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Special Issue "Mechanisms Leading to Genomic Instability"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 May 2017).

Special Issue Editors

Guest Editor
Prof. Dr. Vassilis G. Gorgoulis Website E-Mail
Laboratory of Histology-Embryology, Faculty of Medicine, National & Kapodistrian University of Athens, 75 Mikras Asias Str, Goudi, Athens, 115 27, Greece
Interests: DNA damage and response; replication licensing; DNA repair mechanisms; genomic instability; antitumor barriers
Co-Guest Editor
Dr. Athanassios Kotsinas Website E-Mail
Laboratory of Histology-Embryology, Faculty of Medicine, National & Kapodistrian University of Athens, 75 Mikras Asias Str, Goudi, Athens, 115 27, Greece
Interests: DNA polymorphisms, RNA, miRNAs, carcinogenesis, bioinformatics
Co-Guest Editor
Prof. Dr. Alexandros G. Georgakilas Website E-Mail
DNA Damage Laboratory, Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens, Zografou Campus, 15780 Athens, Greece
Interests: radiation biology; cancer biology; DNA damage and repair; oxidative stress; Carcinogenesis; bioinformatics; systems biology
Co-Guest Editor
Dr. Ioannis Trougakos E-Mail
Department of Cell Biology & Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Zografou, Athens 15784, Greece
Guest Editor
Prof. Dr. Aristides Eliopoulos Website E-Mail
Molecular & Cellular Biology Laboratory, University of Crete Medical School, and Institute of Molecular Biology & Biotechnology, 71003 Heraklion, Crete, Greece
Interests: cancer signaling, inflammatory control of cancer

Special Issue Information

Dear Colleagues,

Disruption of genome maintenance (genomic instability) can occur through a variety of mechanisms, linking it with an expanding range of facets exhibited by cancer cells. Genomic instability is now considered a key hallmark of cancer.

This Special Issue of the International Journal of Molecular Sciences will focus on recent “Mechanisms Leading to Genomic Instability”, in order to provide new and critical insights, as well as updates on mechanisms of DNA damage, repair, and pathophysiological consequences. Furthermore, the link between genomic instability with various responses and adaptations elicited by cancer cells, like activation of antitumor-barriers (apoptosis and senescence), autophagy, ribosomal stress, immune response, proteostasis, and metabolism, will be presented.

Manuscripts covering the above range of themes are welcome for submission.

Prof. Dr. Vassilis G. Gorgoulis
Guest Editor

Dr. Athanassios Kotsinas
Dr. Alexandros Georgakilas
Dr. Ioannis Trougakos
Prof. Dr. Aristides Eliopoulos
Co-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 papers will be 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 damage and repair
  • DNA replication
  • Genomic instability
  • Apoptosis
  • Senescence
  • Autophagy
  • Ribosomal Stress
  • Immune response
  • Proteostasis, Metabolism

Published Papers (19 papers)

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Research

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Open AccessArticle
Combined Virtual and Experimental Screening for CK1 Inhibitors Identifies a Modulator of p53 and Reveals Important Aspects of in Silico Screening Performance
Int. J. Mol. Sci. 2017, 18(10), 2102; https://doi.org/10.3390/ijms18102102 - 06 Oct 2017
Cited by 3
Abstract
A compound collection of pronounced structural diversity was comprehensively screened for inhibitors of the DNA damage-related kinase CK1. The collection was evaluated in vitro. A potent and selective CK1 inhibitor was discovered and its capacity to modulate the endogenous levels of the CK1-regulated [...] Read more.
