scholarly journals miR-200a Modulates the Expression of the DNA Repair Protein OGG1 Playing a Role in Aging of Primary Human Keratinocytes

2018 ◽  
Vol 2018 ◽  
pp. 1-17 ◽  
Author(s):  
Lavinia Tinaburri ◽  
Mariarosaria D’Errico ◽  
Sara Sileno ◽  
Riccardo Maurelli ◽  
Paolo Degan ◽  
...  
Keyword(s):  
Dna Repair ◽  
Oxidative Dna Damage ◽  
Human Keratinocytes ◽  
Primary Human Keratinocytes ◽  
Human Keratinocyte ◽  
Age Related ◽  
Dna Repair Protein ◽  
Repair Activity ◽  
Dna Strand ◽  
Base Lesion

Oxidative DNA damage accumulation may induce cellular senescence. Notably, senescent cells accumulate in aged tissues and are present at the sites of age-related pathologies. Although the signaling of DNA strand breaks has been extensively studied, the role of oxidative base lesions has not fully investigated in primary human keratinocyte aging. In this study, we show that primary human keratinocytes from elderly donors are characterized by a significant accumulation of the oxidative base lesion 8-OH-dG, impairment of oxidative DNA repair, and increase of miR-200a levels. Notably, OGG1-2a, a critical enzyme for 8-OH-dG repair, is a direct target of miR-200a and its expression levels significantly decrease in aged keratinocytes. The 8-OH-dG accumulation displays a significant linear relationship with the aging biomarker p16 expression during keratinocyte senescence. Interestingly, we found that miR-200a overexpression down-modulates its putative target Bmi-1, a well-known p16 repressor, and up-regulates p16 itself. miR-200a overexpression also up-regulates the NLRP3 inflammasome and IL-1β expression. Of note, primary keratinocytes from elderly donors are characterized by NRPL3 activation and IL-1β secretion. These findings point to miR-200a as key player in primary human keratinocyte aging since it is able to reduce oxidative DNA repair activity and may induce several senescence features through p16 and IL-1β up-regulation.

scholarly journals Age-Dependent Protective Effect of Selenium against UVA Irradiation in Primary Human Keratinocytes and the Associated DNA Repair Signature

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
C. Favrot ◽  
D. Beal ◽  
E. Blouin ◽  
M. T. Leccia ◽  
A. M. Roussel ◽  
...  
Keyword(s):  
Dna Repair ◽  
Oxidative Dna Damage ◽  
Human Keratinocytes ◽  
The Elderly ◽  
Protective Role ◽  
Skin Aging ◽  
Primary Human Keratinocytes ◽  
Skin Development ◽  
Uva Irradiation ◽  
The Impact

Few studies have focused on the protective role of selenium (Se) against skin aging and photoaging even though selenoproteins are essential for keratinocyte function and skin development. To the best of our knowledge, the impact of Se supplementation on skin cells from elderly and young donors has not been reported. Therefore, the main objective of our study was to evaluate the effects of Se supplementation on skin keratinocytes at baseline and after exposure to ultraviolet A (UVA) irradiation. Low doses of Se (30 nM) were very potently protective against UVA-induced cytotoxicity in young keratinocytes, whereas the protection efficiency of Se in old keratinocytes required higher concentrations (240 nM). Additionally, the DNA repair ability of the old keratinocytes drastically decreased compared with that of the young keratinocytes at baseline and after the UVA exposure. The Se supplementation significantly enhanced the DNA repair of 8-oxoguanine (8oxoG) only in the keratinocytes isolated from young donors. Therefore, aged keratinocytes have an increased vulnerability to oxidative DNA damage, and the Se needs in the elderly should be considered. Strengthening DNA repair activities with Se supplementation may represent a new strategy to combat aging and skin photoaging.

scholarly journals Molecular Signatures in the Prevention of Radiation Damage by the Synergistic Effect of N-Acetyl Cysteine and Qingre Liyan Decoction, a Traditional Chinese Medicine, Using a 3-Dimensional Cell Culture Model of Oral Mucositis

