Influence of intervening mismatches on long-range guanine oxidation in DNAduplexes

A systematic investigation of the efficiency of oxidative damage at guanine residues through long-range charge transport was carried out as a function of intervening base mismatches. A series of DNA oligonucleotides were synt hesized that incorporate a ruthenium intercalator linked covalently to the 5 ' terminus of one strand and containing two 5 ' -GG-3 ' sites in the comp lementary strand. Single base mismatches were introduced between the two gu anine doublet steps, and the efficiency of transport through the mismatches was determined through measurements of the ratio of oxidative damage at th e guanine doublets distal versus proximal to the intercalated ruthenium oxi dant. Differing relative extents of guanine oxidation were observed for the different mismatches. The damage ratio of oxidation at the distal versus p roximal site for the duplexes containing different mismatches varies in the order GC similar to GG similar to GT similar to GA > AA > CC similar to TT similar to CA similar to CT. For all assemblies, damage found with the A-R u diastereomer was found to be greater than with the A-diastereomer. The ex tent of distal/proximal guanine oxidation in different mismatch-containing duplexes was compared with the helical stability of the duplexes, electroch emical data for intercalator reduction on different mismatch containing DNA films, and base-pair lifetimes for oligomers containing the different mism atches derived from H-1 NMR measurements of the imino proton exchange rates . While a clear correlation is evident both with helix stability and electr ochemical data monitoring reduction of an intercalator through DNA films, d amage ratios correlate most closely with base-pair lifetimes. Competitive h ole trapping at the mismatch site does not appear to be a key factor govern ing the efficiency of transport through the mismatch. These results undersc ore the importance of base dynamics in modulating long-range charge transpo rt through the DNA base-pair stack.