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Special Issue "DNA Damage and Repair in Degenerative Diseases 2016"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2016).

Special Issue Editor

Prof. Dr. Guillermo T. Sáez
E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, Faculty of Medicine and Odontology-INCLIVA, Service of Clinical Analysis, Dr. Peset University Hospital -FISABIO, University of Valencia, Avda. Blasco Ibañez 15, 46010 Valencia, Spain
Interests: oxidative stress-induced DNA damage and its repair in cardiometabolic and cancer diseases
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Special Issue Information

Dear Colleagues,

Damage to genetic material is the result of chemical changes and alterations that occur in the native sequence and conformational structure of DNA. The integrity of the genome is a compulsory hallmark, which much be maintained all along the development of biological organisms. This assumption is especially relevant considering the great amount endogenous and exogenous mechanisms that may compromise genomic stability and function of animal cells. One of the most, but not unique way of, damaging DNA or RNA is based on the production of reactive oxygen species (ROS) and subsequent oxidative modification. As a result of an oxidative stress insult to DNA, a number of damage bases are produced, adopting different molecular structures, some of which have been shown to induce mutagenesis. This is the case of the modified base 8-oxo-7,8-dihydro-2’-deoxyguanine (8-oxo-dG), an excellent indicator of oxidative stress with a promising future as a emergent tumor marker.

It its known that changes in the redox status of the cell have profound implication on the normal function of signal transduction pathways implicated in cell cycle regulation, which may lead to an abnormal cell proliferation and, eventually, cell-malignant transformation. In addition, highly reactive oxygen species, such as the hydroxyl radical (.OH), present great affinity towards DNA, and very easily interacts with its molecular structure to induce different degrees of oxidative modifications, which, depending on the intensity of their attack and impact, may range from single nucleotide oxidation to even the induction of double strands breaks. Recently, exposure to different environmental factors, such tobacco smoke or industry produced nanoparticles, have been shown to induce ROS as an endpoint mechanism, leading to nucleic acid oxidation and chronic inflammatory processes. Metal ion contamination is another way to induce DNA damage, by site-specific hydroxyl radical formation, via the well-known Fenton type reaction. However, there are many other interactive mechanisms which may also induce epigenetic DNA modifications, including adduct formation and addition of specific functional groups through acetylation and methylation reactions of chromatine proteins, with clear effects on their normal molecular processing.

Under normal metabolic conditions, the rate of DNA damage has been estimated at about 105 lesions/cell/day, which, although it represents a reduced proportion of the total genome, critical genes for the transcription of important signal transduction proteins may be affected, and, therefore, alter the normal homeostasis of cells and tissues. This may lead to an increase in the likelihood of genomic instability and the establishment of a broad spectrum of generative diseases, including cancer, neurodegeneration, inflammatory processes, and cardiovascular alterations, among many others. These facts emphasize the important role of DNA repair mechanisms in the preservation of the genome and in the prevention of physiological disturbances leading to disease. During the past few decades, it has been made clear that diminished repair efficiency plays an important role in the pathogenic scenario of degenerative diseases. An imbalance between repair and DNA damage eventually leads to an increase of gene mutations and malignant transformations of the cells. Therefore, impairments of specific DNA repair enzymes underlie the progression of many types of cancers, and knowledge of their molecular mechanisms has provided new tools for the development of advanced technologies allowing a much deeper understanding, diagnosis, and accurate treatment. Different types of DNA lesions accumulate in mammalian tissues with age and critical cell cycle check points with transcription and tumor suppressor function (p53, retinoblastoma, p16, p19, p21, etc.) play an important role in the control of cell proliferation, differentiation, and/or senescence and aging. The purpose of this Special Issue is to collect and offer, to the readers and researchers, recent highlights and advances on the regulatory mechanisms involved in DNA damage and repair, and their clinical implications with respect to widespread, related degenerative diseases.

