Clustered DNA Damage: Electronic Properties and Their Influence on Charge Transfer. 7,8-Dihydro-8-Oxo-2′-Deoxyguaosine Versus 5′,8-Cyclo-2′-Deoxyadenosines: A Theoretical Approach

Boleslaw T Karwowski

doi:10.3390/cells9020424

Abstract

Approximately 3 × 1017 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 - oxodG). Here, the influence of cdA, “the simplest tandem lesion”, on the charge transfer through ds-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′S)- or (5′R)-cdA leads to a slowdown in the hole transfer by one order of magnitude between the neighboring dG→oxodG in comparison to “native” ds-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, oxodG: 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.

Highlights

Each human body cell is exposed to ionization radiation (IR), environmental factors, metabolic processes, etc., which can lead to the formations of DNA lesions
5′,8-cyclo-2′-deoxypurine formation clearly shows that cyclo-2 -deoxyadenosine (cdA) is the single nucleoside which the base and and sugar moieties have have been been modified by a single hydroxyl radicalradical event
Bearing in mind the above, in these studies, the influence of (5’R)- and (5’S)-cdA on (a) vicinal oxo were into consideration

Summary

Introduction

Each human body cell is exposed to ionization radiation (IR), environmental factors, metabolic processes, etc., which can lead to the formations of DNA lesions. Around 90% of observed DSBs have their source in other DNA damage generated by IR [21,22] Modified bases, such as oxo dG, at the beginning of BER processes, are directly converted to the AP site or single-strand break by specific glycosylates, either mono- or bi-functional. Due to its high genotoxicity (i.e., DSB), the cell tries to avoid their production [23,24] To elucidate these phenomena, numerical simulations have been used to visualize and investigate the influence of a DNA lesion on its spatial geometry as well as to demonstrate oligonucleotide interaction with different types of repair enzymes at an atomistic level [24,25,26]. 5′,8-cyclo-2′-deoxypurine formation clearly shows that cdA (tandem lesion) is the single nucleoside which the base and and sugar moieties have have been been modified by a single hydroxyl radicalradical event 5’ OH group [52]

Materials

Computation Methodology of DFT Study

Results

Conclusion