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DNA Replication and DNA Damage Response in Aging and Disease

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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 (31 March 2024) | Viewed by 12122

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Special Issue Editors

Dr. Helmut Pospiech

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Guest Editor

Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, D-07745 Jena, Germany
Interests: DNA replication; DNA damage response; DNA repair

Prof. Dr. Kerstin Borgmann

E-Mail Website
Co-Guest Editor

Laboratory of Radiobiology and Experimental Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Interests: DNA repair, cancer stem cells; radiation resistance; DNA replication stress

Special Issue Information

Dear Colleagues,

DNA replication, which realizes the duplication of genetic information, is one of the most fundamental processes for sustaining life. Error-free and complete DNA replication is a prerequisite for successful cell division and growth. It is therefore not surprising that DNA replication has evolved as a process with amazing plasticity and reliability. This is further ensured by the DNA damage response, which initiates DNA repair processes and removes any DNA damage that occurs. Nevertheless, errors in DNA replication accumulate over an individual’s lifetime and may lead to age-related or tumor-initiating cell and tissue dysfunction. For this Special Issue, we invite contributions that address the interrelationships of DNA replication, DNA damage response for aging, degenerative disease, and carcinogenesis. The topics of interest include:

Aging-related mutation accumulation as a cause of cell and tissue dysfunction;
Replicative senescence;
Replication stress as a cause of cancer and degenerative diseases;
Mechanisms limiting genomic instability during aging;
Genetic diseases leading to replication stress;
Replication error accumulation and tumorigenesis.

Dr. Helmut Pospiech
Prof. Dr. Kerstin Borgmann
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

DNA replication
DNA damage response
replication stress
mutation accumulation
genomic instability
aging
senescence
cancer
tumorigenesis
tissue malfunction

Published Papers (5 papers)

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Research

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23 pages, 3555 KiB

Open AccessArticle

Simulating Space Conditions Evokes Different DNA Damage Responses in Immature and Mature Cells of the Human Hematopoietic System

by Leonie Handwerk, Heike Katrin Schreier, Daniela Kraft, Kateryna Shreder, Ruth Hemmersbach, Jens Hauslage, Halvard Bonig, Lisa Wiesmüller, Claudia Fournier and Melanie Rall-Scharpf

Int. J. Mol. Sci. 2023, 24(18), 13761; https://doi.org/10.3390/ijms241813761 - 06 Sep 2023

Cited by 1 | Viewed by 1072

Abstract

The impact of space radiation and microgravity on DNA damage responses has been discussed controversially, largely due to the variety of model systems engaged. Here, we performed side-by-side analyses of human hematopoietic stem/progenitor cells (HSPC) and peripheral blood lymphocytes (PBL) cultivated in a 2D clinostat to simulate microgravity before, during and after photon and particle irradiation. We demonstrate that simulated microgravity (SMG) accelerates the early phase of non-homologous end joining (NHEJ)-mediated repair of simple, X-ray-induced DNA double-strand breaks (DSBs) in PBL, while repair kinetics in HSPC remained unaltered. Repair acceleration was lost with increasing LET of ion exposures, which increases the complexity of DSBs, precluding NHEJ and requiring end resection for successful repair. Such cell-type specific effect of SMG on DSB repair was dependent on the NF-кB pathway pre-activated in PBL but not HSPC. Already under unperturbed growth conditions HSPC and PBL suffered from SMG-induced replication stress associated with accumulation of single-stranded DNA and DSBs, respectively. We conclude that in PBL, SMG-induced DSBs promote repair of radiation-induced damage in an adaptive-like response. HSPC feature SMG-induced single-stranded DNA and FANCD2 foci, i.e., markers of persistent replication stress and senescence that may contribute to a premature decline of the immune system in space. Full article

(This article belongs to the Special Issue DNA Replication and DNA Damage Response in Aging and Disease)

