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Role of ATM and MRE11 in Genomic Stability and Oxidative...
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Role of ATM and MRE11 in Genomic Stability and Oxidative Stress Responses

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 August 2022) | Viewed by 51410

Special Issue Editors

Dr. Junya Kobayashi

E-Mail Website
Guest Editor
Department of Radiological Sciences, School of Health Sciences at Narita, International University of Health and Welfare, Chiba 286-8686, Japan
Interests: oxidative stress; genomic instability; neurodegeneration; cell cycle checkpoint; DNA repair
Dr. Qiu-Mei Zhang-Akiyama

E-Mail Website
Guest Editor
Department of Zoology, Division of Biological Science, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
Interests: oxidative stress; genomic instability; DNA repair; radiation biology; stress response

Special Issue Information

Dear Colleagues,

Genetic disorders, which are defective in ATM or MRE11, are categorized in radiation-hypersensitive disease and show similar cellular phenotypes, such as radioresistant DNA synthesis and chromosome instability, as well as radiation hypersensitivity. Many studies in the last few decades, have identified ATM and MRE11 as critical players in the maintenance of genomic stability against various types of DNA damages, including radiation-induced DNA double-strand break (DSB) and replication stress. The ATM gene product shows protein kinase activity, which is activated in response to oxidative stress as well as generation of DSB damages. Such an activity upon oxidative stress is suggested to play a role in repressing neurodegeneration.

In this Special Issue, we welcome reviews and original articles covering many aspects of the role of ATM, MRE11, and related factors (ATR, NBS1, RAD50, etc.) in maintaining genomic stability or resisting oxidative stress. We also welcome reviews or original articles providing the clues to solve the mechanisms of pathogenesis in these genetic disorders. We look forward to your contribution.

Dr. Junya Kobayashi
Dr. Qiu-Mei Zhang-Akiyama
Guest Editors

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Keywords

  • genomic instability
  • oxidative stress
  • DNA repair
  • cell cycle checkpoint
  • neurodegeneration
  • radiation
  • DNA damage responses
  • replication stress
  • genetic disorder

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Published Papers (11 papers)

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11 pages, 2355 KiB  
Article
Isorhamnetin Promotes 53BP1 Recruitment through the Enhancement of ATM Phosphorylation and Protects Mice from Radiation Gastrointestinal Syndrome
by Yuichi Nishiyama, Akinori Morita, Shogo Tatsuta, Misaki Kanamaru, Masahiro Sakaue, Kenta Ueda, Manami Shono, Rie Fujita, Bing Wang, Yoshio Hosoi, Shin Aoki and Takeshi Sugai
Genes 2021, 12(10), 1514; https://doi.org/10.3390/genes12101514 - 26 Sep 2021
Cited by 5 | Viewed by 2733
Abstract
Flavonoids are a subclass of polyphenols which are attractive, due to possessing various physiological activities, including a radioprotective effect. Tumor suppressor p53 is a primary regulator in the radiation response and is involved in the pathogenesis of radiation injuries. In this study, we [...] Read more.
Flavonoids are a subclass of polyphenols which are attractive, due to possessing various physiological activities, including a radioprotective effect. Tumor suppressor p53 is a primary regulator in the radiation response and is involved in the pathogenesis of radiation injuries. In this study, we revealed that isorhamnetin inhibited radiation cell death, and investigated its action mechanism focusing on DNA damage response. Although isorhamnetin moderated p53 activity, it promoted phosphorylation of ataxia telangiectasia mutated (ATM) and enhanced 53BP1 recruitment in irradiated cells. The radioprotective effect of isorhamnetin was not observed in the presence of ATM inhibitor, indicating that its protective effect was dependent on ATM. Furthermore, isorhamnetin-treated mice survived gastrointestinal death caused by a lethal dose of abdominal irradiation. These findings suggested that isorhamnetin enhances the ATM-dependent DNA repair process, which is presumably associated with the suppressive effect against GI syndrome. Full article
(This article belongs to the Special Issue Role of ATM and MRE11 in Genomic Stability and Oxidative Stress Responses)
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Review