Prof. Guillermo T. Sáez
Guest Editor

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Keywords

  • DNA damage
  • DNA repair
  • 8-oxo-Dg
  • aging
  • degenerative diseases
  • antioxidants signal transduction
  • oxidative stress
  • byproducts
  • cardiovascular
  • neurogeneration
  • cancer
  • metabolic diseases

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Published Papers (16 papers)

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Editorial

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Editorial
DNA Damage and Repair in Degenerative Diseases 2016
Int. J. Mol. Sci. 2017, 18(1), 166; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18010166 - 16 Jan 2017
Cited by 4 | Viewed by 1775
Abstract
Given the great importance of the integrity of DNA for the correct transmission of the genetic message, repairing the induced lesions to its molecular structure by different endogenous or exogenous origin is crucial for the maintenance of homeostasis and biological functions of living [...] Read more.
Given the great importance of the integrity of DNA for the correct transmission of the genetic message, repairing the induced lesions to its molecular structure by different endogenous or exogenous origin is crucial for the maintenance of homeostasis and biological functions of living organisms.[...] Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)

Research

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Article
v-Src Causes Chromosome Bridges in a Caffeine-Sensitive Manner by Generating DNA Damage
Int. J. Mol. Sci. 2016, 17(6), 871; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17060871 - 02 Jun 2016
Cited by 10 | Viewed by 2990
Abstract
An increase in Src activity is commonly observed in epithelial cancers. Aberrant activation of the kinase activity is associated with malignant progression. However, the mechanisms that underlie the Src-induced malignant progression of cancer are not completely understood. We show here that v-Src, an [...] Read more.
An increase in Src activity is commonly observed in epithelial cancers. Aberrant activation of the kinase activity is associated with malignant progression. However, the mechanisms that underlie the Src-induced malignant progression of cancer are not completely understood. We show here that v-Src, an oncogene that was first identified from a Rous sarcoma virus and a mutant variant of c-Src, leads to an increase in the number of anaphase and telophase cells having chromosome bridges. v-Src increases the number of γH2AX foci, and this increase is inhibited by treatment with PP2, a Src kinase inhibitor. v-Src induces the phosphorylation of KAP1 at Ser824, Chk2 at Thr68, and Chk1 at Ser345, suggesting the activation of the ATM/ATR pathway. Caffeine decreases the number of cells having chromosome bridges at a concentration incapable of inhibiting Chk1 phosphorylation at Ser345. These results suggest that v-Src induces chromosome bridges via generation of DNA damage and the subsequent DNA damage response, possibly by homologous recombination. A chromosome bridge gives rise to the accumulation of DNA damage directly through chromosome breakage and indirectly through cytokinesis failure-induced multinucleation. We propose that v-Src-induced chromosome bridge formation is one of the causes of the v-Src-induced malignant progression of cancer cells. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)
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Article
High DRC Levels Are Associated with Let-7b Overexpression in Women with Breast Cancer
Int. J. Mol. Sci. 2016, 17(6), 865; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17060865 - 02 Jun 2016
Cited by 10 | Viewed by 2232
Abstract
Nucleotide Excision Repair (NER) is a critical pathway involved in breast cancer (BC). We have previously published that a low DNA repair capacity (DRC) is associated with a higher risk of BC in Puerto Rican women. Let-7b belongs to a miRNA family with [...] Read more.
Nucleotide Excision Repair (NER) is a critical pathway involved in breast cancer (BC). We have previously published that a low DNA repair capacity (DRC) is associated with a higher risk of BC in Puerto Rican women. Let-7b belongs to a miRNA family with tumor suppressor activity that targets oncogenes. We isolated miRNAs from plasma of 153 Puerto Rican women with and without BC. DRC was measured in lymphocytes by means of a host cell reactivation assay. These women were divided into four groups according to their DRC level: High (>3.8%) and low (<3.8%). The four groups consisted of BC patients with high (n = 35) and low (n = 43) DRC and controls with high (n = 39) and low (n = 36) DRC. Epidemiologic data were collected at initial BC diagnosis and almost five years after diagnosis. A significant difference in Let-7b expression was found in BC patients with high DRC versus the remaining groups (p < 0.001). Thus, our data reveal a possible role of Let-7b on DRC during breast carcinogenesis. Our study is innovative because it provides the first evidence that Let-7b may play role in DRC regulation (through the NER repair pathway) in BC. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)
