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Molecular Mechanism of DNA Replication and Repair, 2nd Edition 

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 (29 February 2024) | Viewed by 10357

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Special Issue Information

Dear Colleagues,

During cell division, the replisome machinery is capable of quickly and accurately copying billions of DNA bases in order to maintain genome integrity and prevent diseases. Nevertheless, it can produce errors, particularly when the DNA is damaged. dsDNA is a stable, chemically inert molecule continuously subjected to a variety of exogenous and endogenous insults throughout the cell cycle. Unrepaired or misrepaired DNA lesions may cause mutations or chromosomal damage and, ultimately, abnormalities, including oncogenic transformation. For the maintenance of genomic stability, the organisms have developed signal pathways that give rise to a DNA damage response (DDR). This mechanism is characterized by its capability to tolerate DNA damage and structural impediments during DNA synthesis; thus, it replicates fork progression and stability in the presence of blocking structures or DNA lesions. Malfunctioning DDR can cause fork arrest and eventually fork collapse, leading to the formation of DNA double strand breaks.

This Special Issue of IJMS aims to expand our current understanding of molecular and cellular mechanisms of DNA replication and repair. We want to offer a platform for high-quality publications on various sides of DNA replication and repair research. Bringing together different aspects in one issue, hopefully, will trigger findings relevant to the development of new therapies in human diseases.

Dr. Mariarita De Felice
Dr. Mariarosaria De Falco
Guest Editors

Manuscript Submission Information

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Keywords

  • genome stability
  • DNA repair
  • DNA replication
  • DDR

Published Papers (10 papers)