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Maria P. Lambros ◽  
Lavanya Kondapalli ◽  
Cyrus Parsa ◽  
Hari Chandana Mulamalla ◽  
Robert Orlando ◽  
...  
Keyword(s):  
Dna Repair ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Three Dimensional ◽  
Human Keratinocytes ◽  
Transcriptional Level ◽  
Tissue Cultures ◽  
Primary Human Keratinocytes ◽  
Microarray Gene Expression ◽  
Acetyl Cysteine

Qingre Liyan decoction (QYD), a Traditional Chinese medicine, and N-acetyl cysteine (NAC) have been used to prevent radiation induced mucositis. This work evaluates the protective mechanisms of QYD, NAC, and their combination (NAC-QYD) at the cellular and transcriptional level. A validated organotypic model of oral mucosal consisting of a three-dimensional (3D) cell tissue-culture of primary human keratinocytes exposed to X-ray irradiation was used. Six hours after the irradiation, the tissues were evaluated by hematoxylin and eosin (H and E) and a TUNEL assay to assess histopathology and apoptosis, respectively. Total RNA was extracted and used for microarray gene expression profiling. The tissue-cultures treated with NAC-QYD preserved their integrity and showed no apoptosis. Microarray results revealed that the NAC-QYD caused the upregulation of genes encoding metallothioneins,HMOX1, and other components of the Nrf2 pathway, which protects against oxidative stress. DNA repair genes (XCP,GADD45G,RAD9, andXRCC1), protective genes (EGFRandPPARD), and genes of the NFκB pathway were upregulated. Finally, tissue-cultures treated prophylactically with NAC-QYD showed significant downregulation of apoptosis, cytokines and chemokines genes, and constrained damage-associated molecular patterns (DAMPs). NAC-QYD treatment involves the protective effect of Nrf2, NFκB, and DNA repair factors.

scholarly journals New Mechanisms of DNA Repair Defects in Fused in Sarcoma–Associated Neurodegeneration: Stage Set for DNA Repair-Based Therapeutics?

2019 ◽  
Vol 13 ◽  
pp. 117906951985635 ◽  
Author(s):  
Haibo Wang ◽  
Muralidhar L Hegde
Keyword(s):  
Dna Repair ◽  
Oxidative Dna Damage ◽  
Direct Interaction ◽  
Loss Of Function ◽  
Fused In Sarcoma ◽  
Genome Damage ◽  
Damage Repair ◽  
Underlying Mechanisms ◽  
Dna Strand ◽  
Repair Defect

Genome damage and defective DNA repair are etiologically linked to several neurodegenerative disorders, including fused in sarcoma (FUS)–associated amyotrophic lateral sclerosis (ALS). However, the underlying mechanisms remain enigmatic, which is a roadblock for exploiting genome repair-targeted therapies. Our recent studies identified defects in DNA nick ligation and oxidative damage repair caused by mutations in the RNA/DNA-binding protein FUS in familial ALS patients. In healthy neurons, FUS protects the genome by facilitating PARP1-dependent recruitment of XRCC1/DNA Ligase IIIα (LigIII) to oxidized genome sites and activating LigIII via direct interaction. This is a critical step in the repair of oxidative genome damage, a foremost challenge for postmitotic neurons due to their high oxygen consumption. We discovered that mutant FUS significantly inhibited the recruitment of XRCC1/LigIII to DNA strand breaks, causing defects in DNA ligation during the repair of oxidative DNA damage, which contributed to neurodegeneration. While the FUS loss of function was responsible for the repair defects, increased oxidative genome damage due to mutant FUS aggregation could exacerbate the phenomenon. We highlight how these new molecular insights into previously undescribed DNA repair defect linked to FUS-associated neurodegeneration could provide an important opportunity for exploring DNA repair-based therapeutic avenues.

scholarly journals MKP1 phosphatase is recruited by CXCL12 in glioblastoma cells and plays a role in DNA strand breaks repair

2019 ◽  
Vol 41 (4) ◽  
pp. 417-429
Author(s):  
Matthias Dedobbeleer ◽  
Estelle Willems ◽  
Jeremy Lambert ◽  
Arnaud Lombard ◽  
Marina Digregorio ◽  
...  
Keyword(s):  
Dna Repair ◽  
Map Kinases ◽  
Strand Breaks ◽  
Repair Protein ◽  
Map Kinase Phosphatase ◽  
Dna Repair Protein ◽  
The Central Nervous System ◽  
Subventricular Zones ◽  
Dna Strand ◽  
The Brain

