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Special Issue "DNA Replication Stress"

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

Deadline for manuscript submissions: closed (30 November 2018).

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Robert M. Brosh Jr
Website
Guest Editor
Laboratory of Molecular Gerontology, National Institute on Aging, NIH, 251 Bayview Blvd, Baltimore, MD, USA

Special Issue Information

Dear colleagues,

During DNA synthesis in vivo, the replication fork encounters a variety of forms of stress imposed by DNA damage, alternate DNA structures, genetic deficiency, and pharmacologically-induced conditions that ultimately impede fork progression and may lead to the elicitation of signaling cascades.  Covalent lesions induced by environmental exposure or from endogenous biochemical processes as well as noncovalent modifications introduced by DNA binding compounds perturb fork advancement and stability.  Similarly, DNA structures, such as hairpins or G-quadruplexes, which deviate from the noncanonical B-form duplex DNA, can be problematic for the replisome machinery.  Collisions of the replisome with transcription complexes or other protein-DNA complexes may lead to replication stress.  Inhibition of DNA polymerase-catalyzed DNA synthesis or depletion of the nucleotide pool by certain chemical agents stalls the replication fork as well.  Genetic deficiency or depletion of key DNA metabolic proteins, or inhibition of molecular functions of key proteins associated with the replisome can also be a source of DNA replication stress.  To contend with these and other forms of replication stress, eukaryotic cells possess a number of mechanisms involving DNA damage response or DNA repair proteins as well as cell cycle checkpoints to help mediate the appropriate response.  This IJMS Special Issue on “DNA Replication Stress” will address these mechanisms, mediated at the molecular and cellular levels, to respond to adverse genomic perturbations and cellular conditions so that chromosomal stability and cellular homeostasis is maintained.

Dr. Robert M. Brosh Jr.
Guest Editor

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Keywords

  • DNA replication
  • DNA repair
  • Replication Stress
  • Genomic Instability
  • DNA damage response

Published Papers (19 papers)

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Editorial

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Open AccessEditorial
Special Issue on DNA Replication Stress: Summary of Topics Covered
Int. J. Mol. Sci. 2019, 20(12), 2934; https://doi.org/10.3390/ijms20122934 - 15 Jun 2019
Abstract
A Special Issue of International Journal of Molecular Sciences (IJMS) is dedicated to mechanisms mediated at the molecular and cellular levels to respond to adverse genomic perturbations and DNA replication stress (https://www [...] Full article
(This article belongs to the Special Issue DNA Replication Stress) Printed Edition available

