Duplex DNA catalyzes the chemical rearrangement of a malondialdehyde deoxyguanosine adduct.

Mao H, Schnetz-Boutaud NC, Weisenseel JP, Marnett LJ, Stone MP
Proc Natl Acad Sci U S A. 1999 96 (12): 6615-20

PMID: 10359760 · PMCID: PMC21963 · DOI:10.1073/pnas.96.12.6615

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.

MeSH Terms (10)

Animals Deoxyguanosine DNA DNA Adducts DNA Damage DNA Repair Humans Lipid Peroxidation Magnetic Resonance Spectroscopy Malondialdehyde

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