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8 pages, 981 KiB  
Review
Regulation of the Fanconi Anemia DNA Repair Pathway by Phosphorylation and Monoubiquitination
by Masamichi Ishiai
Genes 2021, 12(11), 1763; https://doi.org/10.3390/genes12111763 - 5 Nov 2021
Cited by 9 | Viewed by 3052
Abstract
The Fanconi anemia (FA) DNA repair pathway coordinates a faithful repair mechanism for stalled DNA replication forks caused by factors such as DNA interstrand crosslinks (ICLs) or replication stress. An important role of FA pathway activation is initiated by monoubiquitination of FANCD2 and [...] Read more.
The Fanconi anemia (FA) DNA repair pathway coordinates a faithful repair mechanism for stalled DNA replication forks caused by factors such as DNA interstrand crosslinks (ICLs) or replication stress. An important role of FA pathway activation is initiated by monoubiquitination of FANCD2 and its binding partner of FANCI, which is regulated by the ATM-related kinase, ATR. Therefore, regulation of the FA pathway is a good example of the contribution of ATR to genome stability. In this short review, we summarize the knowledge accumulated over the years regarding how the FA pathway is activated via phosphorylation and monoubiquitination. Full article
(This article belongs to the Special Issue Role of ATM and MRE11 in Genomic Stability and Oxidative Stress Responses)
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11 pages, 1329 KiB  
Review
Cell Death and Survival Pathways Involving ATM Protein Kinase
by Toshihiko Aki and Koichi Uemura
Genes 2021, 12(10), 1581; https://doi.org/10.3390/genes12101581 - 7 Oct 2021
Cited by 18 | Viewed by 3816
Abstract
Cell death is the ultimate form of cellular dysfunction, and is induced by a wide range of stresses including genotoxic stresses. During genotoxic stress, two opposite cellular reactions, cellular protection through DNA repair and elimination of damaged cells by the induction of cell [...] Read more.
Cell death is the ultimate form of cellular dysfunction, and is induced by a wide range of stresses including genotoxic stresses. During genotoxic stress, two opposite cellular reactions, cellular protection through DNA repair and elimination of damaged cells by the induction of cell death, can occur in both separate and simultaneous manners. ATM (ataxia telangiectasia mutated) kinase (hereafter referred to as ATM) is a protein kinase that plays central roles in the induction of cell death during genotoxic stresses. It has long been considered that ATM mediates DNA damage-induced cell death through inducing apoptosis. However, recent research progress in cell death modality is now revealing ATM-dependent cell death pathways that consist of not only apoptosis but also necroptosis, ferroptosis, and dysfunction of autophagy, a cellular survival mechanism. In this short review, we intend to provide a brief outline of cell death mechanisms in which ATM is involved, with emphasis on pathways other than apoptosis. Full article
(This article belongs to the Special Issue Role of ATM and MRE11 in Genomic Stability and Oxidative Stress Responses)
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13 pages, 2015 KiB  
Review
ATM’s Role in the Repair of DNA Double-Strand Breaks
by Atsushi Shibata and Penny A. Jeggo
Genes 2021, 12(9), 1370; https://doi.org/10.3390/genes12091370 - 31 Aug 2021
Cited by 51 | Viewed by 5747
Abstract
Ataxia telangiectasia mutated (ATM) is a central kinase that activates an extensive network of responses to cellular stress via a signaling role. ATM is activated by DNA double strand breaks (DSBs) and by oxidative stress, subsequently phosphorylating a plethora of target proteins. In [...] Read more.
Ataxia telangiectasia mutated (ATM) is a central kinase that activates an extensive network of responses to cellular stress via a signaling role. ATM is activated by DNA double strand breaks (DSBs) and by oxidative stress, subsequently phosphorylating a plethora of target proteins. In the last several decades, newly developed molecular biological techniques have uncovered multiple roles of ATM in response to DNA damage—e.g., DSB repair, cell cycle checkpoint arrest, apoptosis, and transcription arrest. Combinational dysfunction of these stress responses impairs the accuracy of repair, consequently leading to dramatic sensitivity to ionizing radiation (IR) in ataxia telangiectasia (A-T) cells. In this review, we summarize the roles of ATM that focus on DSB repair. Full article