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18 pages, 2106 KiB

Open AccessArticle

Partial Reduction in BRCA1 Gene Dose Modulates DNA Replication Stress Level and Thereby Contributes to Sensitivity or Resistance

by Sandra Classen, Elena Rahlf, Johannes Jungwirth, Nina Albers, Luca Philipp Hebestreit, Alexandra Zielinski, Lena Poole, Marco Groth, Philipp Koch, Thomas Liehr, Stefanie Kankel, Nils Cordes, Cordula Petersen, Kai Rothkamm, Helmut Pospiech and Kerstin Borgmann

Int. J. Mol. Sci. 2022, 23(21), 13363; https://doi.org/10.3390/ijms232113363 - 01 Nov 2022

Cited by 3 | Viewed by 2303

Abstract

BRCA1 is a well-known breast cancer risk gene, involved in DNA damage repair via homologous recombination (HR) and replication fork protection. Therapy resistance was linked to loss and amplification of the BRCA1 gene causing inferior survival of breast cancer patients. Most studies have focused on the analysis of complete loss or mutations in functional domains of BRCA1. How mutations in non-functional domains contribute to resistance mechanisms remains elusive and was the focus of this study. Therefore, clones of the breast cancer cell line MCF7 with indels in BRCA1 exon 9 and 14 were generated using CRISPR/Cas9. Clones with successful introduced BRCA1 mutations were evaluated regarding their capacity to perform HR, how they handle DNA replication stress (RS), and the consequences on the sensitivity to MMC, PARP1 inhibition, and ionizing radiation. Unexpectedly, BRCA1 mutations resulted in both increased sensitivity and resistance to exogenous DNA damage, despite a reduction of HR capacity in all clones. Resistance was associated with improved DNA double-strand break repair and reduction in replication stress (RS). Lower RS was accompanied by increased activation and interaction of proteins essential for the S phase-specific DNA damage response consisting of HR proteins, FANCD2, and CHK1. Full article

(This article belongs to the Special Issue DNA Replication and DNA Damage Response in Aging and Disease)

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18 pages, 2156 KiB

Open AccessArticle

Oxidative Stress Markers and Sperm DNA Fragmentation in Men Recovered from COVID-19

by Anastasiia D. Shcherbitskaia, Evgeniia M. Komarova, Yulia P. Milyutina, Mariia A. Ishchuk, Yanina M. Sagurova, Galina K. Safaryan, Elena A. Lesik, Alexander M. Gzgzyan, Olesya N. Bespalova and Igor Y. Kogan

Int. J. Mol. Sci. 2022, 23(17), 10060; https://doi.org/10.3390/ijms231710060 - 02 Sep 2022

Cited by 14 | Viewed by 3614

Abstract

SARS-CoV-2 negatively affects semen characteristics, impairs various biochemical processes in seminal fluid and within spermatogenic cells ultimately leading to male fertility decline. However, the distinct mechanisms, in particular, the role of oxidative stress on the consequences of coronavirus infection, have not been well investigated, which is the purpose of the present study. The standard semen parameters, its pro- and antioxidant system state, as well as the level of sperm DNA fragmentation, were assessed in 17 semen samples of men five months after the coronavirus infection and in 22 age-matched control patients. We determined that the DNA fragmentation rate negatively correlated with the period after coronavirus recovery, as well as seminal fluid superoxide dismutase activity and uric acid level. It was demonstrated that COVID-19 is not always associated with increased DNA fragmentation, allowing them to be considered as two independent factors. Thus, the most significant changes were noted in the samples of men after COVID-19 and abnormal TUNEL results: increased round cell number, decreased seminal fluid’s nitrotyrosine level, and total antioxidant capacity and Zn, as well as an increased 8-hydroxy-2′-deoxyguanosine level within spermatozoa. The data obtained indicate that increased DNA fragmentation and diminished semen quality in men can be the result of an imbalance in semen pro- and antioxidant components after COVID-19. Full article

(This article belongs to the Special Issue DNA Replication and DNA Damage Response in Aging and Disease)

