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Special Issue "DNA Damage and Repair in Degenerative Diseases"

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

Deadline for manuscript submissions: closed (30 September 2012)

Special Issue Editor

Guest Editor
Prof. Guillermo T. Sáez

Department of Biochemistry and Molecular Biology, Faculty of Medicine and Odontology-INCLIVA, Service of Clinical Analysis, University Hospital Dr. Peset, University of Valencia, Avda. Blasco Ibañez 15, Valencia, Spain
Phone: +34 963864160
Fax: +34 96 386 4101
Interests: Oxidative stress-induced DNA damage and repair and its repair mechanisms in cardiometabolic and cancer diseases.

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Published Papers (23 papers)

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Research

Jump to: Review

Open AccessArticle Topoisomerase II Inhibitors Can Enhance Baculovirus-Mediated Gene Expression in Mammalian Cells through the DNA Damage Response
Int. J. Mol. Sci. 2016, 17(6), 931; doi:10.3390/ijms17060931
Received: 14 March 2016 / Revised: 21 May 2016 / Accepted: 7 June 2016 / Published: 14 June 2016
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Abstract
BacMam is an insect-derived recombinant baculovirus that can deliver genes into mammalian cells. BacMam vectors carrying target genes are able to enter a variety of cell lines by endocytosis, but the level of expression of the transgene depends on the cell line [...] Read more.
BacMam is an insect-derived recombinant baculovirus that can deliver genes into mammalian cells. BacMam vectors carrying target genes are able to enter a variety of cell lines by endocytosis, but the level of expression of the transgene depends on the cell line and the state of the transduced cells. In this study, we demonstrated that the DNA damage response (DDR) could act as an alternative pathway to boost the transgene(s) expression by BacMam and be comparable to the inhibitors of histone deacetylase. Topoisomerase II (Top II) inhibitor-induced DDR can enhance the CMV-IE/enhancer mediated gene expression up to 12-fold in BacMam-transduced U-2OS cells. The combination of a Top II inhibitor, VM-26, can also augment the killing efficiency of a p53-expressing BacMam vector in U-2OS osteosarcoma cells. These results open a new avenue to facilitate the application of BacMam for gene delivery and therapy. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
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Open AccessArticle All-Trans Retinoic Acid Modulates DNA Damage Response and the Expression of the VEGF-A and MKI67 Genes in ARPE-19 Cells Subjected to Oxidative Stress
Int. J. Mol. Sci. 2016, 17(6), 898; doi:10.3390/ijms17060898
Received: 31 March 2016 / Revised: 23 May 2016 / Accepted: 27 May 2016 / Published: 14 June 2016
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Abstract
Age-related macular degeneration (AMD) is characterized by the progressive degradation of photoreceptors and retinal pigment epithelium (RPE) cells. ARPE-19 is an RPE cell line established as an in vitro model for the study of AMD pathogenesis. Oxidative stress is an AMD pathogenesis [...] Read more.
Age-related macular degeneration (AMD) is characterized by the progressive degradation of photoreceptors and retinal pigment epithelium (RPE) cells. ARPE-19 is an RPE cell line established as an in vitro model for the study of AMD pathogenesis. Oxidative stress is an AMD pathogenesis factor that induces DNA damage. Thus, the oxidative stress-mediated DNA damage response (DDR) of ARPE-19 cells can be important in AMD pathogenesis. The metabolism of retinoids—which regulates cell proliferation, differentiation, and the visual cycle in the retina—was reported to be disturbed in AMD patients. In the present work, we studied the effect of all-trans retinoic acid (ATRA, a retinoid) on DDR in ARPE-19 cells subjected to oxidative stress. We observed that ATRA increased the level of reactive oxygen species (ROS), alkali-labile sites in DNA, DNA single-strand breaks, and cell death evoked by oxidative stress. ATRA did not modulate DNA repair or the distribution of cells in cell cycle in the response of ARPE-19 cells to oxidative stress. ATRA induced autophagy in the absence of oxidative stress, but had no effect on this process in the stress. ATRA induced over-expression of proliferation marker MKI67 and neovascularization marker VEGF-A. In conclusion, ATRA increased oxidative stress in ARPE-19 cells, resulting in more lesions to their DNA and cell death. Moreover, ATRA can modulate some properties of these cells, including neovascularization, which is associated with the exudative form of AMD. Therefore, ATRA can be important in the prevention, diagnosis, and therapy of AMD. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
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Open AccessArticle 5-bp Classical Satellite DNA Loci from Chromosome-1 Instability in Cervical Neoplasia Detected by DNA Breakage Detection/Fluorescence in Situ Hybridization (DBD-FISH)
Int. J. Mol. Sci. 2013, 14(2), 4135-4147; doi:10.3390/ijms14024135
Received: 24 December 2012 / Revised: 28 January 2013 / Accepted: 28 January 2013 / Published: 19 February 2013
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Abstract
We aimed to evaluate the association between the progressive stages of cervical neoplasia and DNA damage in 5-bp classical satellite DNA sequences from chromosome-1 in cervical epithelium and in peripheral blood lymphocytes using DNA breakage detection/fluorescence in situ hybridization (DBD-FISH). A hospital-based [...] Read more.