(This article belongs to the Special Issue Role of ATM and MRE11 in Genomic Stability and Oxidative Stress Responses)
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17 pages, 743 KiB  
Review
Mechanisms Underlying the Suppression of Chromosome Rearrangements by Ataxia-Telangiectasia Mutated
by Motohiro Yamauchi
Genes 2021, 12(8), 1232; https://doi.org/10.3390/genes12081232 - 10 Aug 2021
Cited by 5 | Viewed by 4295
Abstract
Chromosome rearrangements are structural variations in chromosomes, such as inversions and translocations. Chromosome rearrangements have been implicated in a variety of human diseases. Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by a broad range of clinical and cellular phenotypes. At the cellular [...] Read more.
Chromosome rearrangements are structural variations in chromosomes, such as inversions and translocations. Chromosome rearrangements have been implicated in a variety of human diseases. Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by a broad range of clinical and cellular phenotypes. At the cellular level, one of the most prominent features of A-T cells is chromosome rearrangement, especially that in T lymphocytes. The gene that is defective in A-T is ataxia-telangiectasia mutated (ATM). The ATM protein is a serine/threonine kinase and plays a central role in the cellular response to DNA damage, particularly DNA double-strand breaks. In this review, the mechanisms by which ATM suppresses chromosome rearrangements are discussed. Full article
(This article belongs to the Special Issue Role of ATM and MRE11 in Genomic Stability and Oxidative Stress Responses)
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19 pages, 2568 KiB  
Review
Post-Translational Modification of MRE11: Its Implication in DDR and Diseases
by Ruiqing Lu, Han Zhang, Yi-Nan Jiang, Zhao-Qi Wang, Litao Sun and Zhong-Wei Zhou
Genes 2021, 12(8), 1158; https://doi.org/10.3390/genes12081158 - 28 Jul 2021
Cited by 12 | Viewed by 4632
Abstract
Maintaining genomic stability is vital for cells as well as individual organisms. The meiotic recombination-related gene MRE11 (meiotic recombination 11) is essential for preserving genomic stability through its important roles in the resection of broken DNA ends, DNA damage response (DDR), DNA double-strand [...] Read more.
Maintaining genomic stability is vital for cells as well as individual organisms. The meiotic recombination-related gene MRE11 (meiotic recombination 11) is essential for preserving genomic stability through its important roles in the resection of broken DNA ends, DNA damage response (DDR), DNA double-strand breaks (DSBs) repair, and telomere maintenance. The post-translational modifications (PTMs), such as phosphorylation, ubiquitination, and methylation, regulate directly the function of MRE11 and endow MRE11 with capabilities to respond to cellular processes in promptly, precisely, and with more diversified manners. Here in this paper, we focus primarily on the PTMs of MRE11 and their roles in DNA response and repair, maintenance of genomic stability, as well as their association with diseases such as cancer. Full article
(This article belongs to the Special Issue Role of ATM and MRE11 in Genomic Stability and Oxidative Stress Responses)
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26 pages, 1980 KiB  
Review
DNA-Dependent Protein Kinase Catalytic Subunit: The Sensor for DNA Double-Strand Breaks Structurally and Functionally Related to Ataxia Telangiectasia Mutated
by Yoshihisa Matsumoto, Anie Day D. C. Asa, Chaity Modak and Mikio Shimada
Genes 2021, 12(8), 1143; https://doi.org/10.3390/genes12081143 - 27 Jul 2021
Cited by 14 | Viewed by 4065
Abstract
The DNA-dependent protein kinase (DNA-PK) is composed of a DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and Ku70/Ku80 heterodimer. DNA-PK is thought to act as the “sensor” for DNA double-stranded breaks (DSB), which are considered the most deleterious type of DNA damage. In particular, [...] Read more.