Abstract Glioblastoma (GBM) is the most frequent and aggressive primary tumor in the central nervous system. Previously, the secretion of CXCL12 in the brain subventricular zones has been shown to attract GBM cells and protect against irradiation. However, the exact molecular mechanism behind this radioprotection is still unknown. Here, we demonstrate that CXCL12 modulates the phosphorylation of MAP kinases and their regulator, the nuclear MAP kinase phosphatase 1 (MKP1). We further show that MKP1 is able to decrease GBM cell death and promote DNA repair after irradiation by regulating major apoptotic players, such as Jun-N-terminal kinase, and by stabilizing the DNA repair protein RAD51. Increases in MKP1 levels caused by different corticoid treatments should be reexamined for GBM patients, particularly during their radiotherapy sessions, in order to prevent or to delay the relapses of this tumor.

scholarly journals Barrier-to-autointegration factor 1 (Banf1) regulates poly [ADP-ribose] polymerase 1 (PARP1) activity following oxidative DNA damage

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Emma Bolderson ◽  
Joshua T. Burgess ◽  
Jun Li ◽  
Neha S. Gandhi ◽  
Didier Boucher ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Repair ◽  
Oxidative Dna Damage ◽  
Repair Capacity ◽  
Dna Repair Capacity ◽  
Dna Repair Protein ◽  
Direct Binding ◽  
Protein Barrier ◽  
Progeria Syndrome

AbstractThe DNA repair capacity of human cells declines with age, in a process that is not clearly understood. Mutation of the nuclear envelope protein barrier-to-autointegration factor 1 (Banf1) has previously been shown to cause a human progeroid disorder, Néstor–Guillermo progeria syndrome (NGPS). The underlying links between Banf1, DNA repair and the ageing process are unknown. Here, we report that Banf1 controls the DNA damage response to oxidative stress via regulation of poly [ADP-ribose] polymerase 1 (PARP1). Specifically, oxidative lesions promote direct binding of Banf1 to PARP1, a critical NAD+-dependent DNA repair protein, leading to inhibition of PARP1 auto-ADP-ribosylation and defective repair of oxidative lesions, in cells with increased Banf1. Consistent with this, cells from patients with NGPS have defective PARP1 activity and impaired repair of oxidative lesions. These data support a model whereby Banf1 is crucial to reset oxidative-stress-induced PARP1 activity. Together, these data offer insight into Banf1-regulated, PARP1-directed repair of oxidative lesions.

scholarly journals The RASSF1A Tumor Suppressor Regulates XPA-Mediated DNA Repair

2014 ◽  
Vol 35 (1) ◽  
pp. 277-287 ◽  
Author(s):  
Howard Donninger ◽  
Jennifer Clark ◽  
Francesca Rinaldo ◽  
Nicholas Nelson ◽  
Thibaut Barnoud ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Tumor Suppressor ◽  
Human Cancer ◽  
Protein A ◽  
Repair Process ◽  
Protein Acetylation ◽  
Repair Protein ◽  
Dna Repair Protein ◽  
Repair Activity

RASSF1A may be the most frequently inactivated tumor suppressor identified in human cancer so far. It is a proapoptotic Ras effector and plays an important role in the apoptotic DNA damage response (DDR). We now show that in addition to DDR regulation, RASSF1A also plays a key role in the DNA repair process itself. We show that RASSF1A forms a DNA damage-regulated complex with the key DNA repair protein xeroderma pigmentosum A (XPA). XPA requires RASSF1A to exert full repair activity, and RASSF1A-deficient cells exhibit an impaired ability to repair DNA. Moreover, a cancer-associated RASSF1A single-nucleotide polymorphism (SNP) variant exhibits differential XPA binding and inhibits DNA repair. The interaction of XPA with other components of the repair complex, such as replication protein A (RPA), is controlled in part by a dynamic acetylation/deacetylation cycle. We found that RASSF1A and its SNP variant differentially regulate XPA protein acetylation, and the SNP variant hyperstabilizes the XPA-RPA70 complex. Thus, we identify two novel functions for RASSF1A in the control of DNA repair and protein acetylation. As RASSF1A modulates both apoptotic DDR and DNA repair, it may play an important and unanticipated role in coordinating the balance between repair and death after DNA damage.

