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Solution structure of an oligodeoxynucleotide containing the malondialdehyde deoxyguanosine adduct N2-(3-oxo-1-propenyl)-dG (ring-opened M1G) positioned in a (CpG)3 frameshift hotspot of the Salmonella typhimurium hisD3052 gene.

Mao H, Reddy GR, Marnett LJ, Stone MP
Biochemistry. 1999 38 (41): 13491-501

PMID: 10521256 · DOI:10.1021/bi9910124

The refined solution structure for the ring-opened N2-(3-oxo-1-propenyl)-dG derivative of the malondialdehyde deoxyguanosine adduct M(1)G [3-(2'-deoxy-beta-D-erythro-pentofuranosyl)pyrimido[1, 2-a]purin-10(3H)-one] in d(ATCGCXCGGCATG) x d(CATGCCGCGCGAT) [X being N(2)-(3-oxo-1-propenyl)-dG], containing the d(CpG)(3) frameshift hotspot of the Salmonella typhimurium hisD3052 gene, is presented. When inserted into this duplex, M(1)G underwent spontaneous ring opening to N2-(3-oxo-1-propenyl)-dG. NMR analysis revealed that N2-(3-oxo-1-propenyl)-dG induced minor structural perturbations in the hisD3052 oligodeoxynucleotide. However, the stability of the duplex DNA was reduced; the N2-(3-oxo-1-propenyl)-dG-modified hisD3052 oligodeoxynucleotide exhibited a 14 degrees C decrease in T(m) relative to that of the native oligodeoxynucleotide. The modified guanine maintained stacking interactions with neighboring bases but was not Watson-Crick hydrogen bonded. A total of 13 NOEs were observed from the 3-oxo-1-propenyl moiety protons of N2-(3-oxo-1-propenyl)-dG to DNA protons. Molecular dynamics calculations, restrained by 602 distance restraints derived from experimental NOE measurements and 23 empirical distance restraints, converged with pairwise rmsd differences of <0.90 A. The sixth-root residual factor with the NMR data was 9.1 x 10(-2). The cytosine complementary to N2-(3-oxo-1-propenyl)-dG was pushed toward the major groove but maintained partial stacking interactions with its neighboring bases. The modified guanine remained in the anti conformation, while the 3-oxo-1-propenyl moiety was positioned in the minor groove of the duplex. Possible correlations between the relatively small structural perturbations induced in this DNA duplex by N2-(3-oxo-1-propenyl)-dG and the mutagenic spectrum of M(1)G are discussed.

MeSH Terms (19)

Alcohol Oxidoreductases Bacterial Proteins CpG Islands Deoxyguanosine DNA, Bacterial DNA Adducts Frameshift Mutation Genes, Bacterial Malondialdehyde Models, Molecular Nuclear Magnetic Resonance, Biomolecular Oligodeoxyribonucleotides Protons Purines Pyrimidine Nucleosides Pyrimidines Salmonella typhimurium Solutions Thermodynamics

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