We aimed to evaluate the association between the progressive stages of cervical neoplasia and DNA damage in 5-bp classical satellite DNA sequences from chromosome-1 in cervical epithelium and in peripheral blood lymphocytes using DNA breakage detection/fluorescence in situ hybridization (DBD-FISH). A hospital-based unmatched case-control study was conducted in 2011 with a sample of 30 women grouped according to disease stage and selected according to histological diagnosis; 10 with low-grade squamous intraepithelial lesions (LG-SIL), 10 with high-grade SIL (HG-SIL), and 10 with no cervical lesions, from the Unidad Medica de Alta Especialidad of The Mexican Social Security Institute, IMSS, Mexico. Specific chromosome damage levels in 5-bp classical satellite DNA sequences from chromosome-1 were evaluated in cervical epithelium and peripheral blood lymphocytes using the DBD-FISH technique. Whole-genome DNA hybridization was used as a reference for the level of damage. Results of Kruskal-Wallis test showed a significant increase according to neoplastic development in both tissues. The instability of 5-bp classical satellite DNA sequences from chromosome-1 was evidenced using chromosome-orientation FISH. In conclusion, we suggest that the progression to malignant transformation involves an increase in the instability of 5-bp classical satellite DNA sequences from chromosome-1. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessArticle Oxidative Stress and DNA Damage in Human Gastric Carcinoma: 8-Oxo-7'8-dihydro-2'-deoxyguanosine (8-oxo-dG) as a Possible Tumor Marker
Int. J. Mol. Sci. 2013, 14(2), 3467-3486; doi:10.3390/ijms14023467
Received: 6 October 2012 / Revised: 8 January 2013 / Accepted: 11 January 2013 / Published: 6 February 2013
Cited by 11 | PDF Full-text (525 KB) | HTML Full-text | XML Full-text
Abstract
We characterized the oxidative stress (OS) status by the levels of reduced/oxidized glutathione (GSH/GSSG), malondialdehyde (MDA) and the mutagenic base 8-oxo-7'8-dihydro-2'-deoxyguanosine (8-oxo-dG) in human gastric carcinoma (HGC) samples and compared the results with normal tissue from the same patients. We also analyzed [...] Read more.
We characterized the oxidative stress (OS) status by the levels of reduced/oxidized glutathione (GSH/GSSG), malondialdehyde (MDA) and the mutagenic base 8-oxo-7'8-dihydro-2'-deoxyguanosine (8-oxo-dG) in human gastric carcinoma (HGC) samples and compared the results with normal tissue from the same patients. We also analyzed 8-oxo-dG in peripheral mononuclear cells (PMNC) and urine from healthy control subjects and in affected patients in the basal state and one, three, six, nine and twelve months after tumor resection. The levels of DNA repair enzyme mRNA expression (hOGG1, RAD51, MUYTH and MTH1) were determined in tumor specimens and compared with normal mucosa. Tumor specimens exhibited increased levels of MDA and 8-oxo-dG compared with normal gastric tissue. GSH levels were also increased, while GSSG levels remained stable. DNA repair enzyme mRNA expression was induced in the tumor tissues. Levels of 8-oxo-dG were significantly elevated in both urine and PMNC of gastric cancer patients compared with healthy controls. After gastrectomy, the levels of the damaged base in urine and PMNC decreased progressively to values close to those found in the healthy population. The high levels of 8-oxo-dG in urine may be related to the increased induction of DNA repair activity in tumor tissue, and the changes observed after tumor resection support its potential use as a tumor marker. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessArticle Identification of Candidate Polymorphisms on Stress Oxidative and DNA Damage Repair Genes Related with Clinical Outcome in Breast Cancer Patients
Int. J. Mol. Sci. 2012, 13(12), 16500-16513; doi:10.3390/ijms131216500
Received: 10 October 2012 / Revised: 23 November 2012 / Accepted: 27 November 2012 / Published: 5 December 2012
Cited by 1 | PDF Full-text (507 KB) | HTML Full-text | XML Full-text
Abstract
Diverse polymorphisms have been associated with the predisposition to develop cancer. On fewer occasions, they have been related to the evolution of the disease and to different responses to treatment. Previous studies of our group have associated polymorphisms on genes related to [...] Read more.
