Oxidative Charge Transfer To Repair Thymine Dimers and Damage Guanine Bases in DNA Assemblies Containing Tethered Metallointercalators

Abstract

Potent oxidants which intercalate in DNA serve as tools to probe DNA-mediated electron-transfer reactions. A photoexcited rhodium intercalator, Rh(phi)2DMB3+ (phi = 9,10-phenanthrenequinone diimine and DMB = 4,4'-dimethyl-2,2'-bipyridine), tethered to DNA, promotes both oxidative damage to 5'-GG-3' doublets in DNA and the repair of thymine dimers from a remote site on the DNA duplex. DNA-mediated repair of a thymine dimer lesion by charge transfer from the tethered rhodium intercalator is quantitative, albeit with low photoefficiency, occurs in an intraduplex reaction over long range (36 A), and requires that the intervening bases be paired. When both oxidative reactions, repair and oxidative damage, are monitored on the same duplex, competition is evident; the presence of both a 5'-GG-3' site and the thymine dimer diminished the dimer repair efficiency by 20-40% and decreased damage at the 5'-GG-3' sites 2-fold compared to similar sequences lacking either the guanine doublet or thymine dimer, respectively. In addition to damage at the 5'-G of 5'-GG-3' sites, we also observe oxidation at the 3'-G of the 5'-GT<>TG-3' tetrad only in the presence of thymine dimer. Overall, the yield of repaired thymine strand was at least 10 times higher than the yield of oxidized guanine in the same sequences. While the 5-GG-3' may represent the thermodynamically favored site for oxidative reaction, repair of the thymine dimer appears to be kinetically more favorable. Dipyridophenanzine (dppz) complexes of ruthenium(III), less potent oxidants which intercalate in DNA, oxidize 5'-GG-3' doublets efficiently but cannot trigger the repair of the thymine dimer lesion. Oxidative damage to DNA from a distance, mediated by the DNA base pair stack, can, however, be utilized to probe the disruption in the base stack generated by the thymine dimer. The presence of the dimer does not diminish oxidation by a Ru(III) intercalator at a distal guanine doublet, suggesting that the disruption caused by the dimer does not block charge transfer through the DNA duplex. DNA-mediated electron-transfer reactions of metallointercalators therefore serve to illustrate important aspects of radical migration and its consequence with respect to reactions at a distance through the DNA base pair stack.

Long-range oxidative damage to cytosines in duplex DNA

“…This model accounts well for the attenuation in CT seen in AT-rich sequences, owing to their inherent flexibility, and tunneling through AT sequences need not be invoked (15,16). It also explains oxidative repair of thymine dimers at a distance, another fast trap (43,44). Although this model is more challenging to test experimentally, and to describe theoretically, than superexchange or localized hopping, these and other data (45,46) show that DNA-mediated CT requires a more complete treatment.…”

Electronic Coupling for Charge Transfer and Transport in DNA

“…[1][2][3][4][5][6][7][8][9] Biological implications of charge transfer and transport in DNA may pertain to repair induced by charge transfer [10][11][12][13] and also to radiation damage followed by long-range charge transport, which leads to mutations. 14,15 The conceptual framework for the quantification of charge migration in DNA rests on the theory of charge transfer, 41 with the rates for the elementary processes being determined by electronic coupling and nuclear Franck-Condon factors.…”

Distance Dependence of Electron Transfer in DNA: The Role of the Reorganization Energy and Free Energy

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14] Some of the experimental systems studied appear to undergo almost distance-independent electron transfer. [4][5][6][7][8][9][10] Theories to explain this work include pair wise hopping mechanisms, 15 wavelike electron transfer through a delocalized bridge system, 16 and thermally activated pair wise transfer via base pairs. 17 Some experimental work shows a distance dependence typical of superexchange or electron tunneling (Marcuslike) observed for inter-and intramolecular electron transfer in a wide variety of environments, including proteins, liquids, and micelles.…”