How Clustered DNA Damage Can Change the Electronic Properties of ds-DNA-Differences between GAG, GA OXO G, and OXO GA OXO G.

Every 24 h, roughly 3 × 10 17 incidences of DNA damage are generated in the human body as a result of intra- or extra-cellular factors. The structure of the formed lesions is identical to that formed during radio- or chemotherapy. Increases in the clustered DNA damage (CDL) level during anticancer treatment have been observed compared to those found in untreated normal tissues. 7,8-dihydro-8-oxo-2'-deoxyguanosine ( OXO G) has been recognized as the most common lesion. In these studies, the influence of OXO G, as an isolated (oligo- O G) or clustered DNA lesion (oligo- O G O G), on charge transfer has been analyzed in comparison to native oligo-G. DNA lesion repair depends on the damage recognition step, probably via charge transfer. Here the electronic properties of short ds-oligonucleotides were calculated and analyzed at the M062x/6-31++G** level of theory in a non-equilibrated and equilibrated solvent state. The rate constant of hole and electron transfer according to Marcus' theory was also discussed. These studies elucidated that OXO G constitutes the sink for migrated radical cations. However, in the case of oligo- O G O G containing a 5'- OXO GA XOX G-3' sequence, the 3'-End OXO G becomes predisposed to electron-hole accumulation contrary to the undamaged GAG fragment. Moreover, it was found that the 5'-End OXO G present in an OXO GA OXO G fragment adopts a higher adiabatic ionization potential than the 2'-deoxyguanosine of an undamaged analog if both ds-oligos are present in a cationic form. Because increases in CDL formation have been observed during radio- or chemotherapy, understanding their role in the above processes can be crucial for the efficiency and safety of medical cancer treatment.