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Cells
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The DNA Damage Response in Cell Physiology and Disease
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The DNA Damage Response in Cell Physiology and Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 38008

Special Issue Editors

Dr. Evangelos Kolettas

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Guest Editor
1. Laboratory of Biology, School of Medicine, Faculty of Health Sciences, and Institute of Biosciences, University Research Centre, University of Ioannina, 451 10 Ioannina, Greece
2. Molecular Cancer Biology & Senescence Labortaory, Biomedical Research Institute (BRI), Foundation for Research and Technology (FORTH), Ioannina, Greece
Interests: cancer; senescence; DNA damage; inflammation; epithelial-to-mesenchymal cell transition; cell signalling; NF-kappaB; transcriptional regulation; epigenetics; miRNA
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Vassilis Gorgoulis

E-Mail Website
Guest Editor
Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, 15784 Athens, Greece
Interests: cancer; cell cycle; cellular senescence; DNA damage response and repair; digital pathology; genomic instability; oncogene
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Eukaryotic genomes are continuously attacked and must be efficiently and accurately repaired to maintain their integrity. Factors causing DNA lesions include exogenous physical and chemical agents, such as ultraviolet light, ionizing radiation, cigarette smoking, and chemotherapeutic agents, and also endogenous factors, such as the intracellular reactive oxygen species and collapsed DNA-replication forks. These factors cause DNA damage, single-stranded DNA breaks (SSBs), and double-stranded DNA breaks (DSBs). Both types of damage are repaired by specific repair mechanisms. SSBs are repaired by single-strand break repair, while DSB repair is carried out by two main pathways, namely: non-homologous end joining and homologous recombination repair. However, DSBs are toxic to cells, as their inefficient or inaccurate repair can result in genomic instability and cancer.

Eukaryotic cells have evolved genome repair and surveillance mechanisms to co-op with DSBs. DSBs result in the activation of complex DNA damage response (DDR) signal transducing pathways, which sense DNA damage and replication stress, and initiate a cascade mediated by the members of the phosphatidylinositol three-kinase-like protein kinase family (ATM, ATR, and DNA-PK), and by the poly(ADP-ribose) polymerase (PARP) family. These lead to the phosphorylation and activation of cell cycle-checkpoint kinases (Chk1 and Chk2 kinases) by ATR/ATR, which phosphorylate and activate p53, leading to the induction of a cell cycle phase arrest of damaged cells until the lesions are repaired. If DSBs exceed the cell’s capacity for repair, then DDR activates p53-dependent pathways, leading to senescence or apoptosis. The activation of DDR is influenced by, and also affects the chromatin status at the site of DNA damage and across the genome. DDR also leads to the induction of noncoding RNAs, which also shape chromatin. Hence, the DNA repair and maintenance of the genome stability are crucial to cellular homeostasis, and defects in both of them can have detrimental effects, resulting in senescence, apoptosis, immune reaction, and inflammation, which is linked to cancer development and other pathologies.

The purpose of this Special Issue is to focus on cutting edge research, and to cover advances across a wide range of topics, relevant to DNA damage responses implicated in senescence, apoptosis, inflammation, and cancer. We invite authours to submit original and review articles on basic research and translational research.

Dr. Evangelos Kolettas
Prof. Dr. Vassilis Gorgoulis
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. 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

  • DNA damage
  • DNA repair
  • senescence
  • apoptosis
  • cancer

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Published Papers (10 papers)

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Editorial

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5 pages, 183 KiB  
Editorial
Drug Repurposing and DNA Damage in Cancer Treatment: Facts and Misconceptions
by Eleni Sertedaki and Athanassios Kotsinas
Cells 2020, 9(5), 1210; https://doi.org/10.3390/cells9051210 - 13 May 2020
Cited by 2 | Viewed by 2342
Abstract
Drug repurposing appears to offer an attractive alternative in finding new anticancer agents. Their applicability seems to have multiple benefits, among which are the potential of immediate efficacy assessment in clinical trials and the existence of patient safety and tolerability evidence. Nevertheless, their [...] Read more.
Drug repurposing appears to offer an attractive alternative in finding new anticancer agents. Their applicability seems to have multiple benefits, among which are the potential of immediate efficacy assessment in clinical trials and the existence of patient safety and tolerability evidence. Nevertheless, their effective application in terms of tumor-type targeting requires accurate knowledge of their exact mechanism of action. In this review, we present such a successful drug, namely Disulfiram (commercially known as Antabuse), and discuss its recently uncovered mode of anticancer action through DNA damage. Full article
(This article belongs to the Special Issue The DNA Damage Response in Cell Physiology and Disease)

