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Article

Back-Up Base Excision DNA Repair in Human Cells Deficient in the Major AP Endonuclease, APE1

by
Daria V. Kim
1,2,
Evgeniia A. Diatlova
1,
Timofey D. Zharkov
1,
Vasily S. Melentyev
1,2,
Anna V. Yudkina
1,2,
Anton V. Endutkin
1 and
Dmitry O. Zharkov
1,2,*
1
Siberian Branch of the Russian Academy of Sciences Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentieva Ave., 630090 Novosibirsk, Russia
2
Department of Natural Sciences, Novosibirsk State University, 2 Pirogova St., 630090 Novosibirsk, Russia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(1), 64; https://doi.org/10.3390/ijms25010064
Submission received: 15 November 2023 / Revised: 15 December 2023 / Accepted: 18 December 2023 / Published: 20 December 2023
(This article belongs to the Special Issue Stem Cell Technology and Genome Editing in Advanced Disease Modeling)
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Abstract

Apurinic/apyrimidinic (AP) sites are abundant DNA lesions generated both by spontaneous base loss and as intermediates of base excision DNA repair. In human cells, they are normally repaired by an essential AP endonuclease, APE1, encoded by the APEX1 gene. Other enzymes can cleave AP sites by either hydrolysis or β-elimination in vitro, but it is not clear whether they provide the second line of defense in living cells. Here, we studied AP site repairs in APEX1 knockout derivatives of HEK293FT cells using a reporter system based on transcriptional mutagenesis in the enhanced green fluorescent protein gene. Despite an apparent lack of AP site-processing activity in vitro, the cells efficiently repaired the tetrahydrofuran AP site analog resistant to β-elimination. This ability persisted even when the second AP endonuclease homolog, APE2, was also knocked out. Moreover, APEX1 null cells were able to repair uracil, a DNA lesion that is removed via the formation of an AP site. If AP site hydrolysis was chemically blocked, the uracil repair required the presence of NTHL1, an enzyme that catalyzes β-elimination. Our results suggest that human cells possess at least two back-up AP site repair pathways, one of which is NTHL1-dependent.
Keywords: DNA repair; abasic sites; uracil; AP endonucleases; DNA glycosylases; APE1; APE2; NTHL1 DNA repair; abasic sites; uracil; AP endonucleases; DNA glycosylases; APE1; APE2; NTHL1

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MDPI and ACS Style

Kim, D.V.; Diatlova, E.A.; Zharkov, T.D.; Melentyev, V.S.; Yudkina, A.V.; Endutkin, A.V.; Zharkov, D.O. Back-Up Base Excision DNA Repair in Human Cells Deficient in the Major AP Endonuclease, APE1. Int. J. Mol. Sci. 2024, 25, 64. https://doi.org/10.3390/ijms25010064

AMA Style

Kim DV, Diatlova EA, Zharkov TD, Melentyev VS, Yudkina AV, Endutkin AV, Zharkov DO. Back-Up Base Excision DNA Repair in Human Cells Deficient in the Major AP Endonuclease, APE1. International Journal of Molecular Sciences. 2024; 25(1):64. https://doi.org/10.3390/ijms25010064

Chicago/Turabian Style

Kim, Daria V., Evgeniia A. Diatlova, Timofey D. Zharkov, Vasily S. Melentyev, Anna V. Yudkina, Anton V. Endutkin, and Dmitry O. Zharkov. 2024. "Back-Up Base Excision DNA Repair in Human Cells Deficient in the Major AP Endonuclease, APE1" International Journal of Molecular Sciences 25, no. 1: 64. https://doi.org/10.3390/ijms25010064

APA Style

Kim, D. V., Diatlova, E. A., Zharkov, T. D., Melentyev, V. S., Yudkina, A. V., Endutkin, A. V., & Zharkov, D. O. (2024). Back-Up Base Excision DNA Repair in Human Cells Deficient in the Major AP Endonuclease, APE1. International Journal of Molecular Sciences, 25(1), 64. https://doi.org/10.3390/ijms25010064

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