Diverse polymorphisms have been associated with the predisposition to develop cancer. On fewer occasions, they have been related to the evolution of the disease and to different responses to treatment. Previous studies of our group have associated polymorphisms on genes related to oxidative stress (rs3736729 on GCLC and rs207454 on XDH) and DNA damage repair (rs1052133 on OGG1) with a predisposition to develop breast cancer. In the present work, we have evaluated the hypothesis that these polymorphisms also play a role in a patient’s survival. A population-based cohort study of 470 women diagnosed with primary breast cancer and a median follow up of 52.44 months was conducted to examine the disease-free and overall survival in rs3736729, rs207454 and rs1052133 genetic variants. Adjusted Cox regression analysis was used to that end. The Kaplan-Meier analysis shows that rs3736729 on GCLC presents a significant association with disease-free survival and overall survival. The polymorphisms rs1052133 on OGG1 and rs207454 on XDH show a trend of association with overall survival. The analysis based on hormonal receptor status revealed a stronger association. The CC genotype on rs207454 (XDH) was significantly associated with lower time of disease free survival (p = 0.024) in progesterone receptor negative (PGR−) patients and rs3736729 (GCLC) was significantly associated with disease free survival (p = 0.001) and overall survival (p = 0.012) in the subgroup of estrogen receptor negative (ER−) patients. This work suggests that unfavorable genetic variants in the rs207454 (XDH) and rs3736729 (GCLC) polymorphisms may act as predictors of the outcome in negative progesterone receptor and negative estrogen receptor breast cancer patients, respectively. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessArticle Alzheimer’s Disease-Associated Neurotoxic Peptide Amyloid-Β Impairs Base Excision Repair in Human Neuroblastoma Cells
Int. J. Mol. Sci. 2012, 13(11), 14766-14787; doi:10.3390/ijms131114766
Received: 14 August 2012 / Revised: 18 September 2012 / Accepted: 8 October 2012 / Published: 13 November 2012
Cited by 8 | PDF Full-text (401 KB) | HTML Full-text | XML Full-text
Abstract
Alzheimer’s disease (AD) is the leading cause of dementia in developed countries. It is characterized by two major pathological hallmarks, one of which is the extracellular aggregation of the neurotoxic peptide amyloid-β (Aβ), which is known to generate oxidative stress. In this [...] Read more.
Alzheimer’s disease (AD) is the leading cause of dementia in developed countries. It is characterized by two major pathological hallmarks, one of which is the extracellular aggregation of the neurotoxic peptide amyloid-β (Aβ), which is known to generate oxidative stress. In this study, we showed that the presence of Aβ in a neuroblastoma cell line led to an increase in both nuclear and mitochondrial DNA damage. Unexpectedly, a concomitant decrease in basal level of base excision repair, a major route for repairing oxidative DNA damage, was observed at the levels of both gene expression and protein activity. Moreover, the addition of copper sulfate or hydrogen peroxide, used to mimic the oxidative stress observed in AD-affected brains, potentiates Aβ-mediated perturbation of DNA damage/repair systems in the “Aβ cell line”. Taken together, these findings indicate that Aβ could act as double-edged sword by both increasing oxidative nuclear/mitochondrial damage and preventing its repair. The synergistic effects of increased ROS production, accumulated DNA damage and impaired DNA repair could participate in, and partly explain, the massive loss of neurons observed in Alzheimer’s disease since both oxidative stress and DNA damage can trigger apoptosis. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessArticle Lower Salinomycin Concentration Increases Apoptotic Detachment in High-Density Cancer Cells
Int. J. Mol. Sci. 2012, 13(10), 13169-13182; doi:10.3390/ijms131013169
Received: 7 September 2012 / Revised: 28 September 2012 / Accepted: 9 October 2012 / Published: 12 October 2012
Cited by 8 | PDF Full-text (717 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The present study identified a novel salinomycin (Sal) sensitization mechanism in cancer. We tested whether Sal reduced proliferation in a high-density population by counting attached cell numbers after Sal treatment. Sal reduced proliferation in high-density cell populations. Longer exposure to Sal further reduced proliferation. Sal concentrations of 0.1 and 5 μM had similar sensitization effects, suggesting that Sal toxicity was minimal with longer exposure to a high-density cell population. The results suggest that Sal can be applied at a relatively low concentration for a longer time to overcome drug-resistant solid tumors. The 0.5 μM Sal treatment resulted in fewer attached cells than that of the 5 μM Sal treatment with a longer exposure. The lower Sal concentration mainly increased the number of easily detachable cells on the surface. In particular, 0.5 μM Sal increased cellular detachment of newly produced daughter cells. The easily-detachable cells were undergoing apoptosis. It seems that the 0.5 μM Sal treatment also increased cellular toxicity. These novel findings may contribute to the development of Sal-based therapy for patients with drug-resistant cancer or a high-density solid tumor. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)

Review

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Open AccessReview p53 and Ceramide as Collaborators in the Stress Response
Int. J. Mol. Sci. 2013, 14(3), 4982-5012; doi:10.3390/ijms14034982
Received: 26 December 2012 / Revised: 22 January 2013 / Accepted: 1 February 2013 / Published: 1 March 2013
Cited by 7 | PDF Full-text (3569 KB) | HTML Full-text | XML Full-text
Abstract
The sphingolipid ceramide mediates various cellular processes in response to several extracellular stimuli. Some genotoxic stresses are able to induce p53-dependent ceramide accumulation leading to cell death. However, in other cases, in the absence of the tumor suppressor protein p53, apoptosis proceeds [...] Read more.