Research

Jump to: Editorial, Review

22 pages, 5653 KiB  
Article
Emerging Role of Oxidative Stress on EGFR and OGG1-BER Cross-Regulation: Implications in Thyroid Physiopathology
by Carmelo Moscatello, Maria Carmela Di Marcantonio, Luca Savino, Emira D’Amico, Giordano Spacco, Pasquale Simeone, Paola Lanuti, Raffaella Muraro, Gabriella Mincione, Roberto Cotellese and Gitana Maria Aceto
Cells 2022, 11(5), 822; https://doi.org/10.3390/cells11050822 - 26 Feb 2022
Cited by 10 | Viewed by 3115
Abstract
Thyroid diseases have a complex and multifactorial aetiology. Despite the numerous studies on the signals referable to the malignant transition, the molecular mechanisms concerning the role of oxidative stress remain elusive. Based on its strong oxidative power, H2O2 could be [...] Read more.
Thyroid diseases have a complex and multifactorial aetiology. Despite the numerous studies on the signals referable to the malignant transition, the molecular mechanisms concerning the role of oxidative stress remain elusive. Based on its strong oxidative power, H2O2 could be responsible for the high level of oxidative DNA damage observed in cancerous thyroid tissue and hyperactivation of mitogen-activated protein kinase (MAPK) and PI3K/Akt, which mediate ErbB signaling. Increased levels of 8-oxoG DNA adducts have been detected in the early stages of thyroid cancer. These DNA lesions are efficiently recognized and removed by the base excision repair (BER) pathway initiated by 8-oxoG glycosylase1 (OGG1). This study investigated the relationships between the EGFR and OGG1-BER pathways and their mutual regulation following oxidative stress stimulus by H2O2 in human thyrocytes. We clarified the modulation of ErbB receptors and their downstream pathways (PI3K/Akt and MAPK/ERK) under oxidative stress (from H2O2) at the level of gene and protein expression, according to the mechanism defined in a human non-pathological cell system, Nthy-ori 3-1. Later, on the basis of the results obtained by gene expression cluster analysis in normal cells, we assessed the dysregulation of the relationships in a model of papillary thyroid cancer with RET/PTC rearrangement (TPC-1). Our observations demonstrated that a H2O2 stress may induce a physiological cross-regulation between ErbB and OGG1-BER pathways in normal thyroid cells (while this is dysregulated in the TPC-1 cells). Gene expression data also delineated that MUTYH gene could play a physiological role in crosstalk between ErbB and BER pathways and this function is instead lost in cancer cells. Overall, our data on OGG1 protein expression suggest that it was physiologically regulated in response to oxidative modulation of ErbB, and that these might be dysregulated in the signaling pathway involving AKT in the progression of thyroid malignancies with RET/PTC rearrangements. Full article
(This article belongs to the Special Issue The DNA Damage Response in Cell Physiology and Disease)
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13 pages, 4709 KiB  
Article
Preclinical Studies on the Effect of Rucaparib in Ovarian Cancer: Impact of BRCA2 Status
by Sayeh Saravi, Zena Alizzi, Sabrina Tosi, Marcia Hall and Emmanouil Karteris
Cells 2021, 10(9), 2434; https://doi.org/10.3390/cells10092434 - 15 Sep 2021
Cited by 3 | Viewed by 3283
Abstract
Background: Approximately 50% of ovarian cancer patients harbour homologous recombination repair deficiencies. These deficiencies have been successfully targeted using poly (ADP-ribose) polymerase inhibitors (PARPi) particularly for patients harbouring BRCA1/2 mutations. The aim of this study is to assess the effects of the PARPi [...] Read more.
