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Cells
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Epigenetics and DNA Repair: Regulatory Mechanisms and Therapeutic Opportunities
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Epigenetics and DNA Repair: Regulatory Mechanisms and Therapeutic Opportunities

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Nuclei: Function, Transport and Receptors".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 3495

Special Issue Editor

Prof. Dr. Vasily M. Studitsky

E-Mail Website
Guest Editor
1. Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
2. Fox Chase Cancer Center, Philadelphia, PA 19111-2497, USA
Interests: mechanisms of transcription and replication in chromatin; mechanisms of histone chaperone action in chromatin
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In eukaryotic cells, DNA damage occurs in chromatin, a DNA–protein complex that strongly compacts DNA. The packaging of DNA in chromatin creates a strong barrier against DNA-damage-response proteins that must interact with DNA to prevent mutations and cell death. Therefore, during DNA repair, chromatin’s structure is extensively and reversibly modified by factors such as chromatin remodelers, histone variants, and histone post-translational modifications ensure access of the regulatory proteins and DNA repair machinery to their DNA targets. The epigenetic factors that modulate the chromatin environment strongly contribute to an efficient DNA damage response. This highly dynamic process of DNA repair in the chromatin environment is essential for the functioning and survival of the cell. Recent studies have revealed a multitude of factors participating in DNA repair; however, researchers have not yet fully established their mechanisms of action, interacting partners, and roles in the regulation of cellular metabolism and the development of human diseases.

In this Special Issue of Cells, we invite researchers to present original studies and state-of-the-art reviews on the mechanisms and regulation of DNA repair in a chromatin environment, and to discuss their data and opinions.

Prof. Dr. Vasily M. Studitsky
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • chromatin
  • DNA damage
  • DNA repair
  • epigenetics
  • chromatin
  • remodeling

Published Papers (3 papers)