A compound collection of pronounced structural diversity was comprehensively screened for inhibitors of the DNA damage-related kinase CK1. The collection was evaluated in vitro. A potent and selective CK1 inhibitor was discovered and its capacity to modulate the endogenous levels of the CK1-regulated tumor suppressor p53 was demonstrated in cancer cell lines. Administration of 10 μM of the compound resulted in significant increase of p53 levels, reaching almost 2-fold in hepatocellular carcinoma cells. In parallel to experimental screening, two representative and orthogonal in silico screening methodologies were implemented for enabling the retrospective assessment of virtual screening performance on a case-specific basis. Results showed that both techniques performed at an acceptable and fairly comparable level, with a slight advantage of the structure-based over the ligand-based approach. However, both approaches demonstrated notable sensitivity upon parameters such as screening template choice and treatment of redundancy in the enumerated compound collection. An effort to combine insight derived by sequential implementation of the two methods afforded poor further improvement of screening performance. Overall, the presented assessment highlights the relation between improper use of enrichment metrics and misleading results, and demonstrates the inherent delicacy of in silico methods, emphasizing the challenging character of virtual screening protocol optimization. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessArticle
Applying Broadband Dielectric Spectroscopy (BDS) for the Biophysical Characterization of Mammalian Tissues under a Variety of Cellular Stresses
Int. J. Mol. Sci. 2017, 18(4), 838; https://doi.org/10.3390/ijms18040838 - 15 Apr 2017
Cited by 1
Abstract
The dielectric properties of biological tissues can contribute non-invasively to a better characterization and understanding of the structural properties and physiology of living organisms. The question we asked, is whether these induced changes are effected by an endogenous or exogenous cellular stress, and [...] Read more.
The dielectric properties of biological tissues can contribute non-invasively to a better characterization and understanding of the structural properties and physiology of living organisms. The question we asked, is whether these induced changes are effected by an endogenous or exogenous cellular stress, and can they be detected non-invasively in the form of a dielectric response, e.g., an AC conductivity switch in the broadband frequency spectrum. This study constitutes the first methodological approach for the detection of environmental stress-induced damage in mammalian tissues by the means of broadband dielectric spectroscopy (BDS) at the frequencies of 1–106 Hz. Firstly, we used non-ionizing (NIR) and ionizing radiation (IR) as a typical environmental stress. Specifically, rats were exposed to either digital enhanced cordless telecommunication (DECT) radio frequency electromagnetic radiation or to γ-radiation, respectively. The other type of stress, characterized usually by high genomic instability, was the pathophysiological state of human cancer (lung and prostate). Analyzing the results of isothermal dielectric measurements provided information on the tissues’ water fraction. In most cases, our methodology proved sufficient in detecting structural changes, especially in the case of IR and malignancy. Useful specific dielectric response patterns are detected and correlated with each type of stress. Our results point towards the development of a dielectric-based methodology for better understanding and, in a relatively invasive way, the biological and structural changes effected by radiation and developing lung or prostate cancer often associated with genomic instability. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Review

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Open AccessReview
G2/M-Phase Checkpoint Adaptation and Micronuclei Formation as Mechanisms That Contribute to Genomic Instability in Human Cells
Int. J. Mol. Sci. 2017, 18(11), 2344; https://doi.org/10.3390/ijms18112344 - 06 Nov 2017
Cited by 11
Abstract
One of the most common characteristics of cancer cells is genomic instability. Recent research has revealed that G2/M-phase checkpoint adaptation—entering mitosis with damaged DNA—contributes to genomic changes in experimental models. When cancer cells are treated with pharmacological concentrations of genotoxic agents, they undergo [...] Read more.
One of the most common characteristics of cancer cells is genomic instability. Recent research has revealed that G2/M-phase checkpoint adaptation—entering mitosis with damaged DNA—contributes to genomic changes in experimental models. When cancer cells are treated with pharmacological concentrations of genotoxic agents, they undergo checkpoint adaptation; however, a small number of cells are able to survive and accumulate micronuclei. These micronuclei harbour damaged DNA, and are able to replicate and reincorporate their DNA into the main nucleus. Micronuclei are susceptible to chromothripsis, which is a phenomenon characterised by extensively rearranged chromosomes that reassemble from pulverized chromosomes in one cellular event. These processes contribute to genomic instability in cancer cells that survive a genotoxic anti-cancer treatment. This review provides insight into checkpoint adaptation and its connection to micronuclei and possibly chromothripsis. Knowledge about these mechanisms is needed to improve the poor cancer treatment outcomes that result from genomic instability. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessReview
Omics Approaches for Identifying Physiological Adaptations to Genome Instability in Aging
Int. J. Mol. Sci. 2017, 18(11), 2329; https://doi.org/10.3390/ijms18112329 - 04 Nov 2017
Cited by 2
Abstract
DNA damage causally contributes to aging and age-related diseases. The declining functioning of tissues and organs during aging can lead to the increased risk of succumbing to aging-associated diseases. Congenital syndromes that are caused by heritable mutations in DNA repair pathways lead to [...] Read more.