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Research

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17 pages, 4130 KiB  
Article
DNA Polymerase I Large Fragment from Deinococcus radiodurans, a Candidate for a Cutting-Edge Room-Temperature LAMP
by Marilena Manzo, Assunta Serra, Emilia Pedone, Luciano Pirone, Viviana Scognamiglio, Mariarita De Felice and Mariarosaria De Falco
Int. J. Mol. Sci. 2024, 25(3), 1392; https://doi.org/10.3390/ijms25031392 - 23 Jan 2024
Viewed by 852
Abstract
In recent years, the loop-mediated isothermal amplification (LAMP) technique, designed for microbial pathogen detection, has acquired fundamental importance in the biomedical field, providing rapid and precise responses. However, it still has some drawbacks, mainly due to the need for a thermostatic block, necessary [...] Read more.
In recent years, the loop-mediated isothermal amplification (LAMP) technique, designed for microbial pathogen detection, has acquired fundamental importance in the biomedical field, providing rapid and precise responses. However, it still has some drawbacks, mainly due to the need for a thermostatic block, necessary to reach 63 °C, which is the BstI DNA polymerase working temperature. Here, we report the identification and characterization of the DNA polymerase I Large Fragment from Deinococcus radiodurans (DraLF-PolI) that functions at room temperature and is resistant to various environmental stress conditions. We demonstrated that DraLF-PolI displays efficient catalytic activity over a wide range of temperatures and pH, maintains its activity even after storage under various stress conditions, including desiccation, and retains its strand-displacement activity required for isothermal amplification technology. All of these characteristics make DraLF-PolI an excellent candidate for a cutting-edge room-temperature LAMP that promises to be very useful for the rapid and simple detection of pathogens at the point of care. Full article
(This article belongs to the Special Issue Molecular Mechanism of DNA Replication and Repair, 2nd Edition )
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25 pages, 4112 KiB  
Article
SMC5/6 Promotes Replication Fork Stability via Negative Regulation of the COP9 Signalosome
by Michelle J. Xu and Philip W. Jordan
Int. J. Mol. Sci. 2024, 25(2), 952; https://doi.org/10.3390/ijms25020952 - 12 Jan 2024
Viewed by 778
Abstract
It is widely accepted that DNA replication fork stalling is a common occurrence during cell proliferation, but there are robust mechanisms to alleviate this and ensure DNA replication is completed prior to chromosome segregation. The SMC5/6 complex has consistently been implicated in the [...] Read more.
It is widely accepted that DNA replication fork stalling is a common occurrence during cell proliferation, but there are robust mechanisms to alleviate this and ensure DNA replication is completed prior to chromosome segregation. The SMC5/6 complex has consistently been implicated in the maintenance of replication fork integrity. However, the essential role of the SMC5/6 complex during DNA replication in mammalian cells has not been elucidated. In this study, we investigate the molecular consequences of SMC5/6 loss at the replication fork in mouse embryonic stem cells (mESCs), employing the auxin-inducible degron (AID) system to deplete SMC5 acutely and reversibly in the defined cellular contexts of replication fork stall and restart. In SMC5-depleted cells, we identify a defect in the restart of stalled replication forks, underpinned by excess MRE11-mediated fork resection and a perturbed localization of fork protection factors to the stalled fork. Previously, we demonstrated a physical and functional interaction of SMC5/6 with the COP9 signalosome (CSN), a cullin deneddylase that enzymatically regulates cullin ring ligase (CRL) activity. Employing a combination of DNA fiber techniques, the AID system, small-molecule inhibition assays, and immunofluorescence microscopy analyses, we show that SMC5/6 promotes the localization of fork protection factors to stalled replication forks by negatively modulating the COP9 signalosome (CSN). We propose that the SMC5/6-mediated modulation of the CSN ensures that CRL activity and their roles in DNA replication fork stabilization are maintained to allow for efficient replication fork restart when a replication fork stall is alleviated. Full article
(This article belongs to the Special Issue Molecular Mechanism of DNA Replication and Repair, 2nd Edition )
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18 pages, 5341 KiB  
Article
