Mapping of the Hot Spots for DNA Damage by One-Electron Oxidation: Efficacy of GG Doublets and GGG Triplets as a Trap in Long-Range Hole Migration

Abstract

There has been much current interest in the long-range oxidative damage to DNA through the DNA duplex caused by one-electron oxidations. 1 Hole (radical cation) migration through the DNA duplex has been suggested to play a crucial role in mutagenesis and carcinogenesis caused by carcinogenic agents, ionizing radiation, and high-intensity laser irradiation. 1,2 As is well-known, guanine (G) is the most easily oxidized base, 3 and the electron-loss center created in duplex DNA ultimately ends up at G residues via hole migration through the DNA duplex. Several years ago, we demonstrated both experimentally and by ab initio calculations that 5′-G residues of 5′-GG-3′ steps in B-form DNA are the most easily oxidized due to the GG stacks and can act as thermodynamic sinks in hole migration across the DNA π stack. 4 We also demonstrated that the highest occupied molecular orbital (HOMO) of a GG stack is especially high in energy and concentrated on the 5′-G. 4b Thereafter, examples of 5′-G selective oxidations have been reported in many different systems. These include (i) photooxidation using different types of DNA-binding agents such as Rh(III)-metallointercalators, 1a-c,f substituted anthraquinones, 1d,e,5 riboflavin, 6 naphthalimide derivatives, 4 a p-cyano-substituted benzophenone, 7 and pterins; 8 (ii) chemical oxidation by Ru(III)-metallointercalators 1c,9 and Ni(II)ligand/sulfite system; 10 (iii) two-photon photoionization of DNA with a high-intensity laser pulse (266 nm); 11 and (iv) direct irradiation with a powerful 193-nm excimer laser. 12 Notably, the 5′-G selectivity of 5′-GG-3′ steps is irrelevant to the structural

Oxidation of Guanine in G, GG, and GGG Sequence Contexts by Aromatic Pyrenyl Radical Cations and Carbonate Radical Anions: Relationship between Kinetics and Distribution of Alkali-Labile Lesions

“…The enhanced rate constants of oxidation at GG and GGG sequences are consistent with the Saito model. 11,19,20 The k G value for sequence 1d with isolated guanines near the ends in AGA sequence contexts are similar in value to k G in the GGG sequence context in duplex 5d. We attribute this large value of k G to end effects rather than to sequence effects (AGA vs. TGT) for the following reasons.…”

“…In early experiments it was shown that photoexcitation of DNA in its normal B-type double helical form by intense nano-or picosecond 266 nm laser pulses induces a greater damage of guanines positioned on the 5′-side of purine bases, especially adjacent to guanine, than on guanines adjacent to pyrimidines. 7 This selectivity of G oxidation in different sequence context has been also observed employing one-electron oxidants generated by photosensitization of metal complexes, 3,8 anthraquinones, 4,9 naphthalimides, 10 riboflavin (RF), 11,12 4′-pivaloyl derivatives, 13,14 cyanobenzoyl and cyanobenzophenone substituted 2′-deoxyuridine 15,16 and other chemical one-electron oxidants. 17, 18 Saito and co-workers have shown that the enhancement of oxidative guanine damage increases with the number of contiguous guanines according to 5′-G < 5′-GG < 5′-GGG and that this phenomenon is correlated with the calculated gas phase ionization potentials (IP) for guanines in different sequence contexts.…”

“…Paradoxically, this rate constant exhibits only small variations within a narrow interval [(1.5 -3.0)× 10 7 M −1 s −1 ] and is thus independent of sequence context. 30 This result is in seeming contradiction to the Saito model 11,19,20 because the yields of oxidized guanine end-products within contiguous …G 1 G 2 … and …G 1 G 2 G 3 … sequences are usually significantly higher at G 1 and G 1 G 2 , respectively. 4,5,11 There are few direct kinetic measurements of electron transfer rate constants relevant to the oxidation of guanines in double-stranded DNA in different sequence contexts.…”

“…However, in 100 μM solutions of the duplexes (Table 3), the fluorescence of the BPT is strongly quenched, 43 and the fluorescence decay profiles can be analyzed in terms of a sum of three exponentials: (11) with lifetimes, τ 1 , τ 2 , and τ 3 , and relative amplitudes, I 1 , I 2 , and I 3 , respectively, where I 1 +I 2 +I 3 = 1. (Figure S1B in Supporting Information).…”

“…17, 18 Saito and co-workers have shown that the enhancement of oxidative guanine damage increases with the number of contiguous guanines according to 5′-G < 5′-GG < 5′-GGG and that this phenomenon is correlated with the calculated gas phase ionization potentials (IP) for guanines in different sequence contexts. 11,19,20 Siebbeles and co-workers calculated distributions of a positive charge in sequences of two or three adjacent guanines, flanked by other nucleobases that provide a useful model for mapping the reactivities of guanines in different sequence contexts. 21,22 By analyzing the detailed kinetics of electron transfer reactions, Lewis, Wasielewski and co-workers determined the rate constants of forward-and back-transfer from single G to a GG doublet and a GGG triplet.…”