzyme itself. 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. The chicken orthologs, ALKBH2 and ALKBH3 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 as an intermediate product. Unlike other mechanisms which involve nuclease activities, this type of repair mechanism leaves the repaired bases intact by simple removal of the bound alkyl groups, thereby effecting accurate restoration of damaged DNA sequences.

Literature References
PubMed ID Title Journal Year
6337736 The release of 3-methyladenine from nucleosomal DNA by a 3-methyladenine DNA glycosylase

Price, JA, Heller, E, Goldthwait, DA

Carcinogenesis 1983
Participant Of
Catalyst Activity
Catalyst Activity
DNA-N1-methyladenine dioxygenase activity of ALKBH2 and 3 [nucleoplasm]
Physical Entity