| Summary: | Approximately 3 × 10<sup>17</sup> 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 - <sup>oxo</sup>dG). Here, the influence of cdA, “the simplest tandem lesion”, on the charge transfer through <i>ds</i>-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′<i>S</i>)- or (5′<i>R</i>)-cdA leads to a slowdown in the hole transfer by one order of magnitude between the neighboring dG→<sup>oxo</sup>dG in comparison to “native” <i>ds</i>-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, <sup>oxo</sup>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.
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