A substantial fraction of these lesions are defect bases originating from the interaction of DNA with ROS and ionizing radiation and the majority among these concern oxidative derivatives of guanine (G). In fact, amongst the four native DNA bases, G has the lowest vertical ionization energy (VIE) in gas phase and in aqueous solution, and is thus considered the most readily oxidizable and the most common target in this kind of attack. The highly mutagenic 8-oxoguanine (8oxoG) lesion, a product of oxidative damage to G, is indeed the most common of all DNA defects. Unlike normal guanine, 8oxoG can more readily form a hydrogen-bonded pair with adenine (A) instead of cytosine (C), resulting in C:G to A:T mutations during replication. Calculations at the single/few base/nucleotide level suggest that 8oxoG has an even lower VIE than G. Moreover, computational investigations showed that G-rich and 8oxoG-containing fragments of up to 3 base pairs have lower IEs than single G and 8oxoG fragments, consistent with experimental studies indicating that these segments can function as hole sinks by sacrificially attracting oxidative damage, thereby protecting other regions of the DNA. Fragments containing 8oxoG have an especially pronounced potential to act as hole sinks as evidenced experimentally (by increased strand cleavage at the 8oxoG site following DNA irradiation), and computationally (by lower IEs for the defect DNA fragments). More broadly, such evidence opens up the possibility that the cell can use local changes in DNA redox chemistry for the efficient detection and repair of DNA lesions. Moreover, facile hole and excess electron transport through DNA are well established and documented phenomena. Taking this into consideration, and based on the conclusions drawn from their experimental investigations, Barton and coworkers have proposed that the recognition of defect bases can occur via a DNA-mediated charge transfer (CT) scheme. Details regarding the mechanism of the suggested CT process have already been extensively discussed. The elementary step of this scheme involves a CT process between two base excision repair (BER) enzymes bound to the DNA, in which a charge traverses the DNA sequence between them. It is proposed that a defect base will act as a trap for the migrating charge, thereby interrupting the transfer of charge between the two BER enzymes. The two enzymes will consequently scan the DNA sequence between them to identify the presence of a lesion and initiate its repair. A theoretical model predicted that, when compared to the conventionally proposed single BER enzyme scanning, such a CT-based scheme leads to a decrease of the total interrogation time of the entire genome by an order of magnitude. As already discussed in detail, evidence of (i) relative differences in ionization energies/electron affinities of small native versus defect fragments of up to three base pairs, 14,15 and (ii) the effect of defect bases or base pair mismatches on CT processes in DNA 17,18,28-31 point out that hole transfer would be much more likely to be exploited for lesion recognition within a CT mechanism. The possibility of a DNA-mediated hole transfer scheme is further supported with experimental studies for oxidative and bulky lesions utilizing cyclic voltammetry and chronocoulometry. 20 Ultimately, from an electrochemical perspective, for such a hole-transfer scheme to be efficient, redox properties of native and damaged DNA need to be substantially different. A relative difference of 0.55 V has been reported between the oxidation potentials (E ox ) of guanosine and 8-oxoguanosine molecules in aqueous solution (-1.29 V versus -0.74 V with respect to standard hydrogen electrode (SHE)). 17 However, an overall assessment of the ensemble of values for small fragments shows that the relative redox differences between native and defect containing systems are not converged up to the largest system sizes considered (ten guanine bases, eight guanine-cytosine base pairs, and six guanine-cytosine nucleotides) with the vertical ionization energy continuing to decrease as the system size is increased. In fact, a recent Quantum Mechanical/Molecular Mechanics (QM/MM) Molecular Dynamics (MD) simulation, in which the redox properties of two extended (39 base pair) DNA fragments, one in its native form and one containing an 8oxoG defect were computed, demonstrated that the insertion of 8oxoG leads to an increase of the oxidation potential by almost 1 eV. Such a pronounced difference is strongly in favour of a DNA-mediated hole transfer scheme for the recognition of 8oxoG by BER enzymes, and underlines the importance of studying extended systems with explicit account of the physiological environment. While all aforementioned investigations do support a DNA-mediated hole transfer scheme for the recognition of 8oxoG and other lesions, they all focus on bare, free DNA systems.