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The Influence of (5′R)- and (5′S)-5′,8-Cyclo-2′-Deoxyadenosine on UDG and hAPE1 Activity. Tandem Lesions are the Base Excision Repair System’s Nightmare

DNA Damage Laboratory of the Food Science Department, Faculty of Pharmacy, Medical University of Lodz, ul. Muszynskiego 1, 90-151 Lodz, Poland
Cells 2019, 8(11), 1303; https://doi.org/10.3390/cells8111303
Received: 15 September 2019 / Revised: 21 October 2019 / Accepted: 22 October 2019 / Published: 23 October 2019
(This article belongs to the Section Cell Nuclei: Function, Transport and Receptors)
DNA lesions are formed continuously in each living cell as a result of environmental factors, ionisation radiation, metabolic processes, etc. Most lesions are removed from the genome by the base excision repair system (BER). The activation of the BER protein cascade starts with DNA damage recognition by glycosylases. Uracil-DNA glycosylase (UDG) is one of the most evolutionary preserved glycosylases which remove the frequently occurring 2′-deoxyuridine from single (ss) and double-stranded (ds) oligonucleotides. Conversely, the unique tandem lesions (5′R)- and (5′S)-5′,8-cyclo-2′-deoxyadenosine (cdA) are not suitable substrates for BER machinery and are released from the genome by the nucleotide excision repair (NER) system. However, the cyclopurines appearing in a clustered DNA damage structure can influence the BER process of other lesions like dU. In this article, UDG inhibition by 5′S- and 5′R-cdA is shown and discussed in an experimental and theoretical manner. This phenomenon was observed when a tandem lesion appears in single or double-stranded oligonucleotides next to dU, on its 3′-end side. The cdA shift to the 5′-end side of dU in ss-DNA stops this effect in both cdA diastereomers. Surprisingly, in the case of ds-DNA, 5′S-cdA completely blocks uracil excision by UDG. Conversely, 5′R-cdA allows glycosylase for uracil removal, but the subsequently formed apurinic/apyrimidinic (AP) site is not suitable for human AP-site endonuclease 1 (hAPE1) activity. In conclusion, the appearance of the discussed tandem lesion in the structure of single or double-stranded DNA can stop the entire base repair process at its beginning, which due to UDG and hAPE1 inhibition can lead to mutagenesis. On the other hand, the presented results can cast some light on the UDG or hAPE1 inhibitors being used as a potential treatment. View Full-Text
Keywords: (5′R)- and (5′S)-5′,8-cyclo-2′-deoxyadenisie; tandem lesions; base excision repair; uracil-DNA glycosylase; human AP-site endonuclease 1 (5′R)- and (5′S)-5′,8-cyclo-2′-deoxyadenisie; tandem lesions; base excision repair; uracil-DNA glycosylase; human AP-site endonuclease 1
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  • Supplementary File 1:

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  • Externally hosted supplementary file 1
    Doi: 10.5281/zenodo.3408613
    Link: https://zenodo.org/deposit/3408613
    Description: Supplementary Materials: Figure S1: CD spectra of investigated ds-oligonucleotidestitle, Figure S2: Spectra of Oligonucleotide Mass Spectrometry Analysis, Table S1: Sequence of oligonucleotides, Tables S2: The raw data presented by graphs on Fig.3. Average and corresponding standard deviations values, PDB files: Cont_pdU.pdb, RcdA(+1)SM.pdb, RcdA(-1)SM.pdb, ScdA(+1)SM.pdb, ScdA(-1)SM.pdb and Selected aminoacids indication in 1emh structure.msv .
MDPI and ACS Style

Karwowski, B.T. The Influence of (5′R)- and (5′S)-5′,8-Cyclo-2′-Deoxyadenosine on UDG and hAPE1 Activity. Tandem Lesions are the Base Excision Repair System’s Nightmare. Cells 2019, 8, 1303.

AMA Style

Karwowski BT. The Influence of (5′R)- and (5′S)-5′,8-Cyclo-2′-Deoxyadenosine on UDG and hAPE1 Activity. Tandem Lesions are the Base Excision Repair System’s Nightmare. Cells. 2019; 8(11):1303.

Chicago/Turabian Style

Karwowski, Bolesław T. 2019. "The Influence of (5′R)- and (5′S)-5′,8-Cyclo-2′-Deoxyadenosine on UDG and hAPE1 Activity. Tandem Lesions are the Base Excision Repair System’s Nightmare" Cells 8, no. 11: 1303.

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