The exocyclic 1,N2-deoxyguanosine pyrimidopurinone M1G is a chemically stable DNA adduct when placed opposite a two-base deletion in the (CpG)3 frameshift hotspot of the Salmonella typhimurium hisD3052 gene.
The pyrimidopurinone adduct M1G [3-(2'-deoxy-beta-D-erythro-pentofuranosyl)pyrimido[1,2-a]-purin-10(3H)-one], formed in DNA upon exposure to malondialdehyde or base propenals, was incorporated into 5'-d(ATCGCMCGGCATG)-3'-5'-d(CATGCCGCGAT)-3', where M = M1G. This duplex contained a two-nucleotide bulge in the modified strand, and was named the M1G-2BD oligodeoxynucleotide. It provided a model for -2 bp strand slippage deletions associated with the (CpG)3-iterated repeat hotspot for frameshift mutations from the Salmonella typhimurium hisD3052 gene. M1G was chemically stable in the M1G-2BD duplex at neutral pH. The two-base bulge in the M1G-2BD oligodeoxynucleotide was localized and consisted of M1G and the 3'-neighbor deoxycytosine. The intrahelical orientation of M1G was established from a combination of NOE and chemical shift data. M1G was in the anti conformation about the glycosyl bond. The 3'-neighbor deoxycytosine appeared to be extruded toward the major groove. In contrast, when M1G was placed into the corresponding fully complementary (CpG)3-iterated repeat duplex at neutral pH, spontaneous and quantitative ring-opening to N(2)-(3-oxo-1-propenyl)-dG (the OPG adduct) was facilitated [Mao, H., Reddy, G. R., Marnett, L. J., and Stone, M. P. (1999) Biochemistry 38, 13491-13501]. The structure of the M1G-2BD duplex suggested that the bulged sequence lacked a cytosine amino group properly positioned to facilitate opening of M1G and supports the notion that proper positioning of deoxycytosine complementary to M1G is necessary to promote ring-opening of the exocyclic adduct in duplex DNA. The structure of the M1G-2BD duplex was similar to that of the structural analogue 1,N(2)-propanodeoxyguanosine (PdG) in the corresponding PdG-2BD duplex [Weisenseel, J. P., Moe, J. G., Reddy, G. R., Marnett, L. J., and Stone, M. P. (1995) Biochemistry 34, 50-64]. The fixed position of the bulged bases in both instances suggests that these exocyclic adducts do not facilitate transient bulge migration.
Schnetz-Boutaud
N C
NC
Department of Chemistry, Center in Molecular Toxicology, A.B. Hancock, Jr. Memorial Laboratory for Cancer Research, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37235, USA.
Saleh
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S
Marnett
L J
LJ
Stone
M P
MP
D000429:Alcohol Oxidoreductases; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics*; D018899:CpG Islands; D018736:DNA Adducts / Q000737:chemistry* / Q000235:genetics; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000235:genetics; D004355:Drug Stability; D016368:Frameshift Mutation; D005798:Genes, Bacterial; D008315:Malondialdehyde / Q000494:pharmacology; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000235:genetics; D011522:Protons; D012486:Salmonella typhimurium / Q000235:genetics*; D017384:Sequence Deletion; D013816:Thermodynamics; D018911:Trinucleotide Repeats
D001426:Bacterial Proteins; D018736:DNA Adducts; D004269:DNA, Bacterial; D009838:Oligodeoxyribonucleotides; D011522:Protons; D008315:Malondialdehyde; C089188:3-(2'-deoxyribofuranosyl)pyrimido(1,2-a)purin-10(3H)-one; D000429:Alcohol Oxidoreductases; C021358:histidinol dehydrogenase; D003849:Deoxyguanosine