DNA damage causally contributes to aging and age-related diseases. The declining functioning of tissues and organs during aging can lead to the increased risk of succumbing to aging-associated diseases. Congenital syndromes that are caused by heritable mutations in DNA repair pathways lead to cancer susceptibility and accelerated aging, thus underlining the importance of genome maintenance for withstanding aging. High-throughput mass-spectrometry-based approaches have recently contributed to identifying signalling response networks and gaining a more comprehensive understanding of the physiological adaptations occurring upon unrepaired DNA damage. The insulin-like signalling pathway has been implicated in a DNA damage response (DDR) network that includes epidermal growth factor (EGF)-, AMP-activated protein kinases (AMPK)- and the target of rapamycin (TOR)-like signalling pathways, which are known regulators of growth, metabolism, and stress responses. The same pathways, together with the autophagy-mediated proteostatic response and the decline in energy metabolism have also been found to be similarly regulated during natural aging, suggesting striking parallels in the physiological adaptation upon persistent DNA damage due to DNA repair defects and long-term low-level DNA damage accumulation occurring during natural aging. These insights will be an important starting point to study the interplay between signalling networks involved in progeroid syndromes that are caused by DNA repair deficiencies and to gain new understanding of the consequences of DNA damage in the aging process. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessReview
The Role of MDM2 in Promoting Genome Stability versus Instability
Int. J. Mol. Sci. 2017, 18(10), 2216; https://doi.org/10.3390/ijms18102216 - 23 Oct 2017
Cited by 8
Abstract
In cancer, the mouse double minute 2 (MDM2) is an oncoprotein that contributes to the promotion of cell growth, survival, invasion, and therapeutic resistance. The impact of MDM2 on cell survival versus cell death is complex and dependent on levels of MDM2 isoforms, [...] Read more.
In cancer, the mouse double minute 2 (MDM2) is an oncoprotein that contributes to the promotion of cell growth, survival, invasion, and therapeutic resistance. The impact of MDM2 on cell survival versus cell death is complex and dependent on levels of MDM2 isoforms, p53 status, and cellular context. Extensive investigations have demonstrated that MDM2 protein–protein interactions with p53 and other p53 family members (p63 and p73) block their ability to function as transcription factors that regulate cell growth and survival. Upon genotoxic insults, a dynamic and intricately regulated DNA damage response circuitry is activated leading to release of p53 from MDM2 and activation of cell cycle arrest. What ensues following DNA damage, depends on the extent of DNA damage and if the cell has sufficient DNA repair capacity. The well-known auto-regulatory loop between p53-MDM2 provides an additional layer of control as the cell either repairs DNA damage and survives (i.e., MDM2 re-engages with p53), or undergoes cell death (i.e., MDM2 does not re-engage p53). Furthermore, the decision to live or die is also influenced by chromatin-localized MDM2 which directly interacts with the Mre11-Rad50-Nbs1 complex and inhibits DNA damage-sensing giving rise to the potential for increased genome instability and cellular transformation. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessReview
Proteome Stability as a Key Factor of Genome Integrity
Int. J. Mol. Sci. 2017, 18(10), 2036; https://doi.org/10.3390/ijms18102036 - 22 Sep 2017
Cited by 8
Abstract
DNA damage is constantly produced by both endogenous and exogenous factors; DNA lesions then trigger the so-called DNA damaged response (DDR). This is a highly synchronized pathway that involves recognition, signaling and repair of the damage. Failure to eliminate DNA lesions is associated [...] Read more.