The DNA-dependent protein kinase (DNA-PK) is composed of a DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and Ku70/Ku80 heterodimer. DNA-PK is thought to act as the “sensor” for DNA double-stranded breaks (DSB), which are considered the most deleterious type of DNA damage. In particular, DNA-PKcs and Ku are shown to be essential for DSB repair through nonhomologous end joining (NHEJ). The phenotypes of animals and human individuals with defective DNA-PKcs or Ku functions indicate their essential roles in these developments, especially in neuronal and immune systems. DNA-PKcs are structurally related to Ataxia–telangiectasia mutated (ATM), which is also implicated in the cellular responses to DSBs. DNA-PKcs and ATM constitute the phosphatidylinositol 3-kinase-like kinases (PIKKs) family with several other molecules. Here, we review the accumulated knowledge on the functions of DNA-PKcs, mainly based on the phenotypes of DNA-PKcs-deficient cells in animals and human individuals, and also discuss its relationship with ATM in the maintenance of genomic stability. Full article
(This article belongs to the Special Issue Role of ATM and MRE11 in Genomic Stability and Oxidative Stress Responses)
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9 pages, 978 KiB  
Review
Autophosphorylation and Self-Activation of DNA-Dependent Protein Kinase
by Aya Kurosawa
Genes 2021, 12(7), 1091; https://doi.org/10.3390/genes12071091 - 19 Jul 2021
Cited by 5 | Viewed by 3567
Abstract
The DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a member of the phosphatidylinositol 3-kinase-related kinase family, phosphorylates serine and threonine residues of substrate proteins in the presence of the Ku complex and double-stranded DNA. Although it has been established that DNA-PKcs is involved in [...] Read more.
The DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a member of the phosphatidylinositol 3-kinase-related kinase family, phosphorylates serine and threonine residues of substrate proteins in the presence of the Ku complex and double-stranded DNA. Although it has been established that DNA-PKcs is involved in non-homologous end-joining, a DNA double-strand break repair pathway, the mechanisms underlying DNA-PKcs activation are not fully understood. Nevertheless, the findings of numerous in vitro and in vivo studies have indicated that DNA-PKcs contains two autophosphorylation clusters, PQR and ABCDE, as well as several autophosphorylation sites and conformational changes associated with autophosphorylation of DNA-PKcs are important for self-activation. Consistent with these features, an analysis of transgenic mice has shown that the phenotypes of DNA-PKcs autophosphorylation mutations are significantly different from those of DNA-PKcs kinase-dead mutations, thereby indicating the importance of DNA-PKcs autophosphorylation in differentiation and development. Furthermore, there has been notable progress in the high-resolution analysis of the conformation of DNA-PKcs, which has enabled us to gain a visual insight into the steps leading to DNA-PKcs activation. This review summarizes the current progress in the activation of DNA-PKcs, focusing in particular on autophosphorylation of this kinase. Full article
(This article belongs to the Special Issue Role of ATM and MRE11 in Genomic Stability and Oxidative Stress Responses)
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8 pages, 422 KiB  
Review
ATM-Mediated Mitochondrial Radiation Responses of Human Fibroblasts
by Tsutomu Shimura
Genes 2021, 12(7), 1015; https://doi.org/10.3390/genes12071015 - 30 Jun 2021
Cited by 14 | Viewed by 3253
Abstract
Ataxia telangiectasia (AT) is characterized by extreme sensitivity to ionizing radiation. The gene mutated in AT, Ataxia Telangiectasia Mutated (ATM), has serine/threonine protein kinase activity and mediates the activation of multiple signal transduction pathways involved in the processing of DNA double-strand breaks. Reactive [...] Read more.
Ataxia telangiectasia (AT) is characterized by extreme sensitivity to ionizing radiation. The gene mutated in AT, Ataxia Telangiectasia Mutated (ATM), has serine/threonine protein kinase activity and mediates the activation of multiple signal transduction pathways involved in the processing of DNA double-strand breaks. Reactive oxygen species (ROS) created as a byproduct of the mitochondria’s oxidative phosphorylation (OXPHOS) has been proposed to be the source of intracellular ROS. Mitochondria are uniquely vulnerable to ROS because they are the sites of ROS generation. ROS-induced mitochondrial mutations lead to impaired mitochondrial respiration and further increase the