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Chemistry of DNA Repair and DNA Replication

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 12506

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Dr. Nikita Kuznetsov

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Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
Interests: DNA repair; DNA damage; DNA synthesis; biocatalysis; enzyme kinetics, fluorescence, molecular dynamics

Special Issue Information

Dear colleagues,

Cellular DNA constantly undergoes chemical alterations, resulting in DNA lesions that are cytotoxic, miscoded, and are believed to be the cause of mutagenesis and cell lethality. The elimination of DNA damage involves several distinct DNA repair pathways. All these pathways are catalyzed by enzymes, and protein factors are responsible for the coordination of the whole repair process. DNA polymerases are also involved in various cellular processes associated with DNA replication and recombination, as well as the repair and maintenance of the integrity of nucleic acids. Differences in the biological functions of these enzymes are associated with cell localization, specificity for certain structures of DNA, fidelity, processivity, etc. It is now hard to find a biochemical process that is not connected to DNA repair and synthesis. The goal of this Special Issue is to present our current knowledge on the mechanistic details of DNA repair and synthesis enzymes, applying different experimental and computational approaches.

Dr. Nikita Kuznetsov
Guest Editor

Manuscript Submission Information

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Keywords

DNA repair
DNA damage
DNA synthesis
Protein–DNA interaction
Protein–protein interaction
Enzymatic catalysis
Biocatalysis

Published Papers (5 papers)

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Research

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20 pages, 6054 KiB

Open AccessArticle

Inner Amino Acid Contacts Are Key Factors of Multistage Structural Rearrangements of DNA and Affect Substrate Specificity of Apurinic/Apyrimidinic Endonuclease APE1

by Anatoly A. Bulygin, Victoria N. Syryamina, Aleksandra A. Kuznetsova, Darya S. Novopashina, Sergei A. Dzuba and Nikita A. Kuznetsov

Int. J. Mol. Sci. 2023, 24(14), 11474; https://doi.org/10.3390/ijms241411474 - 14 Jul 2023

Cited by 1 | Viewed by 764

Abstract

Apurinic/apyrimidinic endonuclease 1 (APE1) is one of the most important enzymes in base excision repair. Studies on this enzyme have been conducted for a long time, but some aspects of its activity remain poorly understood. One such question concerns the mechanism of damaged-nucleotide recognition by the enzyme, and the answer could shed light on substrate specificity control in all enzymes of this class. In the present study, by pulsed electron–electron double resonance (DEER, also known as PELDOR) spectroscopy and pre–steady-state kinetic analysis along with wild-type (WT) APE1 from Danio rerio (zAPE1) or three mutants (carrying substitution N253G, A254G, or E260A), we aimed to elucidate the molecular events in the process of damage recognition. The data revealed that the zAPE1 mutant E260A has much higher activity toward DNA substrates containing 5,6-dihydro-2′-deoxyuridine (DHU), 2′-deoxyuridine (dU), alpha-2′-deoxyadenosine (αA), or 1,N6-ethenoadenosine (εA). Examination of conformational changes in DNA clearly revealed multistep DNA rearrangements during the formation of the catalytic complex. These structural rearrangements of DNA are directly associated with the capacity of damaged DNA for enzyme-induced bending and unwinding, which are required for eversion of the damaged nucleotide from the DNA duplex and for its placement into the active site of the enzyme. Taken together, the results experimentally prove the factors that control substrate specificity of the AP endonuclease zAPE1. Full article

(This article belongs to the Special Issue Chemistry of DNA Repair and DNA Replication)

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17 pages, 6310 KiB

Open AccessArticle

Kinetic Features of 3′–5′–Exonuclease Activity of Apurinic/Apyrimidinic Endonuclease Apn2 from Saccharomyces cerevisiae

by Aleksandra A. Kuznetsova, Anastasia A. Gavrilova, Alexander A. Ishchenko, Murat Saparbaev, Olga S. Fedorova and Nikita A. Kuznetsov

Int. J. Mol. Sci. 2022, 23(22), 14404; https://doi.org/10.3390/ijms232214404 - 19 Nov 2022