DNA damage is constantly produced by both endogenous and exogenous factors; DNA lesions then trigger the so-called DNA damaged response (DDR). This is a highly synchronized pathway that involves recognition, signaling and repair of the damage. Failure to eliminate DNA lesions is associated with genome instability, a driving force in tumorigenesis. Proteins carry out the vast majority of cellular functions and thus proteome quality control (PQC) is critical for the maintenance of cellular functionality. PQC is assured by the proteostasis network (PN), which under conditions of proteome instability address the triage decision of protein fold, hold, or degrade. Key components of the PN are the protein synthesis modules, the molecular chaperones and the two main degradation machineries, namely the autophagy-lysosome and the ubiquitin-proteasome pathways; also, part of the PN are a number of stress-responsive cellular sensors including (among others) heat shock factor 1 (Hsf1) and the nuclear factor erythroid 2-related factor 2 (Nrf2). Nevertheless, the lifestyle- and/or ageing-associated gradual accumulation of stressors results in increasingly damaged and unstable proteome due to accumulation of misfolded proteins and/or protein aggregates. This outcome may then increase genomic instability due to reduced fidelity in processes like DNA replication or repair leading to various age-related diseases including cancer. Herein, we review the role of proteostatic machineries in nuclear genome integrity and stability, as well as on DDR responses. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessReview
Genome Instability and γH2AX
Int. J. Mol. Sci. 2017, 18(9), 1979; https://doi.org/10.3390/ijms18091979 - 15 Sep 2017
Cited by 17
Abstract
γH2AX has emerged in the last 20 years as a central player in the DDR (DNA damage response), with specificity for DSBs (double-strand breaks). Upon the generation of DSBs, γ-phosphorylation extends along megabase-long domains in chromatin, both sides of the damage. The significance [...] Read more.
γH2AX has emerged in the last 20 years as a central player in the DDR (DNA damage response), with specificity for DSBs (double-strand breaks). Upon the generation of DSBs, γ-phosphorylation extends along megabase-long domains in chromatin, both sides of the damage. The significance of this mechanism is of great importance; it depicts a biological amplification mechanism where one DSB induces the γ-phosphorylation of thousands of H2AX molecules along megabaselong domains of chromatin, that are adjusted to the sites of DSBs. A sequential recruitment of signal transduction factors that interact to each other and become activated to further amplify the signal that will travel to the cytoplasm take place on the γ-phosphorylated chromatin. γ-phosphorylation is an early event in the DSB damage response, induced in all phases of the cell cycle, and participates in both DSB repair pathways, the HR (homologous recombination) and NHEJ (non-homologous end joining). Today, numerous studies support the notion that γH2AX functions as a guardian of the genome by preventing misrepaired DSB that increase the mutation load of the cells and may further lead to genome instability and carcinogenesis. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessReview
Principal Aspects Regarding the Maintenance of Mammalian Mitochondrial Genome Integrity
Int. J. Mol. Sci. 2017, 18(8), 1821; https://doi.org/10.3390/ijms18081821 - 22 Aug 2017
Cited by 5
Abstract
Mitochondria have emerged as key players regarding cellular homeostasis not only due to their contribution regarding energy production through oxidative phosphorylation, but also due to their involvement in signaling, ion regulation, and programmed cell death. Indeed, current knowledge supports the notion that mitochondrial [...] Read more.
