title: Duplex DNA catalyzes the chemical rearrangement of a malondialdehyde deoxyguanosine adduct.
abstract: The primary DNA lesion induced by malondialdehyde, a byproduct of lipid peroxidation and prostaglandin synthesis, is 3-(2'-deoxy-beta-D-erythro-pentofuranosyl)-pyrimido[1, 2-a]purin-10(3H)-one (M1G). When placed opposite cytosine (underlined) at neutral pH in either the d(GGTMTCCG).d(CGGACACC) or d(ATCGCMCGGCATG). d(CATGCCGCGCGAT) duplexes, M1G spontaneously and quantitatively converts to the ring-opened derivative N2-(3-oxo-1-propenyl)-dG. Ring-opening is reversible on thermal denaturation. Ring-opening does not occur at neutral pH in single-stranded oligodeoxynucleotides or when T is placed opposite to M1G in a duplex. The presence of a complementary cytosine is not required to stabilize N2-(3-oxo-1-propenyl)-dG in duplex DNA at neutral pH. When N2-(3-oxo-1-propenyl)-dG is placed opposite to thymine in a duplex, it does not revert to M1G. A mechanism for the conversion of M1G to N2-(3-oxo-1-propenyl)-dG is proposed in which the exocyclic amino group of the complementary cytosine attacks the C8 position of the M1G exocyclic ring and facilitates ring opening via formation of a transient Schiff base. Addition of water to the Schiff base regenerates the catalytic cytosine and generates N2-(3-oxo-1-propenyl)-dG. These results document the ability of duplex DNA to catalyze the transformation of one adduct into another, which may have important consequences for mutagenesis and repair.
authors.affiliation: Department of Chemistry, Center in Molecular Toxicology and the E. Bronson Ingram Cancer Center, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: H
authors.initials: H
authors.lastname: Mao
authors.forename: N C
authors.initials: NC
authors.lastname: Schnetz-Boutaud
authors.forename: J P
authors.initials: JP
authors.lastname: Weisenseel
authors.forename: L J
authors.initials: LJ
authors.lastname: Marnett
authors.forename: M P
authors.initials: MP
authors.lastname: Stone
mesh_terms: D000818:Animals; D004247:DNA / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018736:DNA Adducts / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair; D003849:Deoxyguanosine / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation; D009682:Magnetic Resonance Spectroscopy; D008315:Malondialdehyde / Q000633:toxicity*
chemical_list: D018736:DNA Adducts; D008315:Malondialdehyde; D004247:DNA; D003849:Deoxyguanosine