Duplex DNA catalyzes the chemical rearrangement of a malondialdehyde deoxyguanosine adduct

The primary DNA lesion induced by malondialdehyde, a byproduct of lipid peroxidation and prostaglandin synthesis, is 3-(2′-deoxy-β-d-erythro-pentofuranosyl)-pyrimido[1,2-a]purin-10(3H)-one (M(1)G). When placed opposite cytosine (underlined) at neutral pH in either the d(GGTMTCCG)⋅d(CGGACACC) or d(ATCGCMCGGCATG)⋅ d(CATGCCGCGCGAT) duplexes, M(1)G spontaneously and quantitatively converts to the ring-opened derivative N(2)-(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 M(1)G in a duplex. The presence of a complementary cytosine is not required to stabilize N(2)-(3-oxo-1-propenyl)-dG in duplex DNA at neutral pH. When N(2)-(3-oxo-1-propenyl)-dG is placed opposite to thymine in a duplex, it does not revert to M(1)G. A mechanism for the conversion of M(1)G to N(2)-(3-oxo-1-propenyl)-dG is proposed in which the exocyclic amino group of the complementary cytosine attacks the C8 position of the M(1)G 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 N(2)-(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.