Substrate Specificity Diversity of Human Terminal Deoxynucleotidyltransferase May Be a Naturally Programmed Feature Facilitating Its Biological Function
by Aleksandra A. Kuznetsova, Svetlana I. Senchurova, Anastasia A. Gavrilova, Timofey E. Tyugashev, Elena S. Mikushina and Nikita A. Kuznetsov
Int. J. Mol. Sci. 2024, 25(2), 879; https://doi.org/10.3390/ijms25020879 - 10 Jan 2024
Viewed by 638
Abstract
Terminal 2′-deoxynucleotidyl transferase (TdT) is a unique enzyme capable of catalysing template-independent elongation of DNA 3′ ends during V(D)J recombination. The mechanism controlling the enzyme’s substrate specificity, which is necessary for its biological function, remains unknown. Accordingly, in this work, kinetic and mutational [...] Read more.
Terminal 2′-deoxynucleotidyl transferase (TdT) is a unique enzyme capable of catalysing template-independent elongation of DNA 3′ ends during V(D)J recombination. The mechanism controlling the enzyme’s substrate specificity, which is necessary for its biological function, remains unknown. Accordingly, in this work, kinetic and mutational analyses of human TdT were performed and allowed to determine quantitative characteristics of individual stages of the enzyme–substrate interaction, which overall may ensure the enzyme’s operation either in the distributive or processive mode of primer extension. It was found that conformational dynamics of TdT play an important role in the formation of the catalytic complex. Meanwhile, the nature of the nitrogenous base significantly affected both the dNTP-binding and catalytic-reaction efficiency. The results indicated that neutralisation of the charge and an increase in the internal volume of the active site caused a substantial increase in the activity of the enzyme and induced a transition to the processive mode in the presence of Mg2+ ions. Surrogate metal ions Co2+ or Mn2+ also may regulate the switching of the enzymatic process to the processive mode. Thus, the totality of individual factors affecting the activity of TdT ensures effective execution of its biological function. Full article
(This article belongs to the Special Issue Molecular Mechanism of DNA Replication and Repair, 2nd Edition )
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17 pages, 3067 KiB  
Article
Crosstalk between G-Quadruplexes and Dnmt3a-Mediated Methylation of the c-MYC Oncogene Promoter
by Alexander V. Sergeev, Andrei G. Loiko, Adelya I. Genatullina, Alexander S. Petrov, Elena A. Kubareva, Nina G. Dolinnaya and Elizaveta S. Gromova
Int. J. Mol. Sci. 2024, 25(1), 45; https://doi.org/10.3390/ijms25010045 - 19 Dec 2023
Viewed by 746
Abstract
The methylation of cytosines at CpG sites in DNA, carried out de novo by DNA methyltransferase Dnmt3a, is a basic epigenetic modification involved in gene regulation and genome stability. Aberrant CpG methylation in gene promoters leads to oncogenesis. In oncogene promoters, CpG sites [...] Read more.
The methylation of cytosines at CpG sites in DNA, carried out de novo by DNA methyltransferase Dnmt3a, is a basic epigenetic modification involved in gene regulation and genome stability. Aberrant CpG methylation in gene promoters leads to oncogenesis. In oncogene promoters, CpG sites often colocalize with guanine-rich sequences capable of folding into G-quadruplexes (G4s). Our in vitro study aimed to investigate how parallel G4s formed by a sequence derived from the c-MYC oncogene promoter region affect the activity of the Dnmt3a catalytic domain (Dnmt3a-CD). For this purpose, we designed synthetic oligonucleotide constructs: a c-MYC G4-forming oligonucleotide and linear double-stranded DNA containing an embedded stable extrahelical c-MYC G4. The topology and thermal stability of G4 structures in these DNA models were analyzed using physicochemical techniques. We showed that Dnmt3a-CD specifically binds to an oligonucleotide containing c-MYC G4, resulting in inhibition of its methylation activity. c-MYC G4 formation in a double-stranded context significantly reduces Dnmt3a-CD-induced methylation of a CpG site located in close proximity to the quadruplex structure; this effect depends on the distance between the non-canonical structure and the specific CpG site. One would expect DNA hypomethylation near the G4 structure, while regions distant from this non-canonical form would maintain a regular pattern of high methylation levels. We hypothesize that the G4 structure sequesters the Dnmt3a-CD and impedes its proper binding to B-DNA, resulting in hypomethylation and activation of c-MYC transcription. Full article
(This article belongs to the Special Issue Molecular Mechanism of DNA Replication and Repair, 2nd Edition )
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Review