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Article
How Diet Intervention via Modulation of DNA Damage Response through MicroRNAs May Have an Effect on Cancer Prevention and Aging, an in Silico Study
Int. J. Mol. Sci. 2016, 17(5), 752; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17050752 - 19 May 2016
Cited by 13 | Viewed by 2948
Abstract
The DNA damage response (DDR) is a molecular mechanism that cells have evolved to sense DNA damage (DD) to promote DNA repair, or to lead to apoptosis, or cellular senescence if the damage is too extensive. Recent evidence indicates that microRNAs (miRs) play [...] Read more.
The DNA damage response (DDR) is a molecular mechanism that cells have evolved to sense DNA damage (DD) to promote DNA repair, or to lead to apoptosis, or cellular senescence if the damage is too extensive. Recent evidence indicates that microRNAs (miRs) play a critical role in the regulation of DDR. Dietary bioactive compounds through miRs may affect activity of numerous genes. Among the most studied bioactive compounds modulating expression of miRs are epi-gallocatechin-3-gallate, curcumin, resveratrol and n3-polyunsaturated fatty acids. To compare the impact of these dietary compounds on DD/DDR network modulation, we performed a literature search and an in silico analysis by the DIANA-mirPathv3 software. The in silico analysis allowed us to identify pathways shared by different miRs involved in DD/DDR vis-à-vis the specific compounds. The results demonstrate that certain miRs (e.g., -146, -21) play a central role in the interplay among DD/DDR and the bioactive compounds. Furthermore, some specific pathways, such as “fatty acids biosynthesis/metabolism”, “extracellular matrix-receptor interaction” and “signaling regulating the pluripotency of stem cells”, appear to be targeted by most miRs affected by the studied compounds. Since DD/DDR and these pathways are strongly related to aging and carcinogenesis, the present in silico results of our study suggest that monitoring the induction of specific miRs may provide the means to assess the antiaging and chemopreventive properties of particular dietary compounds. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)
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Article
Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET) Radiation Originating from 177Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts
Int. J. Mol. Sci. 2016, 17(5), 736; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17050736 - 16 May 2016
Cited by 15 | Viewed by 2640
Abstract
Radiolabeled antibodies (mAbs) provide efficient tools for cancer therapy. The combination of low energy β-emissions (500 keVmax; 130 keVave) along with a γ-emission for imaging makes 177Lu (T1/2 = 6.7 day) a suitable radionuclide for [...] Read more.
Radiolabeled antibodies (mAbs) provide efficient tools for cancer therapy. The combination of low energy β-emissions (500 keVmax; 130 keVave) along with a γ-emission for imaging makes 177Lu (T1/2 = 6.7 day) a suitable radionuclide for radioimmunotherapy (RIT) of tumor burdens possibly too large to treat with α-particle radiation. RIT with 177Lu-trastuzumab has proven to be effective for treatment of disseminated HER2 positive peritoneal disease in a pre-clinical model. To elucidate mechanisms originating from this RIT therapy at the molecular level, tumor bearing mice (LS-174T intraperitoneal xenografts) were treated with 177Lu-trastuzumab comparatively to animals treated with a non-specific control, 177Lu-HuIgG, and then to prior published results obtained using 212Pb-trastuzumab, an α-particle RIT agent. 177Lu-trastuzumab induced cell death via DNA double strand breaks (DSB), caspase-3 apoptosis, and interfered with DNA-PK expression, which is associated with the repair of DNA non-homologous end joining damage. This contrasts to prior results, wherein 212Pb-trastuzumab was found to down-regulate RAD51, which is involved with homologous recombination DNA damage repair. 177Lu-trastuzumab therapy was associated with significant chromosomal disruption and up-regulation of genes in the apoptotic process. These results suggest an inhibition of the repair mechanism specific to the type of radiation damage being inflicted by either high or low linear energy transfer radiation. Understanding the mechanisms of action of β- and α-particle RIT comparatively through an in vivo tumor environment offers real information suitable to enhance combination therapy regimens involving α- and β-particle RIT for the management of intraperitoneal disease. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)
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Review