Mitochondria have emerged as key players regarding cellular homeostasis not only due to their contribution regarding energy production through oxidative phosphorylation, but also due to their involvement in signaling, ion regulation, and programmed cell death. Indeed, current knowledge supports the notion that mitochondrial dysfunction is a hallmark in the pathogenesis of various diseases. Mitochondrial biogenesis and function require the coordinated action of two genomes: nuclear and mitochondrial. Unfortunately, both intrinsic and environmental genotoxic insults constantly threaten the integrity of nuclear as well as mitochondrial DNA. Despite the extensive research that has been made regarding nuclear genome instability, the importance of mitochondrial genome integrity has only recently begun to be elucidated. The specific architecture and repair mechanisms of mitochondrial DNA, as well as the dynamic behavior that mitochondria exert regarding fusion, fission, and autophagy participate in mitochondrial genome stability, and therefore, cell homeostasis. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessReview
Crosstalk between DNA Damage and Inflammation in the Multiple Steps of Carcinogenesis
Int. J. Mol. Sci. 2017, 18(8), 1808; https://doi.org/10.3390/ijms18081808 - 19 Aug 2017
Cited by 29
Abstract
Inflammation can be induced by chronic infection, inflammatory diseases and physicochemical factors. Chronic inflammation is estimated to contribute to approximately 25% of human cancers. Under inflammatory conditions, inflammatory and epithelial cells release reactive oxygen (ROS) and nitrogen species (RNS), which are capable of [...] Read more.
Inflammation can be induced by chronic infection, inflammatory diseases and physicochemical factors. Chronic inflammation is estimated to contribute to approximately 25% of human cancers. Under inflammatory conditions, inflammatory and epithelial cells release reactive oxygen (ROS) and nitrogen species (RNS), which are capable of causing DNA damage, including the formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine and 8-nitroguanine. We reported that 8-nitroguanine was clearly formed at the sites of cancer induced by infectious agents including Helicobacter pylori, inflammatory diseases including Barrett’s esophagus, and physicochemical factors including asbestos. DNA damage can lead to mutations and genomic instability if not properly repaired. Moreover, DNA damage response can also induce high mobility group box 1-generating inflammatory microenvironment, which is characterized by hypoxia. Hypoxia induces hypoxia-inducible factor and inducible nitric oxide synthase (iNOS), which increases the levels of intracellular RNS and ROS, resulting DNA damage in progression with poor prognosis. Furthermore, tumor-producing inflammation can induce nuclear factor-κB, resulting in iNOS-dependent DNA damage. Therefore, crosstalk between DNA damage and inflammation may play important roles in cancer development. A proposed mechanism for the crosstalk may explain why aspirin decreases the long-term risk of cancer mortality. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessReview
The Retinoblastoma (RB) Tumor Suppressor: Pushing Back against Genome Instability on Multiple Fronts
Int. J. Mol. Sci. 2017, 18(8), 1776; https://doi.org/10.3390/ijms18081776 - 16 Aug 2017
Cited by 12
Abstract
The retinoblastoma (RB) tumor suppressor is known as a master regulator of the cell cycle. RB is mutated or functionally inactivated in the majority of human cancers. This transcriptional regulator exerts its function in cell cycle control through its interaction with the E2F [...] Read more.
The retinoblastoma (RB) tumor suppressor is known as a master regulator of the cell cycle. RB is mutated or functionally inactivated in the majority of human cancers. This transcriptional regulator exerts its function in cell cycle control through its interaction with the E2F family of transcription factors and with chromatin remodelers and modifiers that contribute to the repression of genes important for cell cycle progression. Over the years, studies have shown that RB participates in multiple processes in addition to cell cycle control. Indeed, RB is known to interact with over 200 different proteins and likely exists in multiple complexes. RB, in some cases, acts through its interaction with E2F1, other members of the pocket protein family (p107 and p130), and/or chromatin remodelers and modifiers. RB is a tumor suppressor with important chromatin regulatory functions that affect genomic stability. These functions include the role of RB in DNA repair, telomere maintenance, chromosome condensation and cohesion, and silencing of repetitive regions. In this review we will discuss recent advances in RB biology related to RB, partner proteins, and their non-transcriptional functions fighting back against genomic instability. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessReview
Polycomb Repressor Complex 2 in Genomic Instability and Cancer
Int. J. Mol. Sci. 2017, 18(8), 1657; https://doi.org/10.3390/ijms18081657 - 30 Jul 2017
Cited by 6
Abstract
Polycomb repressor complexes PRC1 and PRC2 regulate chromatin compaction and gene expression, and are widely recognized for their fundamental contributions to developmental processes. Herein, we summarize the existing evidence and molecular mechanisms linking PRC-mediated epigenetic aberrations to genomic instability and malignancy, with a [...] Read more.