Cited by 1 | Viewed by 1507

Abstract

In yeast Saccharomyces cerevisiae cells, apurinic/apyrimidinic (AP) sites are primarily repaired by base excision repair. Base excision repair is initiated by one of two AP endonucleases: Apn1 or Apn2. AP endonucleases catalyze hydrolytic cleavage of the phosphodiester backbone on the 5′ side of an AP site, thereby forming a single–strand break containing 3′–OH and 5′–dRP ends. In addition, Apn2 has 3′–phosphodiesterase activity (removing 3′–blocking groups) and 3′ → 5′ exonuclease activity (both much stronger than its AP endonuclease activity). Nonetheless, the role of the 3′–5′–exonuclease activity of Apn2 remains unclear and presumably is involved in the repair of damage containing single–strand breaks. In this work, by separating reaction products in a polyacrylamide gel and by a stopped–flow assay, we performed a kinetic analysis of the interaction of Apn2 with various model DNA substrates containing a 5′ overhang. The results allowed us to propose a mechanism for the cleaving off of nucleotides and to determine the rate of the catalytic stage of the process. It was found that dissociation of a reaction product from the enzyme active site is not a rate–limiting step in the enzymatic reaction. We determined an influence of the nature of the 3′–terminal nucleotide that can be cleaved off on the course of the enzymatic reaction. Finally, it was found that the efficiency of the enzymatic reaction is context–specific. Full article

(This article belongs to the Special Issue Chemistry of DNA Repair and DNA Replication)

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14 pages, 2401 KiB

Open AccessArticle

Recognition of a Clickable Abasic Site Analog by DNA Polymerases and DNA Repair Enzymes

by Anton V. Endutkin, Anna V. Yudkina, Timofey D. Zharkov, Daria V. Kim and Dmitry O. Zharkov

Int. J. Mol. Sci. 2022, 23(21), 13353; https://doi.org/10.3390/ijms232113353 - 1 Nov 2022

Cited by 4 | Viewed by 1878

Abstract

Azide–alkyne cycloaddition (“click chemistry”) has found wide use in the analysis of molecular interactions in living cells. 5-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (EAP) is a recently developed apurinic/apyrimidinic (AP) site analog functionalized with an ethynyl moiety, which can be introduced into cells in DNA constructs to perform labeling or cross-linking in situ. However, as a non-natural nucleoside, EAP could be subject to removal by DNA repair and misreading by DNA polymerases. Here, we investigate the interaction of this clickable AP site analog with DNA polymerases and base excision repair enzymes. Similarly to the natural AP site, EAP was non-instructive and followed the “A-rule”, directing residual but easily detectable incorporation of dAMP by E. coli DNA polymerase I Klenow fragment, bacteriophage RB69 DNA polymerase and human DNA polymerase β. On the contrary, EAP was blocking for DNA polymerases κ and λ. EAP was an excellent substrate for the major human AP endonuclease APEX1 and E. coli AP exonucleases Xth and Nfo but was resistant to the AP lyase activity of DNA glycosylases. Overall, our data indicate that EAP, once within a cell, would represent a replication block and would be removed through an AP endonuclease-initiated long-patch base excision repair pathway. Full article

(This article belongs to the Special Issue Chemistry of DNA Repair and DNA Replication)

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Review

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18 pages, 1854 KiB

Open AccessReview

Multifaceted Nature of DNA Polymerase θ

by Alexander A. Kruchinin and Alena V. Makarova

Int. J. Mol. Sci. 2023, 24(4), 3619; https://doi.org/10.3390/ijms24043619 - 10 Feb 2023

Cited by 7 | Viewed by 3511

Abstract

DNA polymerase θ belongs to the A family of DNA polymerases and plays a key role in DNA repair and damage tolerance, including double-strand break repair and DNA translesion synthesis. Pol θ is often overexpressed in cancer cells and promotes their resistance to chemotherapeutic agents. In this review, we discuss unique biochemical properties and structural features of Pol θ, its multiple roles in protection of genome stability and the potential of Pol θ as a target for cancer treatment. Full article

(This article belongs to the Special Issue Chemistry of DNA Repair and DNA Replication)

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28 pages, 73115 KiB

Open AccessReview

Structural and Molecular Kinetic Features of Activities of DNA Polymerases

by Aleksandra A. Kuznetsova, Olga S. Fedorova and Nikita A. Kuznetsov

Int. J. Mol. Sci. 2022, 23(12), 6373; https://doi.org/10.3390/ijms23126373 - 7 Jun 2022

Cited by 13 | Viewed by 4168

Abstract

DNA polymerases catalyze DNA synthesis during the replication, repair, and recombination of DNA. Based on phylogenetic analysis and primary protein sequences, DNA polymerases have been categorized into seven families: A, B, C, D, X, Y, and RT. This review presents generalized data on the catalytic mechanism of action of DNA polymerases. The structural features of different DNA polymerase families are described in detail. The discussion highlights the kinetics and conformational dynamics of DNA polymerases from all known polymerase families during DNA synthesis. Full article

(This article belongs to the Special Issue Chemistry of DNA Repair and DNA Replication)

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