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Review
Docosahexaenoic Acid Induces Oxidative DNA Damage and Apoptosis, and Enhances the Chemosensitivity of Cancer Cells
Int. J. Mol. Sci. 2016, 17(8), 1257; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17081257 - 03 Aug 2016
Cited by 26 | Viewed by 3622
Abstract
The human diet contains low amounts of ω-3 polyunsaturated fatty acids (PUFAs) and high amounts of ω-6 PUFAs, which has been reported to contribute to the incidence of cancer. Epidemiological studies have shown that a high consumption of fish oil or ω-3 PUFAs [...] Read more.
The human diet contains low amounts of ω-3 polyunsaturated fatty acids (PUFAs) and high amounts of ω-6 PUFAs, which has been reported to contribute to the incidence of cancer. Epidemiological studies have shown that a high consumption of fish oil or ω-3 PUFAs reduced the risk of colon, pancreatic, and endometrial cancers. The ω-3 PUFA, docosahexaenoic acid (DHA), shows anticancer activity by inducing apoptosis of some human cancer cells without toxicity against normal cells. DHA induces oxidative stress and oxidative DNA adduct formation by depleting intracellular glutathione (GSH) and decreasing the mitochondrial function of cancer cells. Oxidative DNA damage and DNA strand breaks activate DNA damage responses to repair the damaged DNA. However, excessive DNA damage beyond the capacity of the DNA repair processes may initiate apoptotic signaling pathways and cell cycle arrest in cancer cells. DHA shows a variable inhibitory effect on cancer cell growth depending on the cells’ molecular properties and degree of malignancy. It has been shown to affect DNA repair processes including DNA-dependent protein kinases and mismatch repair in cancer cells. Moreover, DHA enhanced the efficacy of anticancer drugs by increasing drug uptake and suppressing survival pathways in cancer cells. In this review, DHA-induced oxidative DNA damage, apoptotic signaling, and enhancement of chemosensitivity in cancer cells will be discussed based on recent studies. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)
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Review
Senescence in Human Mesenchymal Stem Cells: Functional Changes and Implications in Stem Cell-Based Therapy
Int. J. Mol. Sci. 2016, 17(7), 1164; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17071164 - 19 Jul 2016
Cited by 202 | Viewed by 7124
Abstract
Regenerative medicine is extensively interested in developing cell therapies using mesenchymal stem cells (MSCs), with applications to several aging-associated diseases. For successful therapies, a substantial number of cells are needed, requiring extensive ex vivo cell expansion. However, MSC proliferation is limited and it [...] Read more.
Regenerative medicine is extensively interested in developing cell therapies using mesenchymal stem cells (MSCs), with applications to several aging-associated diseases. For successful therapies, a substantial number of cells are needed, requiring extensive ex vivo cell expansion. However, MSC proliferation is limited and it is quite likely that long-term culture evokes continuous changes in MSCs. Therefore, a substantial proportion of cells may undergo senescence. In the present review, we will first present the phenotypic characterization of senescent human MSCs (hMSCs) and their possible consequent functional alterations. The accumulation of oxidative stress and dysregulation of key differentiation regulatory factors determine decreased differentiation potential of senescent hMSCs. Senescent hMSCs also show a marked impairment in their migratory and homing ability. Finally, many factors present in the secretome of senescent hMSCs are able to exacerbate the inflammatory response at a systemic level, decreasing the immune modulation activity of hMSCs and promoting either proliferation or migration of cancer cells. Considering the deleterious effects that these changes could evoke, it would appear of primary importance to monitor the occurrence of senescent phenotype in clinically expanded hMSCs and to evaluate possible ways to prevent in vitro MSC senescence. An updated critical presentation of the possible strategies for in vitro senescence monitoring and prevention constitutes the second part of this review. Understanding the mechanisms that drive toward hMSC growth arrest and evaluating how to counteract these for preserving a functional stem cell pool is of fundamental importance for the development of efficient cell-based therapeutic approaches. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)
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Review
