Long-range oxidative damage to DNA: Effects of distance and sequence

Abstract

Guanines are oxidized as a result of DNA-mediated charge transport over significant distances (e.g. 200 A). Although long-range charge transfer is dependent on distance, it appears to be modulated by intervening sequence and sequence-dependent dynamics. These discoveries hold important implications with respect to DNA damage in vivo.

A guanine-linked end-effect is a sensitive reporter of charge flow through DNA and RNA double helices

“…The above features result in a 5 0 -GGAGGG. sequence at the distal end of the duplex, different from most model duplexes used for hole conduction studies, which typically do not have stretches of guanines at their extreme distal ends (reviewed in [1,2]). …”

“…Such a property of charge migration through DNA helices has led to the suggestion that oxidative lesions, often causative of disease states, may occur at sites distal from the site of the initial oxidative insult [1]. Two kinds of charge conduction have been noted in DNA duplexes: (a) where the charge carrier is a nucleobase radical cation (an ''electron hole'') and (b) where it is a radical anion (an ''excess electron'').…”

“…Of the two, hole transfer has been studied the more intensively; experimentally, hole transfer can conveniently be initiated by photoexcitation of a sensitizer, such as anthraquinone (AQ), appended and stacked upon one end of a double helix. Guanine (G) is the DNA nucleobase most readily oxidized, and guanine radical cations (G þ ) within the helix can propagate over significant distances (w200 Å ) [1,4,5]. Both hopping and superexchange mechanisms operate in hole transfer at different distance scales [6e8]; in particular, the ''phonon-assisted polaron-like hopping'' model, a refinement of the hopping model, appears to successfully describe long-range hole conduction [4,5].…”

Electronic Structure and Spectroscopy of Nucleic Acid Bases: Ionization Energies, Ionization-Induced Structural Changes, and Photoelectron Spectra

“…Based on the gas-phase IEs, G is the easiest to oxidize, however, the positive charge does not necessarily remain on G and can migrate along the DNA strand as far as 200Å [1][2][3] to the other low IE sites (i.e., extended G runs). Charge migration is coupled with ionization-induced proton transfer [4][5][6][7][8][9][10], which separates the hole and the radical center.…”

Stepwise regulation of hole transport in DNA by control of triplex formation

“…In contrast, we confirmed that cleavage at the GG 6 site in Duplex II increased at 20 ˚C (lanes 3) because of the temperature effect on long-range hole transport through the DNA duplex, consistent with previous reports. 34,35,41 These results suggest that the hole injected from the AQ chromophore in Triplex II at 20 ˚C could arrive at the GG 5 sites as a result of the dissociation of ODN 8, whereas hole transport between the GG 5 and GG 6 sites was still suppressed by the binding of ODN 7 to form a partial triplex. Further raising the reaction temperature to 40 ˚C increased DNA cleavage at the GG 6 site in Triplex II (lane 9 in Figure 5A and…”