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Effect of DNA Methylation on the 3′→5′ Exonuclease Activity of Major Human Abasic Site Endonuclease APEX1

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Abstract

Apurinic/apyrimidinic (AP) endonucleases are the key enzymes in the DNA base excision repair, as they hydrolyze the phosphodiester bond in the AP site formed after removal of the damaged base. Major human AP endonuclease APEX1 also possesses the 3′-phosphodiesterase and 3′→5′ exonuclease activities. The biological role of the latter has not been established yet; it is assumed that it corrects DNA synthesis errors during DNA repair. If DNA is damaged at the 3′-side of 5-methylcytosine (mC) residue, the 3′→5′ exonuclease activity can change the epigenetic methylation status of the CpG dinucleotide. It remains unclear whether the 3′→5′ exonuclease activity of APEX1 contributes to the active epigenetic demethylation or, on the contrary, is limited in the case of methylated CpG dinucleotides in order to preserve the epigenetic status upon repair of accidental DNA damage. Here, we report the results of the first systematic study on the efficiency of removal of 3′-terminal nucleotides from the substrates modeling DNA repair intermediates in the CpG dinucleotides. The best substrates for the 3′→5′ exonuclease activity of APEX1 were oligonucleotides with the 3′-terminal bases non-complementary to the template, while the worst substrates contained mC. The presence of mC in the complementary strand significantly reduced the reaction rate even for the non-complementary 3′-ends. Therefore, the efficiency of the 3′→5′ exonuclease reaction catalyzed by APEX1 is limited in the case of the methylated CpG dinucleotides, which likely reflects the need to preserve the epigenetic status during DNA repair.

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Abbreviations

AP:

apurinic/apyrimidinic

APEX1:

apurinic/apyrimidinic endo/exonuclease 1

BER:

base excision repair

dmCMP:

5-methylcytosine-2′-deoxyribose monophosphate

mC:

5-methylcytosine

F:

2-(hydroxymethyl)tetrahydrofuran-3-ol

OGG1:

8-oxoguanine–DNA glycosylase 1

ODN:

oligodeoxyribonucleotide

oxoG:

8-oxoguanine

TET protein:

ten-eleven translocation family protein

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Funding

This study was supported by the Russian Science Foundation (project 17-14-01190P, biochemical experiments) and State Budget Project 0245-2021-0002 (structural analysis).

Author information

Authors and Affiliations

  1. Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090, Novosibirsk, Russia

    Anton V. Endutkin, Darya D. Yatsenko & Dmitry O. Zharkov

  2. Department of Natural Sciences, Novosibirsk State University, 630090, Novosibirsk, Russia

    Dmitry O. Zharkov

Authors
  1. Anton V. Endutkin
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  2. Darya D. Yatsenko
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  3. Dmitry O. Zharkov
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Corresponding author

Correspondence to Dmitry O. Zharkov.

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The authors declare no conflicts of interest in financial or any other sphere. This article does not contain studies with human participants or animals performed by any of the authors.

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Endutkin, A.V., Yatsenko, D.D. & Zharkov, D.O. Effect of DNA Methylation on the 3′→5′ Exonuclease Activity of Major Human Abasic Site Endonuclease APEX1. Biochemistry Moscow 87, 10–20 (2022). https://doi.org/10.1134/S0006297922010023

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  • DOI: https://doi.org/10.1134/S0006297922010023

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