DNA Damage and Pulmonary Hypertension
Int. J. Mol. Sci. 2016, 17(6), 990; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17060990 - 22 Jun 2016
Cited by 54 | Viewed by 4088
Abstract
Pulmonary hypertension (PH) is defined by a mean pulmonary arterial pressure over 25 mmHg at rest and is diagnosed by right heart catheterization. Among the different groups of PH, pulmonary arterial hypertension (PAH) is characterized by a progressive obstruction of distal pulmonary arteries, [...] Read more.
Pulmonary hypertension (PH) is defined by a mean pulmonary arterial pressure over 25 mmHg at rest and is diagnosed by right heart catheterization. Among the different groups of PH, pulmonary arterial hypertension (PAH) is characterized by a progressive obstruction of distal pulmonary arteries, related to endothelial cell dysfunction and vascular cell proliferation, which leads to an increased pulmonary vascular resistance, right ventricular hypertrophy, and right heart failure. Although the primary trigger of PAH remains unknown, oxidative stress and inflammation have been shown to play a key role in the development and progression of vascular remodeling. These factors are known to increase DNA damage that might favor the emergence of the proliferative and apoptosis-resistant phenotype observed in PAH vascular cells. High levels of DNA damage were reported to occur in PAH lungs and remodeled arteries as well as in animal models of PH. Moreover, recent studies have demonstrated that impaired DNA-response mechanisms may lead to an increased mutagen sensitivity in PAH patients. Finally, PAH was linked with decreased breast cancer 1 protein (BRCA1) and DNA topoisomerase 2-binding protein 1 (TopBP1) expression, both involved in maintaining genome integrity. This review aims to provide an overview of recent evidence of DNA damage and DNA repair deficiency and their implication in PAH pathogenesis. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)
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Review
Roles of PTEN with DNA Repair in Parkinson’s Disease
Int. J. Mol. Sci. 2016, 17(6), 954; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17060954 - 15 Jun 2016
Cited by 25 | Viewed by 3146
Abstract
Oxidative stress is considered to play key roles in aging and pathogenesis of many neurodegenerative diseases such as Parkinson’s disease, which could bring DNA damage by cells. The DNA damage may lead to the cell apoptosis, which could contribute to the degeneration of [...] Read more.
Oxidative stress is considered to play key roles in aging and pathogenesis of many neurodegenerative diseases such as Parkinson’s disease, which could bring DNA damage by cells. The DNA damage may lead to the cell apoptosis, which could contribute to the degeneration of neuronal tissues. Recent evidence suggests that PTEN (phosphatase and tensin homolog on chromosome 10) may be involved in the pathophysiology of the neurodegenerative disorders. Since PTEN expression appears to be one dominant determinant of the neuronal cell death, PTEN should be a potential molecular target of novel therapeutic strategies against Parkinson’s disease. In addition, defects in DNA damage response and DNA repair are often associated with modulation of hormone signaling pathways. Especially, many observations imply a role for estrogen in a regulation of the DNA repair action. In the present review, we have attempted to summarize the function of DNA repair molecules at a viewpoint of the PTEN signaling pathway and the hormone related functional modulation of cells, providing a broad interpretation on the molecular mechanisms for treatment of Parkinson’s disease. Particular attention will be paid to the mechanisms proposed to explain the health effects of food ingredients against Parkinson’s disease related to reduce oxidative stress for an efficient therapeutic intervention. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)
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Review
Ectopic Expression of Testis Germ Cell Proteins in Cancer and Its Potential Role in Genomic Instability
Int. J. Mol. Sci. 2016, 17(6), 890; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17060890 - 06 Jun 2016
Cited by 18 | Viewed by 2606
Abstract
Genomic instability is a hallmark of human cancer and an enabling factor for the genetic alterations that drive cancer development. The processes involved in genomic instability resemble those of meiosis, where genetic material is interchanged between homologous chromosomes. In most types of human [...] Read more.