Research

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Open AccessArticle
APIM-Mediated REV3L–PCNA Interaction Important for Error Free TLS Over UV-Induced DNA Lesions in Human Cells
Int. J. Mol. Sci. 2019, 20(1), 100; https://doi.org/10.3390/ijms20010100 - 28 Dec 2018
Cited by 6
Abstract
Proliferating cell nuclear antigen (PCNA) is essential for the organization of DNA replication and the bypass of DNA lesions via translesion synthesis (TLS). TLS is mediated by specialized DNA polymerases, which all interact, directly or indirectly, with PCNA. How interactions between the TLS [...] Read more.
Proliferating cell nuclear antigen (PCNA) is essential for the organization of DNA replication and the bypass of DNA lesions via translesion synthesis (TLS). TLS is mediated by specialized DNA polymerases, which all interact, directly or indirectly, with PCNA. How interactions between the TLS polymerases and PCNA affects TLS specificity and/or coordination is not fully understood. Here we show that the catalytic subunit of the essential mammalian TLS polymerase POLζ, REV3L, contains a functional AlkB homolog 2 PCNA interacting motif, APIM. APIM from REV3L fused to YFP, and full-length REV3L-YFP colocalizes with PCNA in replication foci. Colocalization of REV3L-YFP with PCNA is strongly reduced when an APIM-CFP construct is overexpressed. We also found that overexpression of full-length REV3L with mutated APIM leads to significantly altered mutation frequencies and mutation spectra, when compared to overexpression of full-length REV3L wild-type (WT) protein in multiple cell lines. Altogether, these data suggest that APIM is a functional PCNA-interacting motif in REV3L, and that the APIM-mediated PCNA interaction is important for the function and specificity of POLζ in TLS. Finally, a PCNA-targeting cell-penetrating peptide, containing APIM, reduced the mutation frequencies and changed the mutation spectra in several cell lines, suggesting that efficient TLS requires coordination mediated by interactions with PCNA. Full article
(This article belongs to the Special Issue DNA Replication Stress) Printed Edition available
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Open AccessArticle
Thermococcus Eurythermalis Endonuclease IV Can Cleave Various Apurinic/Apyrimidinic Site Analogues in ssDNA and dsDNA
Int. J. Mol. Sci. 2019, 20(1), 69; https://doi.org/10.3390/ijms20010069 - 24 Dec 2018
Cited by 3
Abstract
Endonuclease IV (EndoIV) is a DNA damage-specific endonuclease that mainly hydrolyzes the phosphodiester bond located at 5′ of an apurinic/apyrimidinic (AP) site in DNA. EndoIV also possesses 3′-exonuclease activity for removing 3′-blocking groups and normal nucleotides. Here, we report that Thermococcus eurythermalis EndoIV [...] Read more.
Endonuclease IV (EndoIV) is a DNA damage-specific endonuclease that mainly hydrolyzes the phosphodiester bond located at 5′ of an apurinic/apyrimidinic (AP) site in DNA. EndoIV also possesses 3′-exonuclease activity for removing 3′-blocking groups and normal nucleotides. Here, we report that Thermococcus eurythermalis EndoIV (TeuendoIV) shows AP endonuclease and 3′-exonuclease activities. The effect of AP site structures, positions and clustered patterns on the activity was characterized. The AP endonuclease activity of TeuendoIV can incise DNA 5′ to various AP site analogues, including the alkane chain Spacer and polyethylene glycol Spacer. However, the short Spacer C2 strongly inhibits the AP endonuclease activity. The kinetic parameters also support its preference to various AP site analogues. In addition, the efficient cleavage at AP sites requires ≥2 normal nucleotides existing at the 5′-terminus. The 3′-exonuclease activity of TeuendoIV can remove one or more consecutive AP sites at the 3′-terminus. Mutations on the residues for substrate recognition show that binding AP site-containing or complementary strand plays a key role for the hydrolysis of phosphodiester bonds. Our results provide a comprehensive biochemical characterization of the cleavage/removal of AP site analogues and some insight for repairing AP sites in hyperthermophile cells. Full article