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19 pages, 1101 KiB  
Review
Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes
by Dimitra Mavroeidi, Anastasia Georganta, Emmanouil Panagiotou, Konstantinos Syrigos and Vassilis L. Souliotis
Int. J. Mol. Sci. 2024, 25(5), 2767; https://doi.org/10.3390/ijms25052767 - 27 Feb 2024
Viewed by 823
Abstract
The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). [...] Read more.
The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). The ATR pathway coordinates processes such as replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair. ATR inhibition disrupts these functions, causing a reduction of DNA repair, accumulation of DNA damage, replication fork collapse, inappropriate mitotic entry, and mitotic catastrophe. Recent data have shown that the inhibition of ATR can lead to synthetic lethality in ATM-deficient malignancies. In addition, ATR inhibition plays a significant role in the activation of the immune system by increasing the tumor mutational burden and neoantigen load as well as by triggering the accumulation of cytosolic DNA and subsequently inducing the cGAS-STING pathway and the type I IFN response. Taken together, we review stimulating data showing that ATR kinase inhibition can alter the DDR network, the immune system, and their interplay and, therefore, potentially provide a novel strategy to improve the efficacy of antitumor therapy, using ATR inhibitors as monotherapy or in combination with genotoxic drugs and/or immunomodulators. Full article
(This article belongs to the Special Issue Molecular Mechanism of DNA Replication and Repair, 2nd Edition )
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24 pages, 4717 KiB  
Review
8-Oxoadenine: A «New» Player of the Oxidative Stress in Mammals?
by Alexander A. Kruchinin, Polina N. Kamzeeva, Dmitry O. Zharkov, Andrey V. Aralov and Alena V. Makarova
Int. J. Mol. Sci. 2024, 25(2), 1342; https://doi.org/10.3390/ijms25021342 - 22 Jan 2024
Viewed by 931
Abstract
Numerous studies have shown that oxidative modifications of guanine (7,8-dihydro-8-oxoguanine, 8-oxoG) can affect cellular functions. 7,8-Dihydro-8-oxoadenine (8-oxoA) is another abundant paradigmatic ambiguous nucleobase but findings reported on the mutagenicity of 8-oxoA in bacterial and eukaryotic cells are incomplete and contradictory. Although several genotoxic [...] Read more.
Numerous studies have shown that oxidative modifications of guanine (7,8-dihydro-8-oxoguanine, 8-oxoG) can affect cellular functions. 7,8-Dihydro-8-oxoadenine (8-oxoA) is another abundant paradigmatic ambiguous nucleobase but findings reported on the mutagenicity of 8-oxoA in bacterial and eukaryotic cells are incomplete and contradictory. Although several genotoxic studies have demonstrated the mutagenic potential of 8-oxoA in eukaryotic cells, very little biochemical and bioinformatics data about the mechanism of 8-oxoA-induced mutagenesis are available. In this review, we discuss dual coding properties of 8-oxoA, summarize historical and recent genotoxicity and biochemical studies, and address the main protective cellular mechanisms of response to 8-oxoA. We also discuss the available structural data for 8-oxoA bypass by different DNA polymerases as well as the mechanisms of 8-oxoA recognition by DNA repair enzymes. Full article
(This article belongs to the Special Issue Molecular Mechanism of DNA Replication and Repair, 2nd Edition )
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15 pages, 2173 KiB  
Review
The Complex Network of ADP-Ribosylation and DNA Repair: Emerging Insights and Implications for Cancer Therapy
by Ziyuan Li, Aiqin Luo and Bingteng Xie
Int. J. Mol. Sci. 2023, 24(19), 15028; https://doi.org/10.3390/ijms241915028 - 09 Oct 2023
Viewed by 1322
Abstract
ADP-ribosylation is a post-translational modification of proteins that plays a key role in various cellular processes, including DNA repair. Recently, significant progress has been made in understanding the mechanism and function of ADP-ribosylation in DNA repair. ADP-ribosylation can regulate the recruitment and activity [...] Read more.
ADP-ribosylation is a post-translational modification of proteins that plays a key role in various cellular processes, including DNA repair. Recently, significant progress has been made in understanding the mechanism and function of ADP-ribosylation in DNA repair. ADP-ribosylation can regulate the recruitment and activity of DNA repair proteins by facilitating protein–protein interactions and regulating protein conformations. Moreover, ADP-ribosylation can influence additional post-translational modifications (PTMs) of proteins involved in DNA repair, such as ubiquitination, methylation, acetylation, phosphorylation, and SUMOylation. The interaction between ADP-ribosylation and these additional PTMs can fine-tune the activity of DNA repair proteins and ensure the proper execution of the DNA repair process. In addition, PARP inhibitors have been developed as a promising cancer therapeutic strategy by exploiting the dependence of certain cancer types on the PARP-mediated DNA repair pathway. In this paper, we review the progress of ADP-ribosylation in DNA repair, discuss the crosstalk of ADP-ribosylation with additional PTMs in DNA repair, and summarize the progress of PARP inhibitors in cancer therapy. Full article
(This article belongs to the Special Issue Molecular Mechanism of DNA Replication and Repair, 2nd Edition )
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27 pages, 3721 KiB  
Review
Base Excision DNA Repair in Plants: Arabidopsis and Beyond
by Inga R. Grin, Daria V. Petrova, Anton V. Endutkin, Chunquan Ma, Bing Yu, Haiying Li and Dmitry O. Zharkov