Genomic instability is a hallmark of human cancer and an enabling factor for the genetic alterations that drive cancer development. The processes involved in genomic instability resemble those of meiosis, where genetic material is interchanged between homologous chromosomes. In most types of human cancer, epigenetic changes, including hypomethylation of gene promoters, lead to the ectopic expression of a large number of proteins normally restricted to the germ cells of the testis. Due to the similarities between meiosis and genomic instability, it has been proposed that activation of meiotic programs may drive genomic instability in cancer cells. Some germ cell proteins with ectopic expression in cancer cells indeed seem to promote genomic instability, while others reduce polyploidy and maintain mitotic fidelity. Furthermore, oncogenic germ cell proteins may indirectly contribute to genomic instability through induction of replication stress, similar to classic oncogenes. Thus, current evidence suggests that testis germ cell proteins are implicated in cancer development by regulating genomic instability during tumorigenesis, and these proteins therefore represent promising targets for novel therapeutic strategies. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)
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Review
DNA Damage and Repair in Schizophrenia and Autism: Implications for Cancer Comorbidity and Beyond
Int. J. Mol. Sci. 2016, 17(6), 856; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17060856 - 01 Jun 2016
Cited by 30 | Viewed by 3749
Abstract
Schizophrenia and autism spectrum disorder (ASD) are multi-factorial and multi-symptomatic psychiatric disorders, each affecting 0.5%–1% of the population worldwide. Both are characterized by impairments in cognitive functions, emotions and behaviour, and they undermine basic human processes of perception and judgment. Despite decades of [...] Read more.
Schizophrenia and autism spectrum disorder (ASD) are multi-factorial and multi-symptomatic psychiatric disorders, each affecting 0.5%–1% of the population worldwide. Both are characterized by impairments in cognitive functions, emotions and behaviour, and they undermine basic human processes of perception and judgment. Despite decades of extensive research, the aetiologies of schizophrenia and ASD are still poorly understood and remain a significant challenge to clinicians and scientists alike. Adding to this unsatisfactory situation, patients with schizophrenia or ASD often develop a variety of peripheral and systemic disturbances, one prominent example of which is cancer, which shows a direct (but sometimes inverse) comorbidity in people affected with schizophrenia and ASD. Cancer is a disease characterized by uncontrolled proliferation of cells, the molecular origin of which derives from mutations of a cell’s DNA sequence. To counteract such mutations and repair damaged DNA, cells are equipped with intricate DNA repair pathways. Oxidative stress, oxidative DNA damage, and deficient repair of oxidative DNA lesions repair have been proposed to contribute to the development of schizophrenia and ASD. In this article, we summarize the current evidence of cancer comorbidity in these brain disorders and discuss the putative roles of oxidative stress, DNA damage and DNA repair in the aetiopathology of schizophrenia and ASD. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)
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Review
Activation of DNA Damage Response Induced by the Kaposi’s Sarcoma-Associated Herpes Virus
Int. J. Mol. Sci. 2016, 17(6), 854; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17060854 - 01 Jun 2016
Cited by 5 | Viewed by 2869
Abstract
The human herpes virus 8 (HHV-8), also known as Kaposi sarcoma-associated herpes virus (KSHV), can infect endothelial cells often leading to cell transformation and to the development of tumors, namely Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and the plasmablastic variant of multicentric [...] Read more.
The human herpes virus 8 (HHV-8), also known as Kaposi sarcoma-associated herpes virus (KSHV), can infect endothelial cells often leading to cell transformation and to the development of tumors, namely Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and the plasmablastic variant of multicentric Castleman’s disease. KSHV is prevalent in areas such as sub-Saharan Africa and the Mediterranean region presenting distinct genotypes, which appear to be associated with differences in disease manifestation, according to geographical areas. In infected cells, KSHV persists in a latent episomal form. However, in a limited number of cells, it undergoes spontaneous lytic reactivation to ensure the production of new virions. During both the latent and the lytic cycle, KSHV is programmed to express genes which selectively modulate the DNA damage response (DDR) through the activation of the ataxia telangiectasia mutated (ATM) pathway and by phosphorylating factors associated with the DDR, including the major tumor suppressor protein p53 tumor suppressor p53. This review will focus on the interplay between the KSHV and the DDR response pathway throughout the viral lifecycle, exploring the putative molecular mechanism/s that may contribute to malignant transformation of host cells. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)