(This article belongs to the Special Issue DNA Replication Stress) Printed Edition available
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Open AccessArticle
Movement of the RecG Motor Domain upon DNA Binding Is Required for Efficient Fork Reversal
Int. J. Mol. Sci. 2018, 19(10), 3049; https://doi.org/10.3390/ijms19103049 - 06 Oct 2018
Cited by 4
Abstract
RecG catalyzes reversal of stalled replication forks in response to replication stress in bacteria. The protein contains a fork recognition (“wedge”) domain that binds branched DNA and a superfamily II (SF2) ATPase motor that drives translocation on double-stranded (ds)DNA. The mechanism by which [...] Read more.
RecG catalyzes reversal of stalled replication forks in response to replication stress in bacteria. The protein contains a fork recognition (“wedge”) domain that binds branched DNA and a superfamily II (SF2) ATPase motor that drives translocation on double-stranded (ds)DNA. The mechanism by which the wedge and motor domains collaborate to catalyze fork reversal in RecG and analogous eukaryotic fork remodelers is unknown. Here, we used electron paramagnetic resonance (EPR) spectroscopy to probe conformational changes between the wedge and ATPase domains in response to fork DNA binding by Thermotoga maritima RecG. Upon binding DNA, the ATPase-C lobe moves away from both the wedge and ATPase-N domains. This conformational change is consistent with a model of RecG fully engaged with a DNA fork substrate constructed from a crystal structure of RecG bound to a DNA junction together with recent cryo-electron microscopy (EM) structures of chromatin remodelers in complex with dsDNA. We show by mutational analysis that a conserved loop within the translocation in RecG (TRG) motif that was unstructured in the RecG crystal structure is essential for fork reversal and DNA-dependent conformational changes. Together, this work helps provide a more coherent model of fork binding and remodeling by RecG and related eukaryotic enzymes. Full article
(This article belongs to the Special Issue DNA Replication Stress) Printed Edition available
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Open AccessArticle
The ATR-Activation Domain of TopBP1 Is Required for the Suppression of Origin Firing during the S Phase
Int. J. Mol. Sci. 2018, 19(8), 2376; https://doi.org/10.3390/ijms19082376 - 13 Aug 2018
Cited by 7
Abstract
The mammalian DNA replication program is controlled at two phases, the licensing of potential origins of DNA replication in early gap 1 (G1), and the selective firing of a subset of licenced origins in the synthesis (S) phase. Upon entry into the S [...] Read more.
The mammalian DNA replication program is controlled at two phases, the licensing of potential origins of DNA replication in early gap 1 (G1), and the selective firing of a subset of licenced origins in the synthesis (S) phase. Upon entry into the S phase, serine/threonine-protein kinase ATR (ATR) is required for successful completion of the DNA replication program by limiting unnecessary dormant origin activation. Equally important is its activator, DNA topoisomerase 2-binding protein 1 (TopBP1), which is also required for the initiation of DNA replication after a rise in S-phase kinase levels. However, it is unknown how the ATR activation domain of TopBP1 affects DNA replication dynamics. Using human cells conditionally expressing a TopBP1 mutant deficient for ATR activation, we show that functional TopBP1 is required in suppressing local dormant origin activation. Our results demonstrate a regulatory role for TopBP1 in the local balancing of replication fork firing within the S phase. Full article
(This article belongs to the Special Issue DNA Replication Stress) Printed Edition available