Background: Approximately 50% of ovarian cancer patients harbour homologous recombination repair deficiencies. These deficiencies have been successfully targeted using poly (ADP-ribose) polymerase inhibitors (PARPi) particularly for patients harbouring BRCA1/2 mutations. The aim of this study is to assess the effects of the PARPi rucaparib in vitro using cell lines with BRCA2 mutations in comparison to those with BRCA2 wild type. Methods: Cell proliferation assays, RT-qPCR, immunofluorescence, annexin V/PI assays were used to assess the effects of rucaparib in vitro. Results: The BRCA2 mutant ovarian cancer cell line PEO1 exhibited higher PARP1 activity when treated with H2O2 compared to wild type cell lines. The migratory and proliferative capacity of PEO1 cells was compromised following treatment with rucaparib 10 µM compared to BRCA2 wild-type cell lines via a mechanism involving the mTOR pathway. Rucaparib treatment significantly increased DNA damage primarily in PEO1 cells and SKOV3 cells compared with wild type. Conclusions: Appropriate identification of robust predictive biomarkers for homologous recombination deficiency using ‘liquid’ biopsies would facilitate the identification of patients suitable for PARPi therapy. Preliminary efforts to undertake such testing are described here. This study also demonstrates the mechanisms of action of rucaparib (PARPi) which may involve elements of the mTOR pathway. Full article
(This article belongs to the Special Issue The DNA Damage Response in Cell Physiology and Disease)
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13 pages, 5450 KiB  
Article
Adsorption of Cd to TiO2-NPs Forms Low Genotoxic Aggregates in Zebrafish Cells
by Filomena Mottola, Marianna Santonastaso, Concetta Iovine, Veronica Feola, Severina Pacifico and Lucia Rocco
Cells 2021, 10(2), 310; https://doi.org/10.3390/cells10020310 - 3 Feb 2021
Cited by 10 | Viewed by 2313
Abstract
The aquatic environment is involved in the pollutants spreading mechanisms, including nanomaterials and heavy metals. The aims of this study were to assess the in vivo genotoxicity of Cd (1 mg/L) and to investigate the genomic effects generated by its co-exposure with TiO [...] Read more.
The aquatic environment is involved in the pollutants spreading mechanisms, including nanomaterials and heavy metals. The aims of this study were to assess the in vivo genotoxicity of Cd (1 mg/L) and to investigate the genomic effects generated by its co-exposure with TiO2-NPs (10 µg/L). The study was performed using zebrafish as a model for 5, 7, 14, 21, and 28 days of exposure. The genotoxic potential was assessed by three experimental approaches: DNA integrity, degree of apoptosis, and molecular alterations at the genomic level by genomic template stability (% GTS) calculation. Results showed an increased in DNA damage after Cd exposure with a decrease in % GTS. The co-exposure (TiO2-NPs + Cd) induced a no statistically significant loss of DNA integrity, a reduction of the apoptotic cell percentage and the recovery of genome stability for prolonged exposure days. Characterization and analytical determinations data showed Cd adsorption to TiO2-NPs, which reduced free TiO2-NPs levels. The results of our study suggest that TiO2-NPs could be used for the development of controlled heavy metal bioremediation systems. Full article
(This article belongs to the Special Issue The DNA Damage Response in Cell Physiology and Disease)
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Review

