title: AlkB reverses etheno DNA lesions caused by lipid oxidation in vitro and in vivo.
abstract: Oxidative stress converts lipids into DNA-damaging agents. The genomic lesions formed include 1,N(6)-ethenoadenine (epsilonA) and 3,N(4)-ethenocytosine (epsilonC), 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 epsilonA and epsilonC. The potent toxicity and mutagenicity of epsilonA in Escherichia coli lacking AlkB was reversed in AlkB(+) cells; AlkB also mitigated the effects of epsilonC. In vitro, AlkB cleaved the lipid-derived alkyl chain from DNA, causing epsilonA and epsilonC to revert to adenine and cytosine, respectively. Biochemically, epsilonA 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.
authors.affiliation: Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Delaney
authors.forename: Lisa
authors.initials: L
authors.lastname: Smeester
authors.forename: Cintyu
authors.initials: C
authors.lastname: Wong
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Frick
authors.forename: Koli
authors.initials: K
authors.lastname: Taghizadeh
authors.forename: John S
authors.initials: JS
authors.lastname: Wishnok
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Drennan
authors.forename: Leona D
authors.initials: LD
authors.lastname: Samson
authors.forename: John M
authors.initials: JM
authors.lastname: Essigmann
mesh_terms: D000079:Acetaldehyde / Q000031:analogs & derivatives / Q000633:toxicity; D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015227:Lipid Peroxidation; D006899:Mixed Function Oxygenases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016296:Mutagenesis
chemical_list: C018289:3,N(4)-ethenocytosine; D018736:DNA Adducts; D029968:Escherichia coli Proteins; C004981:1,N(6)-ethenoadenine; D003596:Cytosine; C004656:chloroacetaldehyde; D006899:Mixed Function Oxygenases; C466427:AlkB protein, E coli; D045647:DNA Glycosylases; C076131:DNA-3-methyladenine glycosidase II; D000079:Acetaldehyde; D000225:Adenine