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Open AccessArticle
DNA Damage-Response Pathway Heterogeneity of Human Lung Cancer A549 and H1299 Cells Determines Sensitivity to 8-Chloro-Adenosine
Int. J. Mol. Sci. 2018, 19(6), 1587; https://doi.org/10.3390/ijms19061587 - 28 May 2018
Cited by 3
Abstract
Human lung cancer H1299 (p53-null) cells often display enhanced susceptibility to chemotherapeutics comparing to A549 (p53-wt) cells. However, little is known regarding to the association of DNA damage-response (DDR) pathway heterogeneity with drug sensitivity in these two cells. We investigated the DDR pathway [...] Read more.
Human lung cancer H1299 (p53-null) cells often display enhanced susceptibility to chemotherapeutics comparing to A549 (p53-wt) cells. However, little is known regarding to the association of DNA damage-response (DDR) pathway heterogeneity with drug sensitivity in these two cells. We investigated the DDR pathway differences between A549 and H1299 cells exposed to 8-chloro-adenosine (8-Cl-Ado), a potential anticancer drug that can induce DNA double-strand breaks (DSBs), and found that the hypersensitivity of H1299 cells to 8-Cl-Ado is associated with its DSB overaccumulation. The major causes of excessive DSBs in H1299 cells are as follows: First, defect of p53-p21 signal and phosphorylation of SMC1 increase S phase cells, where replication of DNA containing single-strand DNA break (SSB) produces more DSBs in H1299 cells. Second, p53 defect and no available induction of DNA repair protein p53R2 impair DNA repair activity in H1299 cells more severely than A549 cells. Third, cleavage of PARP-1 inhibits topoisomerase I and/or topoisomerase I-like activity of PARP-1, aggravates DNA DSBs and DNA repair mechanism impairment in H1299 cells. Together, DDR pathway heterogeneity of cancer cells is linked to cancer susceptibility to DNA damage-based chemotherapeutics, which may provide aid in design of chemotherapy strategy to improve treatment outcomes. Full article
(This article belongs to the Special Issue DNA Replication Stress) Printed Edition available
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Open AccessArticle
Impact of Mutagens on DNA Replication in Barley Chromosomes
Int. J. Mol. Sci. 2018, 19(4), 1070; https://doi.org/10.3390/ijms19041070 - 03 Apr 2018
Cited by 4
Abstract
Replication errors that are caused by mutagens are critical for living cells. The aim of the study was to analyze the distribution of a DNA replication pattern on chromosomes of the H. vulgare ‘Start’ variety using pulse 5-ethynyl-2′-deoxyuridine (EdU) labeling, as well as [...] Read more.
Replication errors that are caused by mutagens are critical for living cells. The aim of the study was to analyze the distribution of a DNA replication pattern on chromosomes of the H. vulgare ‘Start’ variety using pulse 5-ethynyl-2′-deoxyuridine (EdU) labeling, as well as its relationship to the DNA damage that is induced by mutagenic treatment with maleic hydrazide (MH) and γ ray. To the best of our knowledge, this is the first example of a study of the effects of mutagens on the DNA replication pattern in chromosomes, as well as the first to use EdU labeling for these purposes. The duration of the cell cycle of the Hordeum vulgare ‘Start’ variety was estimated for the first time, as well as the influence of MH and γ ray on it. The distribution of the signals of DNA replication along the chromosomes revealed relationships between DNA replication, the chromatin structure, and DNA damage. MH has a stronger impact on replication than γ ray. Application of EdU seems to be promising for precise analyses of cell cycle disturbances in the future, especially in plant species with small genomes. Full article
(This article belongs to the Special Issue DNA Replication Stress) Printed Edition available
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Review