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Research

16 pages, 2516 KiB  
Article
A Knockout of Poly(ADP-Ribose) Polymerase 1 in a Human Cell Line: An Influence on Base Excision Repair Reactions in Cellular Extracts
by Svetlana N. Khodyreva, Ekaterina S. Ilina, Nadezhda S. Dyrkheeva, Alina S. Kochetkova, Alexandra A. Yamskikh, Ekaterina A. Maltseva, Anastasia A. Malakhova, Sergey P. Medvedev, Suren M. Zakian and Olga I. Lavrik
Cells 2024, 13(4), 302; https://doi.org/10.3390/cells13040302 - 06 Feb 2024
Viewed by 839
Abstract
Base excision repair (BER) is the predominant pathway for the removal of most forms of hydrolytic, oxidative, and alkylative DNA lesions. The precise functioning of BER is achieved via the regulation of each step by regulatory/accessory proteins, with the most important of them [...] Read more.
Base excision repair (BER) is the predominant pathway for the removal of most forms of hydrolytic, oxidative, and alkylative DNA lesions. The precise functioning of BER is achieved via the regulation of each step by regulatory/accessory proteins, with the most important of them being poly(ADP-ribose) polymerase 1 (PARP1). PARP1′s regulatory functions extend to many cellular processes including the regulation of mRNA stability and decay. PARP1 can therefore affect BER both at the level of BER proteins and at the level of their mRNAs. Systematic data on how the PARP1 content affects the activities of key BER proteins and the levels of their mRNAs in human cells are extremely limited. In this study, a CRISPR/Cas9-based technique was used to knock out the PARP1 gene in the human HEK 293FT line. The obtained cell clones with the putative PARP1 deletion were characterized by several approaches including PCR analysis of deletions in genomic DNA, Sanger sequencing of genomic DNA, quantitative PCR analysis of PARP1 mRNA, Western blot analysis of whole-cell-extract (WCE) proteins with anti-PARP1 antibodies, and PAR synthesis in WCEs. A quantitative PCR analysis of mRNAs coding for BER-related proteins—PARP2, uracil DNA glycosylase 2, apurinic/apyrimidinic endonuclease 1, DNA polymerase β, DNA ligase III, and XRCC1—did not reveal a notable influence of the PARP1 knockout. The corresponding WCE catalytic activities evaluated in parallel did not differ significantly between the mutant and parental cell lines. No noticeable effect of poly(ADP-ribose) synthesis on the activity of the above WCE enzymes was revealed either. Full article
(This article belongs to the Special Issue Epigenetics and DNA Repair: Regulatory Mechanisms and Therapeutic Opportunities)
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20 pages, 5833 KiB  
Article
Individual Contributions of Amido Acid Residues Tyr122, Ile168, and Asp173 to the Activity and Substrate Specificity of Human DNA Dioxygenase ABH2
by Anastasiia T. Davletgildeeva, Timofey E. Tyugashev, Mingxing Zhao, Nikita A. Kuznetsov, Alexander A. Ishchenko, Murat Saparbaev and Aleksandra A. Kuznetsova
Cells 2023, 12(14), 1839; https://doi.org/10.3390/cells12141839 - 13 Jul 2023
Viewed by 999
Abstract
Human Fe(II)/α-ketoglutarate-dependent dioxygenase ABH2 plays a crucial role in the direct reversal repair of nonbulky alkyl lesions in DNA nucleobases, e.g., N1-methyladenine (m1A), N3-methylcytosine (m3C), and some etheno derivatives. Moreover, ABH2 is capable of a [...] Read more.
Human Fe(II)/α-ketoglutarate-dependent dioxygenase ABH2 plays a crucial role in the direct reversal repair of nonbulky alkyl lesions in DNA nucleobases, e.g., N1-methyladenine (m1A), N3-methylcytosine (m3C), and some etheno derivatives. Moreover, ABH2 is capable of a less efficient oxidation of an epigenetic DNA mark called 5-methylcytosine (m5C), which typically is a specific target of DNA dioxygenases from the TET family. In this study, to elucidate the mechanism of the substrate specificity of ABH2, we investigated the role of several active-site amino acid residues. Functional mapping of the lesion-binding pocket was performed through the analysis of the functions of Tyr122, Ile168, and Asp173 in the damaged base recognition mechanism. Interactions of wild-type ABH2, or its mutants Y122A, I168A, or D173A, with damaged DNA containing the methylated base m1A or m3C or the epigenetic marker m5C were analyzed by molecular dynamics simulations and kinetic assays. Comparative analysis of the enzymes revealed an effect of the substitutions on DNA binding and on catalytic activity. Obtained data clearly demonstrate the effect of the tested amino acid residues on the catalytic activity of the enzymes rather than the DNA-binding ability. Taken together, these data shed light on the molecular and kinetic consequences of the substitution of active-site residues for the mechanism of the substrate recognition. Full article
(This article belongs to the Special Issue Epigenetics and DNA Repair: Regulatory Mechanisms and Therapeutic Opportunities)
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17 pages, 6118 KiB  
Article
The Activity of Natural Polymorphic Variants of Human DNA Polymerase β Having an Amino Acid Substitution in the Transferase Domain
by Olga A. Kladova, Timofey E. Tyugashev, Elena S. Mikushina, Nikita A. Kuznetsov, Daria S. Novopashina and Aleksandra A. Kuznetsova
Cells 2023, 12(9), 1300; https://doi.org/10.3390/cells12091300 - 02 May 2023
Cited by 2 | Viewed by 1347
Abstract
To maintain the integrity of the genome, there is a set of enzymatic systems, one of which is base excision repair (BER), which includes sequential action of DNA glycosylases, apurinic/apyrimidinic endonucleases, DNA polymerases, and DNA ligases. Normally, BER works efficiently, but the enzymes [...] Read more.
To maintain the integrity of the genome, there is a set of enzymatic systems, one of which is base excision repair (BER), which includes sequential action of DNA glycosylases, apurinic/apyrimidinic endonucleases, DNA polymerases, and DNA ligases. Normally, BER works efficiently, but the enzymes themselves (whose primary function is the recognition and removal of damaged bases) are subject to amino acid substitutions owing to natural single-nucleotide polymorphisms (SNPs). One of the enzymes in BER is DNA polymerase β (Polβ), whose function is to fill gaps in DNA with complementary dNMPs. It is known that many SNPs can cause an amino acid substitution in this enzyme and a significant decrease in the enzymatic activity. In this study, the activity of four natural variants of Polβ, containing substitution E154A, G189D, M236T, or R254I in the transferase domain, was analyzed using molecular dynamics simulations and pre-steady-state kinetic analyses. It was shown that all tested substitutions lead to a significant reduction in the ability to form a complex with DNA and with incoming dNTP. The G189D substitution also diminished Polβ catalytic activity. Thus, a decrease in the activity of studied mutant forms may be associated with an increased risk of damage to the genome. Full article
(This article belongs to the Special Issue Epigenetics and DNA Repair: Regulatory Mechanisms and Therapeutic Opportunities)
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