Polycomb repressor complexes PRC1 and PRC2 regulate chromatin compaction and gene expression, and are widely recognized for their fundamental contributions to developmental processes. Herein, we summarize the existing evidence and molecular mechanisms linking PRC-mediated epigenetic aberrations to genomic instability and malignancy, with a particular focus on the role of deregulated PRC2 in tumor suppressor gene expression, the DNA damage response, and the fidelity of DNA replication. We also discuss some of the recent advances in the development of pharmacological and dietary interventions affecting PRC2, which point to promising applications for the prevention and management of human malignancies. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessReview
Chromatin Dynamics in Genome Stability: Roles in Suppressing Endogenous DNA Damage and Facilitating DNA Repair
Int. J. Mol. Sci. 2017, 18(7), 1486; https://doi.org/10.3390/ijms18071486 - 10 Jul 2017
Cited by 21
Abstract
Genomic DNA is compacted into chromatin through packaging with histone and non-histone proteins. Importantly, DNA accessibility is dynamically regulated to ensure genome stability. This is exemplified in the response to DNA damage where chromatin relaxation near genomic lesions serves to promote access of [...] Read more.
Genomic DNA is compacted into chromatin through packaging with histone and non-histone proteins. Importantly, DNA accessibility is dynamically regulated to ensure genome stability. This is exemplified in the response to DNA damage where chromatin relaxation near genomic lesions serves to promote access of relevant enzymes to specific DNA regions for signaling and repair. Furthermore, recent data highlight genome maintenance roles of chromatin through the regulation of endogenous DNA-templated processes including transcription and replication. Here, we review research that shows the importance of chromatin structure regulation in maintaining genome integrity by multiple mechanisms including facilitating DNA repair and directly suppressing endogenous DNA damage. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessReview
The Nucleolus: In Genome Maintenance and Repair
Int. J. Mol. Sci. 2017, 18(7), 1411; https://doi.org/10.3390/ijms18071411 - 01 Jul 2017
Cited by 20
Abstract
The nucleolus is the subnuclear membrane-less organelle where rRNA is transcribed and processed and ribosomal assembly occurs. During the last 20 years, however, the nucleolus has emerged as a multifunctional organelle, regulating processes that go well beyond its traditional role. Moreover, the unique [...] Read more.
The nucleolus is the subnuclear membrane-less organelle where rRNA is transcribed and processed and ribosomal assembly occurs. During the last 20 years, however, the nucleolus has emerged as a multifunctional organelle, regulating processes that go well beyond its traditional role. Moreover, the unique organization of rDNA in tandem arrays and its unusually high transcription rates make it prone to unscheduled DNA recombination events and frequent RNA:DNA hybrids leading to DNA double strand breaks (DSBs). If not properly repaired, rDNA damage may contribute to premature disease onset and aging. Deregulation of ribosomal synthesis at any level from transcription and processing to ribosomal subunit assembly elicits a stress response and is also associated with disease onset. Here, we discuss how genome integrity is maintained within nucleoli and how such structures are functionally linked to nuclear DNA damage response and repair giving an emphasis on the newly emerging roles of the nucleolus in mammalian physiology and disease. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessReview
RNA Binding Proteins and Genome Integrity
Int. J. Mol. Sci. 2017, 18(7), 1341; https://doi.org/10.3390/ijms18071341 - 23 Jun 2017
Cited by 11
Abstract
Genome integrity can be threatened by various endogenous or exogenous events. To counteract these stressors, the DNA damage response network contributes to the prevention and/or repair of genomic DNA damage and serves an essential function in cellular survival. DNA binding proteins are involved [...] Read more.
