Abstract
Ionizing radiation is a factor that seriously damages cellular mechanisms/macromolecules, e.g., by inducing damage in the human genome, such as 5′,8-cyclo-2′-deoxypurines (cdPus). CdPus may become a component of clustered DNA lesions (CDL), which are notably unfavorable for the base excision repair system (BER). In this study, the influence of 5′S and 5′R diastereomers of 5′,8-cyclo-2′-deoxyadenosine (cdA) and 5′,8-cyclo-2′-deoxyguanosine (cdG) on the uracil-DNA glycosylase (UDG) and human AP site endonuclease 1 (hAPE1) activity has been taken under consideration. Synthetic oligonucleotides containing 2′-deoxyuridine (dU) and cdPu were used as a model of single-stranded CDL. The activity of the UDG and hAPE1 enzymes decreased in the presence of RcdG compared to ScdG. Contrary to the above, ScdA reduced enzyme activity more than RcdA. The presented results show the influence of cdPus lesions located within CDL on the activity of the initial stages of BER dependently on their position toward dU. Numerous studies have shown the biological importance of cdPus (e.g., as a risk of carcinogenesis). Due to that, it is important to understand how to recognize and eliminate this type of DNA damage from the genome.
Highlights
The stability of genetic information and the ability to reproduce is a key factor in cell survival
This study aimed to investigate the influence of 5,8-cyclo-2 -deoxypurines ((5 S)−5,8cyclo-2 -deoxyadenosine (ScdA), (5 R)−5,8-cyclo-2 -deoxyadenosine (RcdA), (5 S)−5,8cyclo-2 -deoxyguanosine (ScdG), or (5 R)−5,8-cyclo-2 -deoxyguanosine (RcdG)), being a part of the single-stranded clustered DNA lesions, on the activity of uracil-DNA glycosylase (UDG) and human abasic site (AP site) endonuclease 1 (hAPE1) that removes coexisting lesions
CdPus appear in the genome as a specific type of DNA tandem lesions that could be a part of clustered DNA lesions (CDL)
Summary
The stability of genetic information and the ability to reproduce is a key factor in cell survival. Many factors affect DNA and between 10,000 and a million DNA lesions are formed daily in every single cell in the human body [1,2]. Three main types of DNA lesions can be distinguished: isolated, tandem, and clustered DNA lesions (CDL). Tandem lesions occur as two contiguously damaged nucleotides generated by a single radical event, e.g., hydroxyl radical (OH) and/or one-electron oxidants. They may appear as more than one lesion within a single nucleotide with 5 ,8-cyclo-2 -deoxypurines (cdPus) as an example [3–5]. CDL are referred to as at least two lesions per 1–2 DNA helix turns and are highly mutagenic [6]. The cdPus form as a result of OH action on the H5 -atom of the sugar moiety of 2 -deoxypurines [9–12]. 5 S and 5 R diastereomers of cdPus may change the spatial structure of ds-DNA through perturbing helix twist and base-pair stacking [9,10,13]. (5 R)−5 ,8-cyclo-2 -deoxyadenosine (RcdA) and (5 S)−5 ,8-cyclo-2 -deoxyadenosine (ScdA)
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