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Review
Targeting DNA Damage Response in the Radio(Chemo)therapy of Non-Small Cell Lung Cancer
Int. J. Mol. Sci. 2016, 17(6), 839; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17060839 - 31 May 2016
Cited by 35 | Viewed by 4133
Abstract
Lung cancer is the leading cause of cancer death worldwide due to its high incidence and mortality. As the most common lung cancer, non-small cell lung cancer (NSCLC) is a terrible threat to human health. Despite improvements in diagnosis and combined treatments including [...] Read more.
Lung cancer is the leading cause of cancer death worldwide due to its high incidence and mortality. As the most common lung cancer, non-small cell lung cancer (NSCLC) is a terrible threat to human health. Despite improvements in diagnosis and combined treatments including surgical resection, radiotherapy and chemotherapy, the overall survival for NSCLC patients still remains poor. DNA damage is considered to be the primary cause of lung cancer development and is normally recognized and repaired by the intrinsic DNA damage response machinery. The role of DNA repair pathways in radio(chemo)therapy-resistant cancers has become an area of significant interest in the clinical setting. Meanwhile, some studies have proved that genetic and epigenetic factors can alter the DNA damage response and repair, which results in changes of the radiation and chemotherapy curative effect in NSCLC. In this review, we focus on the effect of genetic polymorphisms and epigenetic factors such as miRNA regulation and lncRNA regulation participating in DNA damage repair in response to radio(chemo)therapy in NSCLC. These may provide novel information on the radio(chemo)therapy of NSCLC based on the individual DNA damage response. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)
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Review
The Growing Complexity of Cancer Cell Response to DNA-Damaging Agents: Caspase 3 Mediates Cell Death or Survival?
Int. J. Mol. Sci. 2016, 17(5), 708; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17050708 - 11 May 2016
Cited by 53 | Viewed by 3867
Abstract
It is widely stated that wild-type p53 either mediates the activation of cell cycle checkpoints to facilitate DNA repair and promote cell survival, or orchestrates apoptotic cell death following exposure to cancer therapeutic agents. This reigning paradigm has been challenged by numerous discoveries [...] Read more.
It is widely stated that wild-type p53 either mediates the activation of cell cycle checkpoints to facilitate DNA repair and promote cell survival, or orchestrates apoptotic cell death following exposure to cancer therapeutic agents. This reigning paradigm has been challenged by numerous discoveries with different human cell types, including solid tumor-derived cell lines. Thus, activation of the p53 signaling pathway by ionizing radiation and other DNA-damaging agents hinders apoptosis and triggers growth arrest (e.g., through premature senescence) in some genetic backgrounds; such growth arrested cells remain viable, secrete growth-promoting factors, and give rise to progeny with stem cell-like properties. In addition, caspase 3, which is best known for its role in the execution phase of apoptosis, has been recently reported to facilitate (rather than suppress) DNA damage-induced genomic instability and carcinogenesis. This observation is consistent with an earlier report demonstrating that caspase 3 mediates secretion of the pro-survival factor prostaglandin E2, which in turn promotes enrichment of tumor repopulating cells. In this article, we review these and related discoveries and point out novel cancer therapeutic strategies. One of our objectives is to demonstrate the growing complexity of the DNA damage response beyond the conventional “repair and survive, or die” hypothesis. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)
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Review
Connecting the Dots: From DNA Damage and Repair to Aging