Genome integrity can be threatened by various endogenous or exogenous events. To counteract these stressors, the DNA damage response network contributes to the prevention and/or repair of genomic DNA damage and serves an essential function in cellular survival. DNA binding proteins are involved in this network. Recently, several RNA-binding proteins (RBPs) that are recruited to DNA damage sites have been shown to be direct players in the prevention or repair of DNA damage. In addition, non-coding RNAs, themselves, are involved in the RNA-mediated DNA repair system. Furthermore, RNA modification such as m6A methylation might also contribute to the ultraviolet-responsive DNA damage response. Accumulating evidence suggests that RNA metabolism is more deeply involved in diverse cellular functions than previously expected, and is also intricately associated with the maintenance of genome integrity. In this review, we highlight the roles of RBPs in the maintenance of genome integrity. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessReview
Oncogene-Induced Replication Stress Drives Genome Instability and Tumorigenesis
Int. J. Mol. Sci. 2017, 18(7), 1339; https://doi.org/10.3390/ijms18071339 - 22 Jun 2017
Cited by 9
Abstract
Genomic instability plays a key role in driving cancer development. It is already found in precancerous lesions and allows the acquisition of additional cancerous features. A major source of genomic instability in early stages of tumorigenesis is DNA replication stress. Normally, origin licensing [...] Read more.
Genomic instability plays a key role in driving cancer development. It is already found in precancerous lesions and allows the acquisition of additional cancerous features. A major source of genomic instability in early stages of tumorigenesis is DNA replication stress. Normally, origin licensing and activation, as well as replication fork progression, are tightly regulated to allow faithful duplication of the genome. Aberrant origin usage and/or perturbed replication fork progression leads to DNA damage and genomic instability. Oncogene activation is an endogenous source of replication stress, disrupting replication regulation and inducing DNA damage. Oncogene-induced replication stress and its role in cancer development have been studied comprehensively, however its molecular basis is still unclear. Here, we review the current understanding of replication regulation, its potential disruption and how oncogenes perturb the replication and induce DNA damage leading to genomic instability in cancer. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessReview
Interactive Roles of DNA Helicases and Translocases with the Single-Stranded DNA Binding Protein RPA in Nucleic Acid Metabolism
Int. J. Mol. Sci. 2017, 18(6), 1233; https://doi.org/10.3390/ijms18061233 - 08 Jun 2017
Cited by 6
Abstract
Helicases and translocases use the energy of nucleoside triphosphate binding and hydrolysis to unwind/resolve structured nucleic acids or move along a single-stranded or double-stranded polynucleotide chain, respectively. These molecular motors facilitate a variety of transactions including replication, DNA repair, recombination, and transcription. A [...] Read more.
Helicases and translocases use the energy of nucleoside triphosphate binding and hydrolysis to unwind/resolve structured nucleic acids or move along a single-stranded or double-stranded polynucleotide chain, respectively. These molecular motors facilitate a variety of transactions including replication, DNA repair, recombination, and transcription. A key partner of eukaryotic DNA helicases/translocases is the single-stranded DNA binding protein Replication Protein A (RPA). Biochemical, genetic, and cell biological assays have demonstrated that RPA interacts with these human molecular motors physically and functionally, and their association is enriched in cells undergoing replication stress. The roles of DNA helicases/translocases are orchestrated with RPA in pathways of nucleic acid metabolism. RPA stimulates helicase-catalyzed DNA unwinding, enlists translocases to sites of action, and modulates their activities in DNA repair, fork remodeling, checkpoint activation, and telomere maintenance. The dynamic interplay between DNA helicases/translocases and RPA is just beginning to be understood at the molecular and cellular levels, and there is still much to be learned, which may inform potential therapeutic strategies. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessReview
Perturbations in the Replication Program Contribute to Genomic Instability in Cancer
Int. J. Mol. Sci. 2017, 18(6), 1138; https://doi.org/10.3390/ijms18061138 - 25 May 2017
Cited by 9
Abstract
Cancer and genomic instability are highly impacted by the deoxyribonucleic acid (DNA) replication program. Inaccuracies in DNA replication lead to the increased acquisition of mutations and structural variations. These inaccuracies mainly stem from loss of DNA fidelity due to replication stress or due [...] Read more.
