TOXI 51 |
| The OPdG adduct N2-(3-oxo-1-propenyl)-dG, formed in DNA exposed to malondialdehyde, was introduced into a frameshift hotspot of the Salmonella typhimuium hisD3052 gene containing a two-base deletion in complementary strand 5'-d(ATCGCXCGGCATG)-3'•5'-d(CATGCCGCGAT)-3' at pH 7; X=OPdG. The OpdG-2BD adduct is the base-catalyzed rearrangement product of the M1dG adduct, 3-(ß-D-ribofuranosyl)pyrimido[1,2a]-purin-10(3H)-one. NMR spectroscopy revealed that the OPdG-2BD underwent rapid bulge migration. This hindered its conversion to the more stable M1dG-2BD duplex, in which the bulge was localized and consisted of the M1dG 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 M1dG-2BD duplex, or alternatively, reverting rapidly formed intermediates in the OPdG to M1dG reaction pathway when dC was placed opposite to OPdG. The approach of initially formed M1dG-2BD or OPdG-2BD duplexes to an equilibrium mixture favoring the M1dG-2BD duplex was monitored as a function of time, using NMR spectroscopy. Both samples attained equilibrium in ~140 days at 25 °C. |
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Poster Session and Awards
6:00 PM-10:00 PM, Tuesday, August 21, 2007 BCEC -- 204 A/B, Poster
Division of Chemical Toxicology |