The sphingolipid ceramide mediates various cellular processes in response to several extracellular stimuli. Some genotoxic stresses are able to induce p53-dependent ceramide accumulation leading to cell death. However, in other cases, in the absence of the tumor suppressor protein p53, apoptosis proceeds partly due to the activity of this “tumor suppressor lipid”, ceramide. In the current review, we describe ceramide and its roles in signaling pathways such as cell cycle arrest, hypoxia, hyperoxia, cell death, and cancer. In a specific manner, we are elaborating on the role of ceramide in mitochondrial apoptotic cell death signaling. Furthermore, after highlighting the role and mechanism of action of p53 in apoptosis, we review the association of ceramide and p53 with respect to apoptosis. Strikingly, the hypothesis for a direct interaction between ceramide and p53 is less favored. Recent data suggest that ceramide can act either upstream or downstream of p53 protein through posttranscriptional regulation or through many potential mediators, respectively. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessReview Mitochondrial and Nuclear DNA Damage and Repair in Age-Related Macular Degeneration
Int. J. Mol. Sci. 2013, 14(2), 2996-3010; doi:10.3390/ijms14022996
Received: 30 November 2012 / Revised: 4 January 2013 / Accepted: 25 January 2013 / Published: 31 January 2013
Cited by 22 | PDF Full-text (1297 KB) | HTML Full-text | XML Full-text
Abstract
Aging and oxidative stress seem to be the most important factors in the pathogenesis of age-related macular degeneration (AMD), a condition affecting many elderly people in the developed world. However, aging is associated with the accumulation of oxidative damage in many biomolecules, [...] Read more.
Aging and oxidative stress seem to be the most important factors in the pathogenesis of age-related macular degeneration (AMD), a condition affecting many elderly people in the developed world. However, aging is associated with the accumulation of oxidative damage in many biomolecules, including DNA. Furthermore, mitochondria may be especially important in this process because the reactive oxygen species produced in their electron transport chain can damage cellular components. Therefore, the cellular response to DNA damage, expressed mainly through DNA repair, may play an important role in AMD etiology. In several studies the increase in mitochondrial DNA (mtDNA) damage and mutations, and the decrease in the efficacy of DNA repair have been correlated with the occurrence and the stage of AMD. It has also been shown that mitochondrial DNA accumulates more DNA lesions than nuclear DNA in AMD. However, the DNA damage response in mitochondria is executed by nucleus-encoded proteins, and thus mutagenesis in nuclear DNA (nDNA) may affect the ability to respond to mutagenesis in its mitochondrial counterpart. We reported that lymphocytes from AMD patients displayed a higher amount of total endogenous basal and oxidative DNA damage, exhibited a higher sensitivity to hydrogen peroxide and UV radiation, and repaired the lesions induced by these factors less effectively than did cells from control individuals. We postulate that poor efficacy of DNA repair (i.e., is impaired above average for a particular age) when combined with the enhanced sensitivity of retinal pigment epithelium cells to environmental stress factors, contributes to the pathogenesis of AMD. Collectively, these data suggest that the cellular response to both mitochondrial and nuclear DNA damage may play an important role in AMD pathogenesis. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessReview Maintenance of Genomic Stability in Mouse Embryonic Stem Cells: Relevance in Aging and Disease
Int. J. Mol. Sci. 2013, 14(2), 2617-2636; doi:10.3390/ijms14022617
Received: 13 November 2012 / Revised: 11 January 2013 / Accepted: 12 January 2013 / Published: 28 January 2013
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Abstract
Recent studies have shown that mouse embryonic stem cells (mESCs) rely on a distinctive genome caretaking network. In this review, we will discuss how mESCs functionally respond to DNA damage and describe several modifications in mESC DNA damage response, which accommodate dynamic [...] Read more.
Recent studies have shown that mouse embryonic stem cells (mESCs) rely on a distinctive genome caretaking network. In this review, we will discuss how mESCs functionally respond to DNA damage and describe several modifications in mESC DNA damage response, which accommodate dynamic cycling and preservation of genetic information. Subsequently, we will discuss how the transition from mESCs to adult stem/progenitor cells can be involved in the decline of tissue integrity and function in the elderly. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessReview The Yin-Yang of DNA Damage Response: Roles in Tumorigenesis and Cellular Senescence
Int. J. Mol. Sci. 2013, 14(2), 2431-2448; doi:10.3390/ijms14022431
Received: 16 November 2012 / Revised: 8 January 2013 / Accepted: 9 January 2013 / Published: 25 January 2013
Cited by 2 | PDF Full-text (394 KB) | HTML Full-text | XML Full-text
Abstract
Senescent cells are relatively stable, lacking proliferation capacity yet retaining metabolic activity. In contrast, cancer cells are rather invasive and devastating, with uncontrolled proliferative capacity and resistance to cell death signals. Although tumorigenesis and cellular senescence are seemingly opposite pathological events, they [...] Read more.
