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.

Interstrand DNA Cross-Links Induced by α,β-Unsaturated Aldehydes Derived from Lipid Peroxidation and Environmental Sources

“…This hypothesis was, in part, developed from the observation that the malondialdehyde-derived adduct 21 opens to a related aldehyde 22 when placed opposite dC in DNA (Scheme 3). [36][37][38] Enal adducts are lower oxidation state homologues of 21 and the notion that acrolein, crotonaldehyde, and 4-HNE undergo similar chemistry was confirmed by the observation that γ-OH-PdG (9) ring-opens to the N 2 -(3-oxopropyl)-dG aldehyde (1) when placed opposite dC. 39 We further hypothesized that these aldehydes react with other nucleobases in the complementary DNA strand, forming interstrand cross-links, which exist as equilibrium mixtures of carbinolamine (17) In this Account, we discuss the chemistry of interstrand cross-links that are likely to be generated in DNA as secondary dG adducts of acrolein, crotonaldehyde, and 4-HNE.…”

Bulge Migration of the Malondialdehdye OPdG DNA Adduct When Placed Opposite a Two-Base Deletion in the (CpG)3 Frameshift Hotspot of the Salmonella typhimurium hisD3052 Gene

“…Interest in the structure of the OPdG and M 1 dG adducts embedded in the frameshift-prone hisD3052-iterated (CG) 3 repeat sequence arose from the observation that MDA induced frameshift mutations (32 It has not been possible to examine the M 1 dG adduct with respect to structure in fully complementary DNA duplexes due to the fact that when placed opposite dC, it rapidly rearranges to the OPdG adduct (28). The saturated analogue 1,N 2 -propanodG (PdG adduct) (49) was used by our laboratory (30,(50)(51)(52)(53)(54) as well as by other laboratories (55-58) as a stable structural surrogate for exocyclic 1,N 2 -dG adducts such as the M 1 dG adduct and the acrolein γ-OH-PdG adduct.…”

“…The data suggest that bulge migration transiently positions OPdG opposite dC in the complementary strand or, alternatively, reverts rapidly formed intermediates in the OPdG to M 1 dG reaction pathway (30) when dC is placed opposite from OPdG. In contrast, the localized bulge in the M 1 dG-2BD duplex consisting of the M 1 dG adduct and the 3′-neighbor dC (33) hinders the conversion of M 1 dG to OPdG that is catalyzed by the positioning of cytosine opposite from M 1 dG (28,29). The addition of either M 1 dG-2BD-or OPdG-2BD-containing samples to an equilibrium mixture was monitored as a function of time, using NMR spectroscopy.…”

Mass Spectrometric Mapping of the DNA Adductome as a Means to Study Genotoxin Exposure, Metabolism, and Effect

“…10,13 However, it appears that only a limited number of studies have studied the stability of a limited number of adduct types, which was discussed in detail by Himmelstein et al 12 DNA adduct stability depends on several factors including pH (e.g. M 1 dG is not stable under alkaline conditions 76 ) and composition of storage buffers (e.g. Tris buffer induces M 1 dG instability 77 ).…”