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Open AccessReview
DNA Damage Stress: Cui Prodest?
Int. J. Mol. Sci. 2019, 20(5), 1073; https://doi.org/10.3390/ijms20051073 - 01 Mar 2019
Cited by 6
Abstract
DNA is an entity shielded by mechanisms that maintain genomic stability and are essential for living cells; however, DNA is constantly subject to assaults from the environment throughout the cellular life span, making the genome susceptible to mutation and irreparable damage. Cells are [...] Read more.
DNA is an entity shielded by mechanisms that maintain genomic stability and are essential for living cells; however, DNA is constantly subject to assaults from the environment throughout the cellular life span, making the genome susceptible to mutation and irreparable damage. Cells are prepared to mend such events through cell death as an extrema ratio to solve those threats from a multicellular perspective. However, in cells under various stress conditions, checkpoint mechanisms are activated to allow cells to have enough time to repair the damaged DNA. In yeast, entry into the cell cycle when damage is not completely repaired represents an adaptive mechanism to cope with stressful conditions. In multicellular organisms, entry into cell cycle with damaged DNA is strictly forbidden. However, in cancer development, individual cells undergo checkpoint adaptation, in which most cells die, but some survive acquiring advantageous mutations and selfishly evolve a conflictual behavior. In this review, we focus on how, in cancer development, cells rely on checkpoint adaptation to escape DNA stress and ultimately to cell death. Full article
(This article belongs to the Special Issue DNA Replication Stress) Printed Edition available
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Open AccessReview
Stress Marks on the Genome: Use or Lose?
Int. J. Mol. Sci. 2019, 20(2), 364; https://doi.org/10.3390/ijms20020364 - 16 Jan 2019
Cited by 7
Abstract
Oxidative stress and the resulting damage to DNA are inevitable consequence of endogenous physiological processes further amplified by cellular responses to environmental exposures. If left unrepaired, oxidative DNA lesions can block essential processes such as transcription and replication or can induce mutations. Emerging [...] Read more.
Oxidative stress and the resulting damage to DNA are inevitable consequence of endogenous physiological processes further amplified by cellular responses to environmental exposures. If left unrepaired, oxidative DNA lesions can block essential processes such as transcription and replication or can induce mutations. Emerging data also indicate that oxidative base modifications such as 8-oxoG in gene promoters may serve as epigenetic marks, and/or provide a platform for coordination of the initial steps of DNA repair and the assembly of the transcriptional machinery to launch adequate gene expression alterations. Here, we briefly review the current understanding of oxidative lesions in genome stability maintenance and regulation of basal and inducible transcription. Full article
(This article belongs to the Special Issue DNA Replication Stress) Printed Edition available
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Open AccessReview
Human Exonuclease 1 (EXO1) Regulatory Functions in DNA Replication with Putative Roles in Cancer
Int. J. Mol. Sci. 2019, 20(1), 74; https://doi.org/10.3390/ijms20010074 - 25 Dec 2018
Cited by 11
Abstract
Human exonuclease 1 (EXO1), a 5′→3′ exonuclease, contributes to the regulation of the cell cycle checkpoints, replication fork maintenance, and post replicative DNA repair pathways. These processes are required for the resolution of stalled or blocked DNA replication that can lead to replication [...] Read more.
Human exonuclease 1 (EXO1), a 5′→3′ exonuclease, contributes to the regulation of the cell cycle checkpoints, replication fork maintenance, and post replicative DNA repair pathways. These processes are required for the resolution of stalled or blocked DNA replication that can lead to replication stress and potential collapse of the replication fork. Failure to restart the DNA replication process can result in double-strand breaks, cell-cycle arrest, cell death, or cellular transformation. In this review, we summarize the involvement of EXO1 in the replication, DNA repair pathways, cell cycle checkpoints, and the link between EXO1 and cancer. Full article
(This article belongs to the Special Issue DNA Replication Stress) Printed Edition available
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Open AccessReview
The Protective Role of Dormant Origins in Response to Replicative Stress
Int. J. Mol. Sci. 2018, 19(11), 3569; https://doi.org/10.3390/ijms19113569 - 12 Nov 2018
Cited by 9
Abstract
Genome stability requires tight regulation of DNA replication to ensure that the entire genome of the cell is duplicated once and only once per cell cycle. In mammalian cells, origin activation is controlled in space and time by a cell-specific and robust program [...] Read more.
Genome stability requires tight regulation of DNA replication to ensure that the entire genome of the cell is duplicated once and only once per cell cycle. In mammalian cells, origin activation is controlled in space and time by a cell-specific and robust program called replication timing. About 100,000 potential replication origins form on the chromatin in the gap 1 (G1) phase but only 20–30% of them are active during the DNA replication of a given cell in the synthesis (S) phase. When the progress of replication forks is slowed by exogenous or endogenous impediments, the cell must activate some of the inactive or “dormant” origins to complete replication on time. Thus, the many origins that may be activated are probably key to protect the genome against replication stress. This review aims to discuss the role of these dormant origins as safeguards of the human genome during replicative stress. Full article