Senescent cells are relatively stable, lacking proliferation capacity yet retaining metabolic activity. In contrast, cancer cells are rather invasive and devastating, with uncontrolled proliferative capacity and resistance to cell death signals. Although tumorigenesis and cellular senescence are seemingly opposite pathological events, they are actually driven by a unified mechanism: DNA damage. Integrity of the DNA damage response (DDR) network can impose a tumorigenesis barrier by navigating abnormal cells to cellular senescence. Compromise of DDR, possibly due to the inactivation of DDR components, may prevent cellular senescence but at the expense of tumor formation. Here we provide an overview of the fundamental role of DDR in tumorigenesis and cellular senescence, under the light of the Yin-Yang concept of Chinese philosophy. Emphasis is placed on discussing DDR outcome in the light of in vivo models. This information is critical as it can help make better decisions for clinical treatments of cancer patients. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessReview Parkinson’s Disease: A Complex Interplay of Mitochondrial DNA Alterations and Oxidative Stress
Int. J. Mol. Sci. 2013, 14(2), 2388-2409; doi:10.3390/ijms14022388
Received: 5 December 2012 / Revised: 14 January 2013 / Accepted: 21 January 2013 / Published: 24 January 2013
Cited by 22 | PDF Full-text (300 KB) | HTML Full-text | XML Full-text
Abstract
Parkinson’s disease (PD) is one of the most common age-related neurodegenerative diseases. This pathology causes a significant loss of dopaminergic neurons in the Substantia Nigra. Several reports have claimed a role of defective nuclear and mitochondrial DNA repair pathways in PD [...] Read more.
Parkinson’s disease (PD) is one of the most common age-related neurodegenerative diseases. This pathology causes a significant loss of dopaminergic neurons in the Substantia Nigra. Several reports have claimed a role of defective nuclear and mitochondrial DNA repair pathways in PD etiology, in particular, of the Base Excision Repair (BER) system. In addition, recent findings, related to PD progression, indicate that oxidative stress pathways involving c-Abl and GST could also be implicated in this pathology. This review focuses on recently described networks most likely involved in an integrated manner in the course of PD. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
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Open AccessReview X-Ray Repair Cross Complementing Protein 1 in Base Excision Repair
Int. J. Mol. Sci. 2012, 13(12), 17210-17229; doi:10.3390/ijms131217210
Received: 9 November 2012 / Revised: 6 December 2012 / Accepted: 7 December 2012 / Published: 17 December 2012
Cited by 6 | PDF Full-text (520 KB) | HTML Full-text | XML Full-text
Abstract
X-ray Repair Cross Complementing protein 1 (XRCC1) acts as a scaffolding protein in the converging base excision repair (BER) and single strand break repair (SSBR) pathways. XRCC1 also interacts with itself and rapidly accumulates at sites of DNA damage. XRCC1 can thus [...] Read more.
X-ray Repair Cross Complementing protein 1 (XRCC1) acts as a scaffolding protein in the converging base excision repair (BER) and single strand break repair (SSBR) pathways. XRCC1 also interacts with itself and rapidly accumulates at sites of DNA damage. XRCC1 can thus mediate the assembly of large multiprotein DNA repair complexes as well as facilitate the recruitment of DNA repair proteins to sites of DNA damage. Moreover, XRCC1 is present in constitutive DNA repair complexes, some of which associate with the replication machinery. Because of the critical role of XRCC1 in DNA repair, its common variants Arg194Trp, Arg280His and Arg399Gln have been extensively studied. However, the prevalence of these variants varies strongly in different populations, and their functional influence on DNA repair and disease remains elusive. Here we present the current knowledge about the role of XRCC1 and its variants in BER and human disease/cancer. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessReview DNA Damage and Repair in Atherosclerosis: Current Insights and Future Perspectives
Int. J. Mol. Sci. 2012, 13(12), 16929-16944; doi:10.3390/ijms131216929
Received: 28 September 2012 / Revised: 20 November 2012 / Accepted: 5 December 2012 / Published: 11 December 2012
Cited by 12 | PDF Full-text (440 KB) | HTML Full-text | XML Full-text
Abstract
Atherosclerosis is the leading cause of morbidity and mortality among Western populations. Over the past two decades, considerable evidence has supported a crucial role for DNA damage in the development and progression of atherosclerosis. These findings support the concept that the prolonged [...] Read more.
