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.
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.
Wang
Yazhen
Y
Departments of Chemistry and Biochemistry, Institute of Chemical Biology, Center in Molecular Toxicology, A. B. Hancock Jr. Memorial Laboratory for Cancer Research, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37235, USA.
Schnetz-Boutaud
Nathalie C
NC
Saleh
Sam
S
Marnett
Lawrence J
LJ
Stone
Michael P
MP
D020029:Base Pairing; D018899:CpG Islands / Q000235:genetics*; D018736:DNA Adducts / Q000737:chemistry* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000235:genetics; D016368:Frameshift Mutation / Q000235:genetics*; D005798:Genes, Bacterial / Q000235:genetics; D006639:Histidine / Q000235:genetics*; D009682:Magnetic Resonance Spectroscopy; D008315:Malondialdehyde / Q000031:analogs & derivatives*; D012486:Salmonella typhimurium / Q000235:genetics*; D013997:Time Factors
C090855:1,N(2)-(1,3-propano)-2'-deoxyguanosine; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D006639:Histidine; D008315:Malondialdehyde; D003849:Deoxyguanosine