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16 pages, 1230 KiB  
Review
The DNA Damage Response in Fully Grown Mammalian Oocytes
by Alexandros Pailas, Konstantina Niaka, Chrysoula Zorzompokou and Petros Marangos
Cells 2022, 11(5), 798; https://doi.org/10.3390/cells11050798 - 24 Feb 2022
Cited by 9 | Viewed by 3693
Abstract
DNA damage in cells can occur physiologically or may be induced by exogenous factors. Genotoxic damage may cause cancer, ageing, serious developmental diseases and anomalies. If the damage occurs in the germline, it can potentially lead to infertility or chromosomal and genetic aberrations [...] Read more.
DNA damage in cells can occur physiologically or may be induced by exogenous factors. Genotoxic damage may cause cancer, ageing, serious developmental diseases and anomalies. If the damage occurs in the germline, it can potentially lead to infertility or chromosomal and genetic aberrations in the developing embryo. Mammalian oocytes, the female germ cells, are produced before birth, remaining arrested at the prophase stage of meiosis over a long period of time. During this extensive state of arrest the oocyte may be exposed to different DNA-damaging insults for months, years or even decades. Therefore, it is of great importance to understand how these cells respond to DNA damage. In this review, we summarize the most recent developments in the understanding of the DNA damage response mechanisms that function in fully grown mammalian oocytes. Full article
(This article belongs to the Special Issue The DNA Damage Response in Cell Physiology and Disease)
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10 pages, 684 KiB  
Review
Coupling DNA Replication and Spindle Function in Saccharomyces cerevisiae
by Dimitris Liakopoulos
Cells 2021, 10(12), 3359; https://doi.org/10.3390/cells10123359 - 30 Nov 2021
Viewed by 2271
Abstract
In the yeast Saccharomyces cerevisiae DNA replication and spindle assembly can overlap. Therefore, signaling mechanisms modulate spindle dynamics in order to ensure correct timing of chromosome segregation relative to genome duplication, especially when replication is incomplete or the DNA becomes damaged. This review [...] Read more.
In the yeast Saccharomyces cerevisiae DNA replication and spindle assembly can overlap. Therefore, signaling mechanisms modulate spindle dynamics in order to ensure correct timing of chromosome segregation relative to genome duplication, especially when replication is incomplete or the DNA becomes damaged. This review focuses on the molecular mechanisms that coordinate DNA replication and spindle dynamics, as well as on the role of spindle-dependent forces in DNA repair. Understanding the coupling between genome duplication and spindle function in yeast cells can provide important insights into similar processes operating in other eukaryotic organisms, including humans. Full article
(This article belongs to the Special Issue The DNA Damage Response in Cell Physiology and Disease)
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14 pages, 1244 KiB  
Review
Cockayne Syndrome Group B (CSB): The Regulatory Framework Governing the Multifunctional Protein and Its Plausible Role in Cancer
by Zoi Spyropoulou, Angelos Papaspyropoulos, Nefeli Lagopati, Vassilios Myrianthopoulos, Alexandros G. Georgakilas, Maria Fousteri, Athanassios Kotsinas and Vassilis G. Gorgoulis
Cells 2021, 10(4), 866; https://doi.org/10.3390/cells10040866 - 10 Apr 2021
Cited by 11 | Viewed by 4692
Abstract
Cockayne syndrome (CS) is a DNA repair syndrome characterized by a broad spectrum of clinical manifestations such as neurodegeneration, premature aging, developmental impairment, photosensitivity and other symptoms. Mutations in Cockayne syndrome protein B (CSB) are present in the vast majority of CS patients [...] Read more.
Cockayne syndrome (CS) is a DNA repair syndrome characterized by a broad spectrum of clinical manifestations such as neurodegeneration, premature aging, developmental impairment, photosensitivity and other symptoms. Mutations in Cockayne syndrome protein B (CSB) are present in the vast majority of CS patients and in other DNA repair-related pathologies. In the literature, the role of CSB in different DNA repair pathways has been highlighted, however, new CSB functions have been identified in DNA transcription, mitochondrial biology, telomere maintenance and p53 regulation. Herein, we present an overview of identified structural elements and processes that impact on CSB activity and its post-translational modifications, known to balance the different roles of the protein not only during normal conditions but most importantly in stress situations. Moreover, since CSB has been found to be overexpressed in a number of different tumors, its role in cancer is presented and possible therapeutic targeting is discussed. Full article
(This article belongs to the Special Issue The DNA Damage Response in Cell Physiology and Disease)
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11 pages, 1364 KiB  
Review
Crosstalk between the mTOR and DNA Damage Response Pathways in Fission Yeast
by John-Patrick Alao, Luc Legon and Charalampos Rallis
Cells 2021, 10(2), 305; https://doi.org/10.3390/cells10020305 - 2 Feb 2021
Cited by 5 | Viewed by 4413
Abstract