Atherosclerosis is the leading cause of morbidity and mortality among Western populations. Over the past two decades, considerable evidence has supported a crucial role for DNA damage in the development and progression of atherosclerosis. These findings support the concept that the prolonged exposure to risk factors (e.g., dyslipidemia, smoking and diabetes mellitus) leading to reactive oxygen species are major stimuli for DNA damage within the plaque. Genomic instability at the cellular level can directly affect vascular function, leading to cell cycle arrest, apoptosis and premature vascular senescence. The purpose of this paper is to review current knowledge on the role of DNA damage and DNA repair systems in atherosclerosis, as well as to discuss the cellular response to DNA damage in order to shed light on possible strategies for prevention and treatment. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessReview DNA Damage Due to Oxidative Stress in Chronic Obstructive Pulmonary Disease (COPD)
Int. J. Mol. Sci. 2012, 13(12), 16853-16864; doi:10.3390/ijms131216853
Received: 28 September 2012 / Revised: 31 October 2012 / Accepted: 19 November 2012 / Published: 10 December 2012
Cited by 15 | PDF Full-text (177 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
According to the American Thorasic Society (ATS)/European Respiratory Society (ERS) Statement, chronic obstructive pulmonary disease (COPD) is defined as a preventable and treatable disease with a strong genetic component, characterized by airflow limitation that is not fully reversible, but is usually progressive [...] Read more.
According to the American Thorasic Society (ATS)/European Respiratory Society (ERS) Statement, chronic obstructive pulmonary disease (COPD) is defined as a preventable and treatable disease with a strong genetic component, characterized by airflow limitation that is not fully reversible, but is usually progressive and associated with an enhanced inflammatory response of the lung to noxious particles or gases. The main features of COPD are chronic inflammation of the airways and progressive destruction of lung parenchyma and alveolar structure. The pathogenesis of COPD is complex due to the interactions of several mechanisms, such as inflammation, proteolytic/antiproteolytic imbalance, oxidative stress, DNA damage, apoptosis, enhanced senescence of the structural cells and defective repair processes. This review focuses on the effects of oxidative DNA damage and the consequent immune responses in COPD. In susceptible individuals, cigarette smoke injures the airway epithelium generating the release of endogenous intracellular molecules or danger-associated molecular patterns from stressed or dying cells. These signals are captured by antigen presenting cells and are transferred to the lymphoid tissue, generating an adaptive immune response and enhancing chronic inflammation. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
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Open AccessReview UBE4B: A Promising Regulatory Molecule in Neuronal Death and Survival
Int. J. Mol. Sci. 2012, 13(12), 16865-16879; doi:10.3390/ijms131216865
Received: 7 October 2012 / Revised: 22 November 2012 / Accepted: 27 November 2012 / Published: 10 December 2012
Cited by 1 | PDF Full-text (200 KB) | HTML Full-text | XML Full-text
Abstract
Neuronal survival and death of neurons are considered a fundamental mechanism in the regulation of the nervous system during early development of the system and in adulthood. Defects in this mechanism are highly problematic and are associated with many neurodegenerative diseases. Because [...] Read more.
Neuronal survival and death of neurons are considered a fundamental mechanism in the regulation of the nervous system during early development of the system and in adulthood. Defects in this mechanism are highly problematic and are associated with many neurodegenerative diseases. Because neuronal programmed death is apoptotic in nature, indicating that apoptosis is a key regulatory process, the p53 family members (p53, p73, p63) act as checkpoints in neurons due to their role in apoptosis. The complexity of this system is due to the existence of different naturally occurring isoforms that have different functions from the wild types (WT), varying from apoptotic to anti-apoptotic effects. In this review, we focus on the role of UBE4B (known as Ube4b or Ufd2a in mouse), an E3/E4 ligase that triggers substrate polyubiquitination, as a master regulatory ligase associated with the p53 family WT proteins and isoforms in regulating neuronal survival. UBE4B is also associated with other pathways independent of the p53 family, such as polyglutamine aggregation and Wallerian degeneration, both of which are critical in neurodegenerative diseases. Many of the hypotheses presented here are gateways to understanding the programmed death/survival of neurons regulated by UBE4B in normal physiology, and a means of introducing potential therapeutic approaches with implications in treating several neurodegenerative diseases. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessReview Integration of DNA Damage and Repair with Murine Double-Minute 2 (Mdm2) in Tumorigenesis
Int. J. Mol. Sci. 2012, 13(12), 16373-16386; doi:10.3390/ijms131216373
Received: 27 September 2012 / Revised: 27 November 2012 / Accepted: 27 November 2012 / Published: 3 December 2012
Cited by 2 | PDF Full-text (184 KB) | HTML Full-text | XML Full-text
Abstract
The alteration of tumorigenic pathways leading to cancer is a degenerative disease process typically involving inactivation of tumor suppressor proteins and hyperactivation of oncogenes. One such oncogenic protein product is the murine double-minute 2, or Mdm2. While, Mdm2 has been primarily associated [...] Read more.