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Open AccessReview
Werner Syndrome Protein and DNA Replication
Int. J. Mol. Sci. 2018, 19(11), 3442; https://doi.org/10.3390/ijms19113442 - 02 Nov 2018
Cited by 10
Abstract
Werner Syndrome (WS) is an autosomal recessive disorder characterized by the premature development of aging features. Individuals with WS also have a greater predisposition to rare cancers that are mesenchymal in origin. Werner Syndrome Protein (WRN), the protein mutated in WS, is unique [...] Read more.
Werner Syndrome (WS) is an autosomal recessive disorder characterized by the premature development of aging features. Individuals with WS also have a greater predisposition to rare cancers that are mesenchymal in origin. Werner Syndrome Protein (WRN), the protein mutated in WS, is unique among RecQ family proteins in that it possesses exonuclease and 3′ to 5′ helicase activities. WRN forms dynamic sub-complexes with different factors involved in DNA replication, recombination and repair. WRN binding partners either facilitate its DNA metabolic activities or utilize it to execute their specific functions. Furthermore, WRN is phosphorylated by multiple kinases, including Ataxia telangiectasia mutated, Ataxia telangiectasia and Rad3 related, c-Abl, Cyclin-dependent kinase 1 and DNA-dependent protein kinase catalytic subunit, in response to genotoxic stress. These post-translational modifications are critical for WRN to function properly in DNA repair, replication and recombination. Accumulating evidence suggests that WRN plays a crucial role in one or more genome stability maintenance pathways, through which it suppresses cancer and premature aging. Among its many functions, WRN helps in replication fork progression, facilitates the repair of stalled replication forks and DNA double-strand breaks associated with replication forks, and blocks nuclease-mediated excessive processing of replication forks. In this review, we specifically focus on human WRN’s contribution to replication fork processing for maintaining genome stability and suppressing premature aging. Understanding WRN’s molecular role in timely and faithful DNA replication will further advance our understanding of the pathophysiology of WS. Full article
(This article belongs to the Special Issue DNA Replication Stress) Printed Edition available
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Open AccessReview
Detours to Replication: Functions of Specialized DNA Polymerases during Oncogene-induced Replication Stress
Int. J. Mol. Sci. 2018, 19(10), 3255; https://doi.org/10.3390/ijms19103255 - 20 Oct 2018
Cited by 5
Abstract
Incomplete and low-fidelity genome duplication contribute to genomic instability and cancer development. Difficult-to-Replicate Sequences, or DiToRS, are natural impediments in the genome that require specialized DNA polymerases and repair pathways to complete and maintain faithful DNA synthesis. DiToRS include non B-DNA secondary structures [...] Read more.
Incomplete and low-fidelity genome duplication contribute to genomic instability and cancer development. Difficult-to-Replicate Sequences, or DiToRS, are natural impediments in the genome that require specialized DNA polymerases and repair pathways to complete and maintain faithful DNA synthesis. DiToRS include non B-DNA secondary structures formed by repetitive sequences, for example within chromosomal fragile sites and telomeres, which inhibit DNA replication under endogenous stress conditions. Oncogene activation alters DNA replication dynamics and creates oncogenic replication stress, resulting in persistent activation of the DNA damage and replication stress responses, cell cycle arrest, and cell death. The response to oncogenic replication stress is highly complex and must be tightly regulated to prevent mutations and tumorigenesis. In this review, we summarize types of known DiToRS and the experimental evidence supporting replication inhibition, with a focus on the specialized DNA polymerases utilized to cope with these obstacles. In addition, we discuss different causes of oncogenic replication stress and its impact on DiToRS stability. We highlight recent findings regarding the regulation of DNA polymerases during oncogenic replication stress and the implications for cancer development. Full article
(This article belongs to the Special Issue DNA Replication Stress) Printed Edition available
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Open AccessReview
The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis
Int. J. Mol. Sci. 2018, 19(10), 3137; https://doi.org/10.3390/ijms19103137 - 12 Oct 2018
Cited by 11