likelihood of ROS generation, establishing a vicious cycle of further ROS production and mitochondrial damage. AT patients and ATM-deficient mice display intrinsic mitochondrial dysfunction and exhibit constitutive elevations in ROS levels. ATM plays a critical role in maintaining cellular redox homeostasis. However, the precise mechanism of ATM-mediated mitochondrial antioxidants remains unclear. The aim of this review paper is to introduce our current research surrounding the role of ATM on maintaining cellular redox control in human fibroblasts. ATM-mediated signal transduction is important in the mitochondrial radiation response. Perturbation of mitochondrial redox control elevates ROS which are key mediators in the development of cancer by many mechanisms, including ROS-mediated genomic instability, tumor microenvironment formation, and chronic inflammation. Full article
(This article belongs to the Special Issue Role of ATM and MRE11 in Genomic Stability and Oxidative Stress Responses)
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14 pages, 2511 KiB  
Review
Role of Histone Methylation in Maintenance of Genome Integrity
by Arjamand Mushtaq, Ulfat Syed Mir, Clayton R. Hunt, Shruti Pandita, Wajahat W. Tantray, Audesh Bhat, Raj K. Pandita, Mohammad Altaf and Tej K. Pandita
Genes 2021, 12(7), 1000; https://doi.org/10.3390/genes12071000 - 29 Jun 2021
Cited by 18 | Viewed by 4878
Abstract
Packaging of the eukaryotic genome with histone and other proteins forms a chromatin structure that regulates the outcome of all DNA mediated processes. The cellular pathways that ensure genomic stability detect and repair DNA damage through mechanisms that are critically dependent upon chromatin [...] Read more.
Packaging of the eukaryotic genome with histone and other proteins forms a chromatin structure that regulates the outcome of all DNA mediated processes. The cellular pathways that ensure genomic stability detect and repair DNA damage through mechanisms that are critically dependent upon chromatin structures established by histones and, particularly upon transient histone post-translational modifications. Though subjected to a range of modifications, histone methylation is especially crucial for DNA damage repair, as the methylated histones often form platforms for subsequent repair protein binding at damaged sites. In this review, we highlight and discuss how histone methylation impacts the maintenance of genome integrity through effects related to DNA repair and repair pathway choice. Full article
(This article belongs to the Special Issue Role of ATM and MRE11 in Genomic Stability and Oxidative Stress Responses)
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11 pages, 1092 KiB  
Review
ATM: Main Features, Signaling Pathways, and Its Diverse Roles in DNA Damage Response, Tumor Suppression, and Cancer Development
by Liem Minh Phan and Abdol-Hossein Rezaeian
Genes 2021, 12(6), 845; https://doi.org/10.3390/genes12060845 - 30 May 2021
Cited by 43 | Viewed by 9097
Abstract
ATM is among of the most critical initiators and coordinators of the DNA-damage response. ATM canonical and non-canonical signaling pathways involve hundreds of downstream targets that control many important cellular processes such as DNA damage repair, apoptosis, cell cycle arrest, metabolism, proliferation, oxidative [...] Read more.
ATM is among of the most critical initiators and coordinators of the DNA-damage response. ATM canonical and non-canonical signaling pathways involve hundreds of downstream targets that control many important cellular processes such as DNA damage repair, apoptosis, cell cycle arrest, metabolism, proliferation, oxidative sensing, among others. Of note, ATM is often considered a major tumor suppressor because of its ability to induce apoptosis and cell cycle arrest. However, in some advanced stage tumor cells, ATM signaling is increased and confers remarkable advantages for cancer cell survival, resistance to radiation and chemotherapy, biosynthesis, proliferation, and metastasis. This review focuses on addressing major characteristics, signaling pathways and especially the diverse roles of ATM in cellular homeostasis and cancer development. Full article
(This article belongs to the Special Issue Role of ATM and MRE11 in Genomic Stability and Oxidative Stress Responses)
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