Int. J. Mol. Sci. 2016, 17(5), 685; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17050685 - 06 May 2016
Cited by 29 | Viewed by 3654
Abstract
Mammalian cells evolve a delicate system, the DNA damage response (DDR) pathway, to monitor genomic integrity and to prevent the damage from both endogenous end exogenous insults. Emerging evidence suggests that aberrant DDR and deficient DNA repair are strongly associated with cancer and [...] Read more.
Mammalian cells evolve a delicate system, the DNA damage response (DDR) pathway, to monitor genomic integrity and to prevent the damage from both endogenous end exogenous insults. Emerging evidence suggests that aberrant DDR and deficient DNA repair are strongly associated with cancer and aging. Our understanding of the core program of DDR has made tremendous progress in the past two decades. However, the long list of the molecules involved in the DDR and DNA repair continues to grow and the roles of the new “dots” are under intensive investigation. Here, we review the connection between DDR and DNA repair and aging and discuss the potential mechanisms by which deficient DNA repair triggers systemic effects to promote physiological or pathological aging. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)
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Review
Roles of RNA-Binding Proteins in DNA Damage Response
Int. J. Mol. Sci. 2016, 17(3), 310; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17030310 - 27 Feb 2016
Cited by 54 | Viewed by 6967 | Correction
Abstract
Living cells experience DNA damage as a result of replication errors and oxidative metabolism, exposure to environmental agents (e.g., ultraviolet light, ionizing radiation (IR)), and radiation therapies and chemotherapies for cancer treatments. Accumulation of DNA damage can lead to multiple diseases such as [...] Read more.
Living cells experience DNA damage as a result of replication errors and oxidative metabolism, exposure to environmental agents (e.g., ultraviolet light, ionizing radiation (IR)), and radiation therapies and chemotherapies for cancer treatments. Accumulation of DNA damage can lead to multiple diseases such as neurodegenerative disorders, cancers, immune deficiencies, infertility, and also aging. Cells have evolved elaborate mechanisms to deal with DNA damage. Networks of DNA damage response (DDR) pathways are coordinated to detect and repair DNA damage, regulate cell cycle and transcription, and determine the cell fate. Upstream factors of DNA damage checkpoints and repair, “sensor” proteins, detect DNA damage and send the signals to downstream factors in order to maintain genomic integrity. Unexpectedly, we have discovered that an RNA-processing factor is involved in DNA repair processes. We have identified a gene that contributes to glioblastoma multiforme (GBM)’s treatment resistance and recurrence. This gene, RBM14, is known to function in transcription and RNA splicing. RBM14 is also required for maintaining the stem-like state of GBM spheres, and it controls the DNA-PK-dependent non-homologous end-joining (NHEJ) pathway by interacting with KU80. RBM14 is a RNA-binding protein (RBP) with low complexity domains, called intrinsically disordered proteins (IDPs), and it also physically interacts with PARP1. Furthermore, RBM14 is recruited to DNA double-strand breaks (DSBs) in a poly(ADP-ribose) (PAR)-dependent manner (unpublished data). DNA-dependent PARP1 (poly-(ADP) ribose polymerase 1) makes key contributions in the DNA damage response (DDR) network. RBM14 therefore plays an important role in a PARP-dependent DSB repair process. Most recently, it was shown that the other RBPs with intrinsically disordered domains are recruited to DNA damage sites in a PAR-dependent manner, and that these RBPs form liquid compartments (also known as “liquid-demixing”). Among the PAR-associated IDPs are FUS/TLS (fused in sarcoma/translocated in sarcoma), EWS (Ewing sarcoma), TARF15 (TATA box-binding protein-associated factor 68 kDa) (also called FET proteins), a number of heterogeneous nuclear ribonucleoproteins (hnRNPs), and RBM14. Importantly, various point mutations within the FET genes have been implicated in pathological protein aggregation in neurodegenerative diseases, specifically with amyotrophic lateral sclerosis (ALS), and frontotemporal lobe degeneration (FTLD). The FET proteins also frequently exhibit gene translocation in human cancers, and emerging evidence shows their physical interactions with DDR proteins and thus implies their involvement in the maintenance of genome stability. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)
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