The alteration of tumorigenic pathways leading to cancer is a degenerative disease process typically involving inactivation of tumor suppressor proteins and hyperactivation of oncogenes. One such oncogenic protein product is the murine double-minute 2, or Mdm2. While, Mdm2 has been primarily associated as the negative regulator of the p53 tumor suppressor protein there are many p53-independent roles demonstrated for this oncogene. DNA damage and chemotherapeutic agents are known to activate Mdm2 and DNA repair pathways. There are five primary DNA repair pathways involved in the maintenance of genomic integrity: Nucleotide excision repair (NER), Base excision repair (BER), Mismatch repair (MMR), Non-homologous end joining (NHEJ) and homologous recombination (HR). In this review, we will briefly describe these pathways and also delineate the functional interaction of Mdm2 with multiple DNA repair proteins. We will illustrate the importance of these interactions with Mdm2 and discuss how this is important for tumor progression, cellular proliferation in cancer. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessReview Base Excision Repair in Physiology and Pathology of the Central Nervous System
Int. J. Mol. Sci. 2012, 13(12), 16172-16222; doi:10.3390/ijms131216172
Received: 21 September 2012 / Revised: 6 November 2012 / Accepted: 12 November 2012 / Published: 30 November 2012
Cited by 5 | PDF Full-text (742 KB) | HTML Full-text | XML Full-text
Abstract
Relatively low levels of antioxidant enzymes and high oxygen metabolism result in formation of numerous oxidized DNA lesions in the tissues of the central nervous system. Accumulation of damage in the DNA, due to continuous genotoxic stress, has been linked to both [...] Read more.
Relatively low levels of antioxidant enzymes and high oxygen metabolism result in formation of numerous oxidized DNA lesions in the tissues of the central nervous system. Accumulation of damage in the DNA, due to continuous genotoxic stress, has been linked to both aging and the development of various neurodegenerative disorders. Different DNA repair pathways have evolved to successfully act on damaged DNA and prevent genomic instability. The predominant and essential DNA repair pathway for the removal of small DNA base lesions is base excision repair (BER). In this review we will discuss the current knowledge on the involvement of BER proteins in the maintenance of genetic stability in different brain regions and how changes in the levels of these proteins contribute to aging and the onset of neurodegenerative disorders. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessReview DNA Damage and Repair in Epithelium after Allogeneic Hematopoietic Stem Cell Transplantation
Int. J. Mol. Sci. 2012, 13(12), 15813-15825; doi:10.3390/ijms131215813
Received: 19 October 2012 / Revised: 18 November 2012 / Accepted: 19 November 2012 / Published: 27 November 2012
Cited by 2 | PDF Full-text (1247 KB) | HTML Full-text | XML Full-text
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in humans, following hematoablative treatment, results in biological chimeras. In this case, the transplanted hematopoietic, immune cells and their derivatives can be considered the donor genotype, while the other tissues are the recipient genotype. The first [...] Read more.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in humans, following hematoablative treatment, results in biological chimeras. In this case, the transplanted hematopoietic, immune cells and their derivatives can be considered the donor genotype, while the other tissues are the recipient genotype. The first sequel, which has been recognized in the development of chimerical organisms after allo-HSCT, is the graft versus host (GvH) reaction, in which the new developed immune cells from the graft recognize the host’s epithelial cells as foreign and mount an inflammatory response to kill them. There is now accumulating evidence that this chronic inflammatory tissue stress may contribute to clinical consequences in the transplant recipient. It has been recently reported that host epithelial tissue acquire genomic alterations and display a mutator phenotype that may be linked to the occurrence of a GvH reaction. The current review discusses existing data on this recently discovered phenomenon and focuses on the possible pathogenesis, clinical significance and therapeutic implications. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessReview A DNA Repair BRCA1 Estrogen Receptor and Targeted Therapy in Breast Cancer
Int. J. Mol. Sci. 2012, 13(11), 14898-14916; doi:10.3390/ijms131114898
Received: 24 September 2012 / Revised: 1 November 2012 / Accepted: 12 November 2012 / Published: 14 November 2012
Cited by 5 | PDF Full-text (829 KB) | HTML Full-text | XML Full-text
Abstract
BRCA1 is a key mediator of DNA repair pathways and participates in the maintenance of the genomic integrity of cells. The control of DNA damage repair mechanisms by BRCA1 is of great interest since molecular defects in this pathway may reflect a [...] Read more.
BRCA1 is a key mediator of DNA repair pathways and participates in the maintenance of the genomic integrity of cells. The control of DNA damage repair mechanisms by BRCA1 is of great interest since molecular defects in this pathway may reflect a predictive value in terms of a cell’s sensitivity to DNA damaging agents or anticancer drugs. BRCA1 has been found to exhibit a hormone-dependent pattern of expression in breast cells. Wild-type BRCA1 is required for the inhibition of the growth of breast tumor cells in response to the pure steroidal ERα antagonist fulvestrant. Also a loss of BRCA1-mediated transcriptional activation of ERα expression results in increased resistance to ERα antagonists. Platinum-based drugs, poly(ADP-ribose) polymerase (PARP) inhibitors, and their combination are currently included in chemotherapy regimens for breast cancer. Preclinical and clinical studies in a BRCA1-defective setting have recently indicated a rationale for the use of these compounds against hereditary breast cancers. Initial findings indicate that neoadjuvant use of cisplatin results in high rates of complete pathological response in patients with breast cancer who have BRCA1 mutations. Cisplatin produces a better response in triple-negative breast cancer (TNBC) than in non-TNBC diseases in both the neoadjuvant and adjuvant settings. This implies that TNBC cells may harbor a dysfunctional BRCA1 repair pathway. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessReview Genetic Variability in DNA Repair Proteins in Age-Related Macular Degeneration
Int. J. Mol. Sci. 2012, 13(10), 13378-13397; doi:10.3390/ijms131013378
Received: 8 August 2012 / Revised: 11 September 2012 / Accepted: 14 September 2012 / Published: 18 October 2012
Cited by 9 | PDF Full-text (205 KB) | HTML Full-text | XML Full-text
Abstract
The pathogenesis of age-related macular degeneration (AMD) is complex and involves interactions between environmental and genetic factors, with oxidative stress playing an important role inducing damage in biomolecules, including DNA. Therefore, genetic variability in the components of DNA repair systems may influence [...] Read more.