Int. J. Mol. Sci. 2023, 24(19), 14746; https://doi.org/10.3390/ijms241914746 - 29 Sep 2023
Viewed by 1285
Abstract
Base excision DNA repair (BER) is a key pathway safeguarding the genome of all living organisms from damage caused by both intrinsic and environmental factors. Most present knowledge about BER comes from studies of human cells, E. coli, and yeast. Plants may [...] Read more.
Base excision DNA repair (BER) is a key pathway safeguarding the genome of all living organisms from damage caused by both intrinsic and environmental factors. Most present knowledge about BER comes from studies of human cells, E. coli, and yeast. Plants may be under an even heavier DNA damage threat from abiotic stress, reactive oxygen species leaking from the photosynthetic system, and reactive secondary metabolites. In general, BER in plant species is similar to that in humans and model organisms, but several important details are specific to plants. Here, we review the current state of knowledge about BER in plants, with special attention paid to its unique features, such as the existence of active epigenetic demethylation based on the BER machinery, the unexplained diversity of alkylation damage repair enzymes, and the differences in the processing of abasic sites that appear either spontaneously or are generated as BER intermediates. Understanding the biochemistry of plant DNA repair, especially in species other than the Arabidopsis model, is important for future efforts to develop new crop varieties. Full article
(This article belongs to the Special Issue Molecular Mechanism of DNA Replication and Repair, 2nd Edition )
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18 pages, 5568 KiB  
Review
BRCA1 the Versatile Defender: Molecular to Environmental Perspectives
by Amy X. Zhong, Yumay Chen and Phang-Lang Chen
Int. J. Mol. Sci. 2023, 24(18), 14276; https://doi.org/10.3390/ijms241814276 - 19 Sep 2023
Cited by 3 | Viewed by 999
Abstract
The evolving history of BRCA1 research demonstrates the profound interconnectedness of a single protein within the web of crucial functions in human cells. Mutations in BRCA1, a tumor suppressor gene, have been linked to heightened breast and ovarian cancer risks. However, despite decades [...] Read more.
The evolving history of BRCA1 research demonstrates the profound interconnectedness of a single protein within the web of crucial functions in human cells. Mutations in BRCA1, a tumor suppressor gene, have been linked to heightened breast and ovarian cancer risks. However, despite decades of extensive research, the mechanisms underlying BRCA1’s contribution to tissue-specific tumor development remain elusive. Nevertheless, much of the BRCA1 protein’s structure, function, and interactions has been elucidated. Individual regions of BRCA1 interact with numerous proteins to play roles in ubiquitination, transcription, cell checkpoints, and DNA damage repair. At a cellular scale, these BRCA1 functions coordinate tumor suppression, R-loop prevention, and cellular differentiation, all of which may contribute to BRCA1’s role in cancer tissue specificity. As research on BRCA1 and breast cancer continues to evolve, it will become increasingly evident that modern materials such as Bisphenol A should be examined for their relationship with DNA stability, cancer incidence, and chemotherapy. Overall, this review offers a comprehensive understanding of BRCA1’s many roles at a molecular, cellular, organismal, and environmental scale. We hope that the knowledge gathered here highlights both the necessity of BRCA1 research and the potential for novel strategies to prevent and treat cancer in individuals carrying BRCA1 mutations. Full article
(This article belongs to the Special Issue Molecular Mechanism of DNA Replication and Repair, 2nd Edition )
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11 pages, 915 KiB  
Review
Untousling the Role of Tousled-like Kinase 1 in DNA Damage Repair
by Ishita Ghosh and Arrigo De Benedetti
Int. J. Mol. Sci. 2023, 24(17), 13369; https://doi.org/10.3390/ijms241713369 - 29 Aug 2023
Cited by 1 | Viewed by 1016
Abstract
DNA damage repair lies at the core of all cells’ survival strategy, including the survival strategy of cancerous cells. Therefore, targeting such repair mechanisms forms the major goal of cancer therapeutics. The mechanism of DNA repair has been tousled with the discovery of [...] Read more.
DNA damage repair lies at the core of all cells’ survival strategy, including the survival strategy of cancerous cells. Therefore, targeting such repair mechanisms forms the major goal of cancer therapeutics. The mechanism of DNA repair has been tousled with the discovery of multiple kinases. Recent studies on tousled-like kinases have brought significant clarity on the effectors of these kinases which stand to regulate DSB repair. In addition to their well-established role in DDR and cell cycle checkpoint mediation after DNA damage or inhibitors of replication, evidence of their suspected involvement in the actual DSB repair process has more recently been strengthened by the important finding that TLK1 phosphorylates RAD54 and regulates some of its activities in HRR and localization in the cell. Earlier findings of its regulation of RAD9 during checkpoint deactivation, as well as defined steps during NHEJ end processing, were earlier hints of its broadly important involvement in DSB repair. All this has opened up new avenues to target cancer cells in combination therapy with genotoxins and TLK inhibitors. Full article
(This article belongs to the Special Issue Molecular Mechanism of DNA Replication and Repair, 2nd Edition )
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