Clustered DNA Damage: Electronic Properties and Their Influence on Charge Transfer. 78-Dihydro-8-Oxo-2′-Deoxyguaosine Versus 5′8-Cyclo-2′-Deoxyadenosines: A Theoretical Approach

摘要

Approximately 3 × 10 DNA damage events take place per hour in the human body. Within clustered DNA lesions, they pose a serious problem for repair proteins, especially for iron–sulfur glycosylases (MutyH), which can recognize them by the electron-transfer process. It has been found that the presence of both 5′,8-cyclo-2′-deoxyadenosine (cdA) diastereomers in the ds-DNA structure, as part of a clustered lesion, can influence vertical radical cation distribution within the proximal part of the double helix, i.e., d[~oxoGcAoxoG~] (7,8-dihydro-8-oxo-2′-deoxyguaosine - dG). Here, the influence of cdA, “the simplest tandem lesion”, on the charge transfer through -DNA was taken into theoretical consideration at the M062x/6-31+G** level of theory in the aqueous phase. It was shown that the presence of (5′ )- or (5′ )-cdA leads to a slowdown in the hole transfer by one order of magnitude between the neighboring dG→ dG in comparison to “native” -DNA. Therefore, it can be concluded that such clustered lesions can lead to defective damage recognition with a subsequent slowing down of the DNA repair process, giving rise to an increase in mutations. As a result, the unrepaired, dG: dA base pair prior to genetic information replication can finally result in GC → TA or AT→CG transversion. This type of mutation is commonly observed in human cancer cells. Moreover, because local multiple damage sites (LMSD) are effectively produced as a result of ionization factors, the presented data in this article might be useful in developing a new scheme of radiotherapy treatment against the background of DNA repair efficiency.