Cells have developed response systems to constantly monitor environmental changes and accordingly adjust growth, differentiation, and cellular stress programs. The evolutionarily conserved, nutrient-responsive, mechanistic target of rapamycin signaling (mTOR) pathway coordinates basic anabolic and catabolic cellular processes such as gene transcription, protein translation, [...] Read more.
Cells have developed response systems to constantly monitor environmental changes and accordingly adjust growth, differentiation, and cellular stress programs. The evolutionarily conserved, nutrient-responsive, mechanistic target of rapamycin signaling (mTOR) pathway coordinates basic anabolic and catabolic cellular processes such as gene transcription, protein translation, autophagy, and metabolism, and is directly implicated in cellular and organismal aging as well as age-related diseases. mTOR mediates these processes in response to a broad range of inputs such as oxygen, amino acids, hormones, and energy levels, as well as stresses, including DNA damage. Here, we briefly summarize data relating to the interplays of the mTOR pathway with DNA damage response pathways in fission yeast, a favorite model in cell biology, and how these interactions shape cell decisions, growth, and cell-cycle progression. We, especially, comment on the roles of caffeine-mediated DNA-damage override. Understanding the biology of nutrient response, DNA damage and related pharmacological treatments can lead to the design of interventions towards improved cellular and organismal fitness, health, and survival. Full article
(This article belongs to the Special Issue The DNA Damage Response in Cell Physiology and Disease)
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19 pages, 1600 KiB  
Review
Programmed DNA Damage and Physiological DSBs: Mapping, Biological Significance and Perturbations in Disease States
by Sara Oster and Rami I. Aqeilan
Cells 2020, 9(8), 1870; https://doi.org/10.3390/cells9081870 - 10 Aug 2020
Cited by 11 | Viewed by 3845
Abstract
DNA double strand breaks (DSBs) are known to be the most toxic and threatening of the various types of breaks that may occur to the DNA. However, growing evidence continuously sheds light on the regulatory roles of programmed DSBs. Emerging studies demonstrate the [...] Read more.
DNA double strand breaks (DSBs) are known to be the most toxic and threatening of the various types of breaks that may occur to the DNA. However, growing evidence continuously sheds light on the regulatory roles of programmed DSBs. Emerging studies demonstrate the roles of DSBs in processes such as T and B cell development, meiosis, transcription and replication. A significant recent progress in the last few years has contributed to our advanced knowledge regarding the functions of DSBs is the development of many next generation sequencing (NGS) methods, which have considerably advanced our capabilities. Other studies have focused on the implications of programmed DSBs on chromosomal aberrations and tumorigenesis. This review aims to summarize what is known about DNA damage in its physiological context. In addition, we will examine the advancements of the past several years, which have made an impact on the study of genome landscape and its organization. Full article
(This article belongs to the Special Issue The DNA Damage Response in Cell Physiology and Disease)
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16 pages, 1445 KiB  
Review
Senescence and Host–Pathogen Interactions
by Daniel Humphreys, Mohamed ElGhazaly and Teresa Frisan
Cells 2020, 9(7), 1747; https://doi.org/10.3390/cells9071747 - 21 Jul 2020
Cited by 25 | Viewed by 5948
Abstract
Damage to our genomes triggers cellular senescence characterised by stable cell cycle arrest and a pro-inflammatory secretome that prevents the unrestricted growth of cells with pathological potential. In this way, senescence can be considered a powerful innate defence against cancer and viral infection. [...] Read more.
Damage to our genomes triggers cellular senescence characterised by stable cell cycle arrest and a pro-inflammatory secretome that prevents the unrestricted growth of cells with pathological potential. In this way, senescence can be considered a powerful innate defence against cancer and viral infection. However, damage accumulated during ageing increases the number of senescent cells and this contributes to the chronic inflammation and deregulation of the immune function, which increases susceptibility to infectious disease in ageing organisms. Bacterial and viral pathogens are masters of exploiting weak points to establish infection and cause devastating diseases. This review considers the emerging importance of senescence in the host–pathogen interaction: we discuss the pathogen exploitation of ageing cells and senescence as a novel hijack target of bacterial pathogens that deploys senescence-inducing toxins to promote infection. The persistent induction of senescence by pathogens, mediated directly through virulence determinants or indirectly through inflammation and chronic infection, also contributes to age-related pathologies such as cancer. This review highlights the dichotomous role of senescence in infection: an innate defence that is exploited by pathogens to cause disease. Full article
(This article belongs to the Special Issue The DNA Damage Response in Cell Physiology and Disease)
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