Cancer and genomic instability are highly impacted by the deoxyribonucleic acid (DNA) replication program. Inaccuracies in DNA replication lead to the increased acquisition of mutations and structural variations. These inaccuracies mainly stem from loss of DNA fidelity due to replication stress or due to aberrations in the temporal organization of the replication process. Here we review the mechanisms and impact of these major sources of error to the replication program. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessReview
Cytokinesis Failure Leading to Chromosome Instability in v-Src-Induced Oncogenesis
Int. J. Mol. Sci. 2017, 18(4), 811; https://doi.org/10.3390/ijms18040811 - 12 Apr 2017
Cited by 4
Abstract
v-Src, an oncogene found in Rous sarcoma virus, is a constitutively active variant of c-Src. Activation of Src is observed frequently in colorectal and breast cancers, and is critical in tumor progression through multiple processes. However, in some experimental conditions, v-Src causes growth [...] Read more.
v-Src, an oncogene found in Rous sarcoma virus, is a constitutively active variant of c-Src. Activation of Src is observed frequently in colorectal and breast cancers, and is critical in tumor progression through multiple processes. However, in some experimental conditions, v-Src causes growth suppression and apoptosis. In this review, we highlight recent progress in our understanding of cytokinesis failure and the attenuation of the tetraploidy checkpoint in v-Src-expressing cells. v-Src induces cell cycle changes—such as the accumulation of the 4N cell population—and increases the number of binucleated cells, which is accompanied by an excess number of centrosomes. Time-lapse analysis of v-Src-expressing cells showed that cytokinesis failure is caused by cleavage furrow regression. Microscopic analysis revealed that v-Src induces delocalization of cytokinesis regulators including Aurora B and Mklp1. Tetraploid cell formation is one of the causes of chromosome instability; however, tetraploid cells can be eliminated at the tetraploidy checkpoint. Interestingly, v-Src weakens the tetraploidy checkpoint by inhibiting the nuclear exclusion of the transcription coactivator YAP, which is downstream of the Hippo pathway and its nuclear exclusion is critical in the tetraploidy checkpoint. We also discuss the relationship between v-Src-induced chromosome instability and growth suppression in v-Src-induced oncogenesis. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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Open AccessBrief Report
Monitoring Autophagy Immunohistochemically and Ultrastructurally during Human Head and Neck Carcinogenesis. Relationship with the DNA Damage Response Pathway
Int. J. Mol. Sci. 2017, 18(9), 1920; https://doi.org/10.3390/ijms18091920 - 07 Sep 2017
Cited by 2
Abstract
Autophagy is a catabolic process that preserves cellular homeostasis. Its exact role during carcinogenesis is not completely defined. Specifically in head and neck cancer, such information from clinical settings that comprise the whole spectrum of human carcinogenesis is very limited. Towards this direction, [...] Read more.
Autophagy is a catabolic process that preserves cellular homeostasis. Its exact role during carcinogenesis is not completely defined. Specifically in head and neck cancer, such information from clinical settings that comprise the whole spectrum of human carcinogenesis is very limited. Towards this direction, we examined the in situ status of the autophagy-related factors, Beclin-1, microtubule-associated protein 1 light chain 3, member B (LC3B) and sequestosome 1/p62 (p62) in clinical material covering all histopathological stages of human head and neck carcinogenesis. This material is unique as each panel of lesions is derived from the same patient and moreover we have previously assessed it for the DNA damage response (DDR) activation status. Since Beclin-1, LC3B and p62 reflect the nucleation, elongation and degradation stages of autophagy, respectively, their combined immunohistochemical (IHC) expression profiles could grossly mirror the autophagic flux. This experimental approach was further corroborated by ultrastructural analysis, applying transmission electron microscopy (TEM). The observed Beclin-1/LC3B/p62 IHC patterns, obtained from serial sections analysis, along with TEM findings are suggestive of a declined authophagic activity in preneoplastic lesions that was restored in full blown cancers. Correlating these findings with DDR status in the same pathological stages are indicative of: (i) an antitumor function of autophagy in support to that of DDR, possibly through energy deprivation in preneoplastic stages, thus preventing incipient cancer cells from evolving; and (ii) a tumor-supporting role in the cancerous stage. Full article
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
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