AlkB reverses etheno DNA lesions caused by lipid oxidation in vitro and in vivo

Oxidative stress converts lipids into DNA-damaging agents. The genomic lesions formed include 1, N-6-ethenoadenine (epsilon A) and 3,N-4-ethenocytosine (epsilon C), in which two carbons of the lipid alkyl chain form an exocyclic adduct with a DNA base. Here we show that the newly characterized enzyme AlkB repairs epsilon A and epsilon C. The potent toxicity and mutagenicity of epsilon A in Escherichia coli lacking AlkB was reversed in AlkB(+) cells; AlkB also mitigated the effects of epsilon C. In vitro, AlkB cleaved the lipid-derived alkyl chain from DNA, causing epsilon A and epsilon C to revert to adenine and cytosine, respectively. Biochemically, epsilon A is epoxidized at the etheno bond. The epoxide is putatively hydrolyzed to a glycol, and the glycol moiety is released as glyoxal. These reactions show a previously unrecognized chemical versatility of AlkB. In mammals, the corresponding AlkB homologs may defend against aging, cancer and oxidative stress.