scholarly journals MicroRNAs Modulate Oxidative Stress in Hypertension through PARP-1 Regulation

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Douglas F. Dluzen ◽  
Yoonseo Kim ◽  
Paul Bastian ◽  
Yongqing Zhang ◽  
Elin Lehrmann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Survival ◽  
Oxidative Dna Damage ◽  
White Women ◽  
Luciferase Reporter ◽  
Coding Region ◽  
Age Related ◽  
Parp 1

Oxidative stress is thought to contribute to aging and age-related diseases, such as cardiovascular and neurodegenerative diseases, and is a risk factor for systemic arterial hypertension. Previously, we reported differential mRNA and microRNA (miRNA) expression between African American (AA) and white women with hypertension. Here, we found that the poly-(ADP-ribose) polymerase 1 (PARP-1), a DNA damage sensor protein involved in DNA repair and other cellular processes, is upregulated in AA women with hypertension. To explore this mechanism, we identified two miRNAs, miR-103a-2-5p and miR-585-5p, that are differentially expressed with hypertension and were predicted to target PARP1. Through overexpression of each miRNA-downregulated PARP-1 mRNA and protein levels and using heterologous luciferase reporter assays, we demonstrate that miR-103a-2-5p and miR-585-5p regulate PARP1 through binding within the coding region. Given the important role of PARP-1 in DNA repair, we assessed whether overexpression of miR-103a-2-5p or miR-585-5p affected DNA damage and cell survival. Overexpression of these miRNAs enhanced DNA damage and decreased both cell survival and colony formation. These findings highlight the role for PARP-1 in regulating oxidative DNA damage in hypertension and identify important new miRNA regulators of PARP-1 expression. These insights may provide additional avenues to understand hypertension health disparities.

scholarly journals An Overview of DNA Repair in Amyotrophic Lateral Sclerosis

2011 ◽  
Vol 11 ◽  
pp. 1679-1691 ◽  
Author(s):  
Fabio Coppedè
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Oxidative Dna Damage ◽  
Neurodegenerative Disorder ◽  
Repair Enzymes ◽  
Repair Activity ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is an adult onset neurodegenerative disorder characterised by the degeneration of cortical and spinal cord motor neurons, resulting in progressive muscular weakness and death. Increasing evidence supports mitochondrial dysfunction and oxidative DNA damage in ALS motor neurons. Several DNA repair enzymes are activated following DNA damage to restore genome integrity, and impairments in DNA repair capabilities could contribute to motor neuron degeneration. After a brief description of the evidence of DNA damage in ALS, this paper focuses on the available data on DNA repair activity in ALS neuronal tissue and disease animal models. Moreover, biochemical and genetic data on DNA repair in ALS are discussed in light of similar findings in other neurodegenerative diseases.

scholarly journals DNA Damage/Repair and Polymorphism of thehOGG1Gene in Lymphocytes of AMD Patients

2009 ◽  
Vol 2009 ◽  
pp. 1-9 ◽  
Author(s):  
Katarzyna Wozniak ◽  
Jacek P. Szaflik ◽  
Malgorzata Zaras ◽  
Anna Sklodowska ◽  
Katarzyna Janik-Papis ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Oxidative Dna Damage ◽  
Age Related Macular Degeneration ◽  
Repair Enzymes ◽  
Age Related ◽  
Damage Repair ◽  
Ser326cys Polymorphism ◽  
Kinetics Of ◽  
Wet Amd

Oxidative stress is thought to play a role in the pathogenesis of age-related macular degeneration (AMD). We determined the extent of oxidative DNA damage and the kinetics of its removal as well as the genotypes of the Ser326Cys polymorphism of thehOGG1gene in lymphocytes of 30 wet AMD patients and 30 controls. Oxidative DNA damage induced by hydrogen peroxide and its repair were evaluated by the comet assay and DNA repair enzymes. We observed a higher extent of endogenous oxidative DNA damage and a lower efficacy of its repair in AMD patients as compared with the controls. We did not find any correlation between the extent of DNA damage and efficacy of DNA repair with genotypes of the Ser326Cys polymorphism. The results obtained suggest that oxidative DNA damage and inefficient DNA repair can be associated with AMD and the variability of thehOOG1gene may not contribute to this association.

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