Fapy dG in the Shadow of OXO dG-A Theoretical Study of Clustered DNA Lesions.

Genetic information, irrespective of cell type (normal or cancerous), is exposed to a range of harmful factors, which can lead to more than 80 different types of DNA damage. Of these, oxo G and Fapy G have been identified as the most abundant in normoxic and hypoxic conditions, respectively. This article considers d[A Fapy GA OXO GA]*[TCTCT] (oligo- Fapy G) with clustered DNA lesions (CDLs) containing both the above types of damage at the M06-2x/6-31++G** level of theory in the condensed phase. Furthermore, the electronic properties of oligo- Fapy G were analysed in both equilibrated and non-equilibrated solvation-solute interaction modes. The vertical/adiabatic ionization potential (VIP, AIP) and electron affinity (VEA, AEA) of the investigated ds-oligo were found as follows in [eV]: 5.87/5.39 and -1.41/-2.09, respectively. The optimization of the four ds-DNA spatial geometries revealed that the trans Fapy dG was energetically privileged. Additionally, CDLs were found to have little influence on the ds-oligo structure. Furthermore, for the Fapy GC base-pair isolated from the discussed ds-oligo, the ionization potential and electron affinity values were higher than those assigned to OXO GC. Finally, a comparison of the influence of Fapy GC and OXO GC on charge transfer revealed that, in contrast to the OXO GC base-pair, which, as expected, acted as a radical cation/anion sink in the oligo- Fapy G structure, Fapy GC did not significantly affect charge transfer (electron-hole and excess-electron). The results presented below indicate that 7,8-dihydro-8-oxo-2'-deoxyguanosine plays a significant role in charge transfer through ds-DNA containing CDL and indirectly has an influence on the DNA lesion recognition and repair process. In contrast, the electronic properties obtained for 2,6-diamino-4-hydroxy-5-foramido-2'deoxypyrimidine were found to be too weak to compete with OXO G to influence charge transfer through the discussed ds-DNA containing CDL. Because increases in multi-damage site formation are observed during radio- or chemotherapy, understanding their role in the above processes can be crucial for the efficiency and safety of medical cancer treatment.