Structure of the malondialdehyde deoxyguanosine adduct M1G when placed opposite a two-base deletion in the (CpG)3 frameshift hotspot of the Salmonella typhimurium hisD3052 gene.

Schnetz-Boutaud NC, Saleh S, Marnett LJ, Stone MP
Adv Exp Med Biol. 2001 500: 513-6

PMID: 11764989 · DOI:10.1007/978-1-4615-0667-6_77

Malondialdehyde (MDA) is a toxic and mutagenic metabolite produced by lipid peroxidation, and prostaglandin biosynthesis. MDA induces frameshift mutations in tester strains of Salmonella typhimurium. It reacts with DNA, and at physiological pH the major adduct is a pyrimidopurinone formed by reaction with guanine: M1G [3-(2'-deoxy-beta-D-erythropentofuranosyl)pyrimido[1,2-alpha]-purin-10(3H)-one]. When site-specifically incorporated into a duplex oligodeoxynucleotide containing a frameshift-prone (CG)3 repeat derived from the Salmonella typhimurium hisd3052 gene, spontaneous opening of M1G to the N2-(3-oxo-1-propenyl)-dG species occurred. In this work d(ATCGCMCGGCATG), (M=M1G) was annealed to d(CATGCCGCGAT) to model the putative strand slippage intermediate which would precede a two base deletion in the (CG)3 iterated repeat. 1H NMR studies indicate that in contrast to the duplex DNA structure, M1G remains intact. A single bulge conformation exists. M1G and its 3'-neighbor cytosine are unpaired. The M1G is intrahelical and stacked, whereas the unpaired cytosine is poorly stacked and appears to be extrahelical.

MeSH Terms (10)

Base Pairing CpG Islands Deoxyguanosine DNA, Bacterial DNA Adducts Frameshift Mutation Genes, Bacterial Mutagenesis Nucleic Acid Conformation Salmonella typhimurium

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