Bulge migration of the malondialdehyde OPdG DNA adduct when placed opposite a two-base deletion in the (CpG)3 frameshift hotspot of the Salmonella typhimurium hisD3052 gene.

Wang Y, Schnetz-Boutaud NC, Saleh S, Marnett LJ, Stone MP
Chem Res Toxicol. 2007 20 (8): 1200-10

PMID: 17645303 · PMCID: PMC2728581 · DOI:10.1021/tx700121j

The OPdG adduct N (2)-(3-oxo-1-propenyl)dG, formed in DNA exposed to malondialdehyde, was introduced into 5'-d(ATCGC XCGGCATG)-3'.5'-d(CATGCCGCGAT)-3' at pH 7 (X = OPdG). The OPdG adduct is the base-catalyzed rearrangement product of the M 1dG adduct, 3-(beta- d-ribofuranosyl)pyrimido[1,2- a]purin-10(3 H)-one. This duplex, named the OPdG-2BD oligodeoxynucleotide, was derived from a frameshift hotspot of the Salmonella typhimuium hisD3052 gene and contained a two-base deletion in the complementary strand. NMR spectroscopy revealed that the OPdG-2BD oligodeoxynucleotide underwent rapid bulge migration. This hindered its conversion to the M 1dG-2BD duplex, in which the bulge was localized and consisted of the M 1dG adduct and the 3'-neighbor dC [ Schnetz-Boutaud, N. C. , Saleh, S. , Marnett, L. J. , and Stone, M. P. ( 2001) Biochemistry 40, 15638- 15649 ]. The spectroscopic data suggested that bulge migration transiently positioned OPdG opposite dC in the complementary strand, hindering formation of the M 1dG-2BD duplex, or alternatively, reverting rapidly formed intermediates in the OPdG to M 1dG reaction pathway when dC was placed opposite from OPdG. The approach of initially formed M 1dG-2BD or OPdG-2BD duplexes to an equilibrium mixture of the M 1dG-2BD and OPdG-2BD duplexes was monitored as a function of time, using NMR spectroscopy. Both samples attained equilibrium in approximately 140 days at pH 7 and 25 degrees C.

MeSH Terms (12)

Base Pairing CpG Islands Deoxyguanosine DNA-Binding Proteins DNA Adducts Frameshift Mutation Genes, Bacterial Histidine Magnetic Resonance Spectroscopy Malondialdehyde Salmonella typhimurium Time Factors

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