Oxidation of DNA: Damage to Nucleobases

Abstract

All organisms store the information necessary to maintain life in their DNA. Any process that damages DNA, causing a loss or corruption of that information, jeopardizes the viability of the organism. One-electron oxidation is such a process. In this Account, we address three of the central features of one-electron oxidation of DNA: (i) the migration of the radical cation away from the site of its formation; (ii) the electronic and structural factors that determine the nucleobases at which irreversible reactions most readily occur; (iii) the mechanism of reaction for nucleobase radical cations. The loss of an electron (ionization) from DNA generates an electron "hole" (a radical cation), located most often on its nucleobases, that migrates reversibly through duplex DNA by hopping until it is trapped in an irreversible chemical reaction. The particular sequence of nucleobases in a DNA oligomer determines both the efficiency of hopping and the specific location and nature of the damaging chemical reaction. In aqueous solution, DNA is a polyanion because of the negative charge carried by its phosphate groups. Counterions to the phosphate groups (typically Na(+)) play an important role in facilitating both hopping and the eventual reaction of the radical cation with H(2)O. Irreversible reaction of a radical cation with H(2)O in duplex DNA occurs preferentially at the most reactive site. In normal DNA, comprising the four common DNA nucleobases G, C, A, and T, reaction occurs most commonly at a guanine, resulting in its conversion primarily to 8-oxo-7,8-dihydroguanine (8-OxoG). Both electronic and steric effects control the outcome of this process. If the DNA oligomer does not contain a suitable guanine, then reaction of the radical cation occurs at the thymine of a TT step, primarily by a tandem process. The oxidative damage of DNA is a complex process, influenced by charge transport and reactions that are controlled by a combination of enthalpic, entropic, steric, and compositional factors. These processes occur over a broad distribution of energies, times, and spatial scales. The emergence of a complete picture of DNA oxidation will require additional exploration of the structural, kinetic, and dynamic properties of DNA, but this Account offers insight into key elements of this challenge.

Charge separation and charge delocalization identified in long-living states of photoexcited DNA

“…However, the present investigation reveals that charge transfer in DNA oligonucleotides is a natural process, occurring to a high probability after absorption of UV light. The presence of charges along a DNA strand may have severe consequences for the integrity of a DNA strand, because charged base radicals form starting points for oxidative (42) and reductive (43) DNA damage. Thus, the presented observation of charged states with relatively long lifetime adds an important element to the discussion of DNA photolesions and mutational hot spots (44).…”

Aerobiosis is not associated with GC content and G to T mutations are not the signature of oxidative stress in prokaryotic evolution

“…ROS are highly reactive with most cellular organic molecules, including nucleotides and their polymerized products, DNA and RNA. Among the four bases, guanine has the lowest oxidation potential and is the most susceptible to oxidation (Kanvah, et al 2010). The direct products of deoxyguanosine oxidation are 8-oxo-7,8-dihydro-guanosine (8-oxoG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-G).…”

Vibronic couplings and coherent electron transfer in bridged systems

“…Time resolved spectroscopy and steady state oxidative damage analyses point toward an incoherent multistep hopping mechanism, 49,60,[76][77][78][79][80][81][82] in which the hole migrates essentially by hopping between G neighboring sites, 59 with the possibility of tunnelling over short distances, when two G sites are separated by two or almost three A and/or T sites. The hopping process is in most of the cases slow, thus limiting potential applications to nano-scale electronic devices, 83,84 but since significant enhancements of HT rates have been observed both by including in the strand modified nucleobases, with a lower oxidation potentials than natural ones, or by using sequences consisting of blocks of homopurine sequences, 85,86 research in the field is still very active.…”