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15 pages, 1861 KiB

Open AccessArticle

ATR Contributes More Than ATM in Intra-S-Phase Checkpoint Activation after IR, and DNA-PKcs Facilitates Recovery: Evidence for Modular Integration of ATM/ATR/DNA-PKcs Functions

by Aashish Soni, Xiaolu Duan, Martin Stuschke and George Iliakis

Int. J. Mol. Sci. 2022, 23(14), 7506; https://doi.org/10.3390/ijms23147506 - 06 Jul 2022

Cited by 3 | Viewed by 1573

Abstract

The intra-S-phase checkpoint was among the first reported cell cycle checkpoints in mammalian cells. It transiently slows down the rate of DNA replication after DNA damage to facilitate repair and thus prevents genomic instability. The ionizing radiation (IR)-induced intra-S-phase checkpoint in mammalian cells is thought to be mainly dependent upon the kinase activity of ATM. Defects in the intra-S-phase checkpoint result in radio-resistant DNA synthesis (RDS), which promotes genomic instability. ATM belongs to the PI3K kinase family along with ATR and DNA-PKcs. ATR has been shown to be the key kinase for intra-S-phase checkpoint signaling in yeast and has also been implicated in this checkpoint in higher eukaryotes. Recently, contributions of DNA-PKcs to IR-induced G₂-checkpoint could also be established. Whether and how ATR and DNA-PKcs are involved in the IR-induced intra-S-phase checkpoint in mammalian cells is incompletely characterized. Here, we investigated the contributions of ATM, ATR, and DNA-PKcs to intra-S-phase checkpoint activation after exposure to IR of human and hamster cells. The results suggest that the activities of both ATM and ATR are essential for efficient intra-S-phase checkpoint activation. Indeed, in a wild-type genetic background, ATR inhibition generates stronger checkpoint defects than ATM inhibition. Similar to G2 checkpoint, DNA-PKcs contributes to the recovery from the intra-S-phase checkpoint. DNA-PKcs–deficient cells show persistent, mainly ATR-dependent intra-S-phase checkpoints. A correlation between the degree of DSB end resection and the strength of the intra-S-phase checkpoint is observed, which again compares well to the G2 checkpoint response. We conclude that the organization of the intra-S-phase checkpoint has a similar mechanistic organization to that of the G₂ checkpoint in cells irradiated in the G₂ phase. Full article

(This article belongs to the Special Issue DNA Replication and DNA Damage Response in Aging and Disease)

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Review

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32 pages, 3104 KiB

Open AccessReview

Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets

by Alvina I. Khamidullina, Yaroslav E. Abramenko, Alexandra V. Bruter and Victor V. Tatarskiy

Int. J. Mol. Sci. 2024, 25(2), 1263; https://doi.org/10.3390/ijms25021263 - 19 Jan 2024

Cited by 2 | Viewed by 2469

Abstract

Replication stress (RS) is a characteristic state of cancer cells as they tend to exchange precision of replication for fast proliferation and increased genomic instability. To overcome the consequences of improper replication control, malignant cells frequently inactivate parts of their DNA damage response (DDR) pathways (the ATM-CHK2-p53 pathway), while relying on other pathways which help to maintain replication fork stability (ATR-CHK1). This creates a dependency on the remaining DDR pathways, vulnerability to further destabilization of replication and synthetic lethality of DDR inhibitors with common oncogenic alterations such as mutations of TP53, RB1, ATM, amplifications of MYC, CCNE1 and others. The response to RS is normally limited by coordination of cell cycle, transcription and replication. Inhibition of WEE1 and PKMYT1 kinases, which prevent unscheduled mitosis entry, leads to fragility of under-replicated sites. Recent evidence also shows that inhibition of Cyclin-dependent kinases (CDKs), such as CDK4/6, CDK2, CDK8/19 and CDK12/13 can contribute to RS through disruption of DNA repair and replication control. Here, we review the main causes of RS in cancers as well as main therapeutic targets—ATR, CHK1, PARP and their inhibitors. Full article

(This article belongs to the Special Issue DNA Replication and DNA Damage Response in Aging and Disease)

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