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressing neurodegenerative disease affecting motor neurons, and frontotemporal dementia (FTD) is a behavioural disorder resulting in early-onset dementia. Hexanucleotide (G4C2) repeat expansions in the gene encoding chromosome 9 open reading frame 72 (C9orf72) [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressing neurodegenerative disease affecting motor neurons, and frontotemporal dementia (FTD) is a behavioural disorder resulting in early-onset dementia. Hexanucleotide (G4C2) repeat expansions in the gene encoding chromosome 9 open reading frame 72 (C9orf72) are the major cause of familial forms of both ALS (~40%) and FTD (~20%) worldwide. The C9orf72 repeat expansion is known to form abnormal nuclei acid structures, such as hairpins, G-quadruplexes, and R-loops, which are increasingly associated with human diseases involving microsatellite repeats. These configurations form during normal cellular processes, but if they persist they also damage DNA, and hence are a serious threat to genome integrity. It is unclear how the repeat expansion in C9orf72 causes ALS, but recent evidence implicates DNA damage in neurodegeneration. This may arise from abnormal nucleic acid structures, the greatly expanded C9orf72 RNA, or by repeat-associated non-ATG (RAN) translation, which generates toxic dipeptide repeat proteins. In this review, we detail recent advances implicating DNA damage in C9orf72-ALS. Furthermore, we also discuss increasing evidence that targeting these aberrant C9orf72 confirmations may have therapeutic value for ALS, thus revealing new avenues for drug discovery for this disorder. Full article
(This article belongs to the Special Issue DNA Replication Stress) Printed Edition available
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Open AccessReview
Ageing, Cellular Senescence and Neurodegenerative Disease
Int. J. Mol. Sci. 2018, 19(10), 2937; https://doi.org/10.3390/ijms19102937 - 27 Sep 2018
Cited by 55
Abstract
Ageing is a major risk factor for developing many neurodegenerative diseases. Cellular senescence is a homeostatic biological process that has a key role in driving ageing. There is evidence that senescent cells accumulate in the nervous system with ageing and neurodegenerative disease and [...] Read more.
Ageing is a major risk factor for developing many neurodegenerative diseases. Cellular senescence is a homeostatic biological process that has a key role in driving ageing. There is evidence that senescent cells accumulate in the nervous system with ageing and neurodegenerative disease and may predispose a person to the appearance of a neurodegenerative condition or may aggravate its course. Research into senescence has long been hindered by its variable and cell-type specific features and the lack of a universal marker to unequivocally detect senescent cells. Recent advances in senescence markers and genetically modified animal models have boosted our knowledge on the role of cellular senescence in ageing and age-related disease. The aim now is to fully elucidate its role in neurodegeneration in order to efficiently and safely exploit cellular senescence as a therapeutic target. Here, we review evidence of cellular senescence in neurons and glial cells and we discuss its putative role in Alzheimer’s disease, Parkinson’s disease and multiple sclerosis and we provide, for the first time, evidence of senescence in neurons and glia in multiple sclerosis, using the novel GL13 lipofuscin stain as a marker of cellular senescence. Full article
(This article belongs to the Special Issue DNA Replication Stress) Printed Edition available
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Open AccessReview
G Protein-Coupled Receptor Systems as Crucial Regulators of DNA Damage Response Processes
Int. J. Mol. Sci. 2018, 19(10), 2919; https://doi.org/10.3390/ijms19102919 - 26 Sep 2018
Cited by 11
Abstract
G protein-coupled receptors (GPCRs) and their associated proteins represent one of the most diverse cellular signaling systems involved in both physiological and pathophysiological processes. Aging represents perhaps the most complex biological process in humans and involves a progressive degradation of systemic integrity and [...] Read more.
G protein-coupled receptors (GPCRs) and their associated proteins represent one of the most diverse cellular signaling systems involved in both physiological and pathophysiological processes. Aging represents perhaps the most complex biological process in humans and involves a progressive degradation of systemic integrity and physiological resilience. This is in part mediated by age-related aberrations in energy metabolism, mitochondrial function, protein folding and sorting, inflammatory activity and genomic stability. Indeed, an increased rate of unrepaired DNA damage is considered to be one of the ‘hallmarks’ of aging. Over the last two decades our appreciation of the complexity of GPCR signaling systems has expanded their functional signaling repertoire. One such example of this is the incipient role of GPCRs and GPCR-interacting proteins in DNA damage and repair mechanisms. Emerging data now suggest that GPCRs could function as stress sensors for intracellular damage, e.g., oxidative stress. Given this role of GPCRs in the DNA damage response process, coupled to the effective history of drug targeting of these receptors, this suggests that one important future activity of GPCR therapeutics is the rational control of DNA damage repair systems. Full article
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Ubiquitylation at the Fork: Making and Breaking Chains to Complete DNA Replication
Int. J. Mol. Sci. 2018, 19(10), 2909; https://doi.org/10.3390/ijms19102909 - 25 Sep 2018
Cited by 6
Abstract
