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Molecular Mechanism of DNA Replication and Repair, 2nd Edition

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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 (29 February 2024) | Viewed by 10690

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Dr. Mariarita De Felice

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Institute of Biosciences and BioResources, CNR, Via P. Castellino 111, 80131 Naples, Italy
Interests: DNA repair; DNA nuclease; DNA helicase; archaea; HR
Special Issues, Collections and Topics in MDPI journals

Dr. Mariarosaria De Falco

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Institute of Biosciences and BioResources, CNR, Via P. Castellino 111, 80131 Naples, Italy
Interests: DNA replication and repair; genome stability; archaea
Special Issues, Collections and Topics in MDPI journals

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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

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Keywords

genome stability
DNA repair
DNA replication
DDR

Related Special Issues

Molecular Mechanism of DNA Replication and Repair in International Journal of Molecular Sciences (9 articles)
Molecular Mechanism of DNA Replication and Repair, 3rd Edition in International Journal of Molecular Sciences (1 article)

Published Papers (10 papers)

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Research

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17 pages, 4130 KiB

Open AccessArticle

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 875

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 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

Open AccessArticle

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 803

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 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

Open AccessArticle

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 667

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 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

Open AccessArticle

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 766

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 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

Open AccessReview

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 894

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). 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

Open AccessReview

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 974

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 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

Open AccessReview

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 1349

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 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

Open AccessReview

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 1336

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 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

Open AccessReview

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 1027

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 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

Open AccessReview

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 1031

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 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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