The pathogenesis of age-related macular degeneration (AMD) is complex and involves interactions between environmental and genetic factors, with oxidative stress playing an important role inducing damage in biomolecules, including DNA. Therefore, genetic variability in the components of DNA repair systems may influence the ability of the cell to cope with oxidative stress and in this way contribute to the pathogenesis of AMD. However, few reports have been published on this subject so far. We demonstrated that the c.977C>G polymorphism (rs1052133) in the hOGG1 gene and the c.972G>C polymorphism (rs3219489) in the MUTYH gene, the products of which play important roles in the repair of oxidatively damaged DNA, might be associated with the risk of AMD. Oxidative stress may promote misincorporation of uracil into DNA, where it is targeted by several DNA glycosylases. We observed that the g.4235T>C (rs2337395) and c.−32A>G (rs3087404) polymorphisms in two genes encoding such glycosylases, UNG and SMUG1, respectively, could be associated with the occurrence of AMD. Polymorphisms in some other DNA repair genes, including XPD (ERCC2), XRCC1 and ERCC6 (CSB) have also been reported to be associated with AMD. These data confirm the importance of the cellular reaction to DNA damage, and this may be influenced by variability in DNA repair genes, in AMD pathogenesis. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessReview Common Fragile Sites: Genomic Hotspots of DNA Damage and Carcinogenesis
Int. J. Mol. Sci. 2012, 13(9), 11974-11999; doi:10.3390/ijms130911974
Received: 17 July 2012 / Revised: 9 August 2012 / Accepted: 5 September 2012 / Published: 20 September 2012
Cited by 18 | PDF Full-text (425 KB) | HTML Full-text | XML Full-text
Abstract
Genomic instability, a hallmark of cancer, occurs preferentially at specific genomic regions known as common fragile sites (CFSs). CFSs are evolutionarily conserved and late replicating regions with AT-rich sequences, and CFS instability is correlated with cancer. In the last decade, much progress [...] Read more.
Genomic instability, a hallmark of cancer, occurs preferentially at specific genomic regions known as common fragile sites (CFSs). CFSs are evolutionarily conserved and late replicating regions with AT-rich sequences, and CFS instability is correlated with cancer. In the last decade, much progress has been made toward understanding the mechanisms of chromosomal instability at CFSs. However, despite tremendous efforts, identifying a cancer-associated CFS gene (CACG) remains a challenge and little is known about the function of CACGs at most CFS loci. Recent studies of FATS (for Fragile-site Associated Tumor Suppressor), a new CACG at FRA10F, reveal an active role of this CACG in regulating DNA damage checkpoints and suppressing tumorigenesis. The identification of FATS may inspire more discoveries of other uncharacterized CACGs. Further elucidation of the biological functions and clinical significance of CACGs may be exploited for cancer biomarkers and therapeutic benefits. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)
Open AccessReview Damaged DNA Binding Protein 2 in Reactive Oxygen Species (ROS) Regulation and Premature Senescence
Int. J. Mol. Sci. 2012, 13(9), 11012-11026; doi:10.3390/ijms130911012
Received: 6 August 2012 / Revised: 22 August 2012 / Accepted: 28 August 2012 / Published: 5 September 2012
Cited by 5 | PDF Full-text (308 KB) | HTML Full-text | XML Full-text
Abstract
Premature senescence induced by DNA damage or oncogene is a critical mechanism of tumor suppression. Reactive oxygen species (ROS) have been implicated in the induction of premature senescence response. Several pathological disorders such as cancer, aging and age related neurological abnormalities have [...] Read more.
Premature senescence induced by DNA damage or oncogene is a critical mechanism of tumor suppression. Reactive oxygen species (ROS) have been implicated in the induction of premature senescence response. Several pathological disorders such as cancer, aging and age related neurological abnormalities have been linked to ROS deregulation. Here, we discuss how Damaged DNA binding Protein-2 (DDB2), a nucleotide excision repair protein, plays an important role in ROS regulation by epigenetically repressing the antioxidant genes MnSOD and Catalase. We further revisit a model in which DDB2 plays an instrumental role in DNA damage induced ROS accumulation, ROS induced premature senescence and inhibition of skin tumorigenesis. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)

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