The complete and accurate replication of the genome is a crucial aspect of cell proliferation that is often perturbed during oncogenesis. Replication stress arising from a variety of obstacles to replication fork progression and processivity is an important contributor to genome destabilization. Accordingly, [...] Read more.
The complete and accurate replication of the genome is a crucial aspect of cell proliferation that is often perturbed during oncogenesis. Replication stress arising from a variety of obstacles to replication fork progression and processivity is an important contributor to genome destabilization. Accordingly, cells mount a complex response to this stress that allows the stabilization and restart of stalled replication forks and enables the full duplication of the genetic material. This response articulates itself on three important platforms, Replication Protein A/RPA-coated single-stranded DNA, the DNA polymerase processivity clamp PCNA and the FANCD2/I Fanconi Anemia complex. On these platforms, the recruitment, activation and release of a variety of genome maintenance factors is regulated by post-translational modifications including mono- and poly-ubiquitylation. Here, we review recent insights into the control of replication fork stability and restart by the ubiquitin system during replication stress with a particular focus on human cells. We highlight the roles of E3 ubiquitin ligases, ubiquitin readers and deubiquitylases that provide the required flexibility at stalled forks to select the optimal restart pathways and rescue genome stability during stressful conditions. Full article
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Single-Strand Break End Resection in Genome Integrity: Mechanism and Regulation by APE2
Int. J. Mol. Sci. 2018, 19(8), 2389; https://doi.org/10.3390/ijms19082389 - 14 Aug 2018
Cited by 14
Abstract
DNA single-strand breaks (SSBs) occur more than 10,000 times per mammalian cell each day, representing the most common type of DNA damage. Unrepaired SSBs compromise DNA replication and transcription programs, leading to genome instability. Unrepaired SSBs are associated with diseases such as cancer [...] Read more.
DNA single-strand breaks (SSBs) occur more than 10,000 times per mammalian cell each day, representing the most common type of DNA damage. Unrepaired SSBs compromise DNA replication and transcription programs, leading to genome instability. Unrepaired SSBs are associated with diseases such as cancer and neurodegenerative disorders. Although canonical SSB repair pathway is activated to repair most SSBs, it remains unclear whether and how unrepaired SSBs are sensed and signaled. In this review, we propose a new concept of SSB end resection for genome integrity. We propose a four-step mechanism of SSB end resection: SSB end sensing and processing, as well as initiation, continuation, and termination of SSB end resection. We also compare different mechanisms of SSB end resection and DSB end resection in DNA repair and DNA damage response (DDR) pathways. We further discuss how SSB end resection contributes to SSB signaling and repair. We focus on the mechanism and regulation by APE2 in SSB end resection in genome integrity. Finally, we identify areas of future study that may help us gain further mechanistic insight into the process of SSB end resection. Overall, this review provides the first comprehensive perspective on SSB end resection in genome integrity. Full article
(This article belongs to the Special Issue DNA Replication Stress) Printed Edition available
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Open AccessReview
Deoxyribonucleic Acid Damage and Repair: Capitalizing on Our Understanding of the Mechanisms of Maintaining Genomic Integrity for Therapeutic Purposes
Int. J. Mol. Sci. 2018, 19(4), 1148; https://doi.org/10.3390/ijms19041148 - 11 Apr 2018
Cited by 7
Abstract
Deoxyribonucleic acid (DNA) is the self-replicating hereditary material that provides a blueprint which, in collaboration with environmental influences, produces a structural and functional phenotype. As DNA coordinates and directs differentiation, growth, survival, and reproduction, it is responsible for life and the continuation of [...] Read more.
Deoxyribonucleic acid (DNA) is the self-replicating hereditary material that provides a blueprint which, in collaboration with environmental influences, produces a structural and functional phenotype. As DNA coordinates and directs differentiation, growth, survival, and reproduction, it is responsible for life and the continuation of our species. Genome integrity requires the maintenance of DNA stability for the correct preservation of genetic information. This is facilitated by accurate DNA replication and precise DNA repair. DNA damage may arise from a wide range of both endogenous and exogenous sources but may be repaired through highly specific mechanisms. The most common mechanisms include mismatch, base excision, nucleotide excision, and double-strand DNA (dsDNA) break repair. Concurrent with regulation of the cell cycle, these mechanisms are precisely executed to ensure full restoration of damaged DNA. Failure or inaccuracy in DNA repair contributes to genome instability and loss of genetic information which may lead to mutations resulting in disease or loss of life. A detailed understanding of the mechanisms of DNA damage and its repair provides insight into disease pathogeneses and may facilitate diagnosis and the development of targeted therapies. Full article
(This article belongs to the Special Issue DNA Replication Stress) Printed Edition available
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