LONG-RANGE OXIDATION OF GUANINE BY RU(III) IN DUPLEX DNA

Background: Theoretical and experimental studies have demonstrated tha t 5'-GG-3' sequences in DNA are 'hot spots' for oxidative damage, but few studies have definitively addressed whether oxidative damage to DN A may arise from a distance via long-range charge migration. Towards t his end, we have prepared tethered ruthenium(Ru)-oligonucleotide duple xes and used a flash-quench strategy to demonstrate long-range charge transport through the DNA double helix. Results: DNA assemblies contai ning a tethered Ru(II) intercalator have been synthesized. Ru(III), ge nerated in situ in the presence of externally bound electron-transfer quenchers, promotes base damage selectively at the 5'-G of a 5'-GG-3' doublet located similar to 37 Angstrom from the binding site of the ox idant. In the absence of a guanine doublet, oxidative damage occurs eq ually at all guanine bases in the strand. Oxidative damage is also obs erved at long range for guanine in a G.A mismatch but not in a G.T mis match. Conclusions: The present study expands the scope of long-range electron-transfer chemistry in terms of experiments, applications, and possible reactions within the cell. Here we demonstrate oxidative dam age to DNA occurring with a high quantum yield over a distance of simi lar to 37 Angstrom using a ground-state oxidant, These results point t o the equilibration of the radical across the DNA duplex to the sites of lowest energy. In addition, this charge migration is sensitive to t he intervening pi-stack formed by DNA base pairs and hence may be usef ul for the detection of mismatches.