Molecular mechanisms by which oxidative DNA damage promotes telomerase activity

Background: Zinc oxide nanoparticles (ZnO NPs) are among the most frequently applied nanomaterials in consumer products. Evidence exists regarding the cytotoxic effects of ZnO NPs in mammalian cells; however, knowledge about the potential genotoxicity of ZnO NPs is rare, and results presented in the current literature are inconsistent. Objectives: The aim of this review is to summarize the existing data regarding the DNA damage that ZnO NPs induce, and focus on the possible molecular mechanisms underlying genotoxic events. Methods: Electronic literature databases were systematically searched for studies that report on the genotoxicity of ZnO NPs. Results: Several methods and different endpoints demonstrate the genotoxic potential of ZnO NPs. Most publications describe in vitro assessments of the oxidative DNA damage triggered by dissoluted Zn2+ ions. Most genotoxicological investigations of ZnO NPs address acute exposure situations. Conclusion: Existing evidence indicates that ZnO NPs possibly have the potential to damage DNA. However, there is a lack of long-term exposure experiments that clarify the intracellular bioaccumulation of ZnO NPs and the possible mechanisms of DNA repair and cell survival.

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Updated Understanding of Cancer as a Metabolic and Telomere-Driven Disease, and Proposal for Complex Personalized Treatment, a Hypothesis

International Journal of Molecular Sciences ◽

10.3390/ijms21186521 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6521

Author(s):

Cristian Muresanu ◽

Siva G. Somasundaram ◽

Sergey V. Vissarionov ◽

Luis Fernando Torres Solis ◽

Arturo Solís Herrera ◽

...

Keyword(s):

Metabolic Disease ◽

Dna Damage ◽

Telomere Length ◽

Oxidative Dna Damage ◽

Nuclear Gene ◽

Holistic Approach ◽

Telomerase Activity ◽

Metabolic Reprogramming ◽

Intermittent Fasting ◽

Nuclear Gene Expression

In this review, we propose a holistic approach to understanding cancer as a metabolic disease. Our search for relevant studies in medical databases concludes that cancer cells do not evolve directly from normal healthy cells. We hypothesize that aberrant DNA damage accumulates over time—avoiding the natural DNA controls that otherwise repair or replace the rapidly replicating cells. DNA damage starts to accumulate in non-replicating cells, leading to senescence and aging. DNA damage is linked with genetic and epigenetic factors, but the development of cancer is favored by telomerase activity. Evidence indicates that telomere length is affected by chronic inflammations, alterations of mitochondrial DNA, and various environmental factors. Emotional stress also influences telomere length. Chronic inflammation can cause oxidative DNA damage. Oxidative stress, in turn, can trigger mitochondrial changes, which ultimately alter nuclear gene expression. This vicious cycle has led several scientists to view cancer as a metabolic disease. We have proposed complex personalized treatments that seek to correct multiple changes simultaneously using a psychological approach to reduce chronic stress, immune checkpoint therapy with reduced doses of chemo and radiotherapy, minimal surgical intervention, if any, and mitochondrial metabolic reprogramming protocols supplemented by intermittent fasting and personalized dietary plans without interfering with the other therapies.

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Genomic landscape of oxidative DNA damage and repair reveals regioselective protection from mutagenesis

10.1101/168153 ◽

2017 ◽

Cited By ~ 1

Author(s):

Anna R Poetsch ◽

Simon J Boulton ◽

Nicholas M Luscombe

Keyword(s):

Dna Damage ◽

Oxidative Damage ◽

Oxidative Dna Damage ◽

Molecular Mechanisms ◽

Accumulation Rate ◽

Repetitive Sequences ◽

Open Chromatin ◽

Regulatory Sequences ◽

Dna Damage And Repair ◽

A Genome

AbstractDNA is subject to constant chemical modification and damage, which eventually results in variable mutation rates throughout the genome. Although detailed molecular mechanisms of DNA damage and repair are well-understood, damage impact and execution of repair across a genome remains poorly defined. To bridge the gap between our understanding of DNA repair and mutation distributions we developed a novel method, AP-seq, capable of mapping apurinic sitesand 8-oxo-7,8-dihydroguanine bases at ∼300bp resolution on a genome-wide scale. We directly demonstrate that the accumulation rate of oxidative damage varies widely across the genome, with hot spots acquiring many times more damage than cold spots. Unlike SNVs in cancers, damage burden correlates with marks for open chromatin notably H3K9ac and H3K4me2. Oxidative damage is also highly enriched in transposable elements and other repetitive sequences. In contrast, we observe decreased damage at promoters, exons and termination sites, but not introns, in a seemingly transcription-independent manner. Leveraging cancer genomic data, we also find locally reduced SNV rates in promoters, genes and other functional elements. Taken together, our study reveals that oxidative DNA damage accumulation and repair differ strongly across the genome, but culminate in a previously unappreciated mechanism that safe-guards the regulatory sequences and the coding regions of genes from mutations.

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Counteracting Environmental Chemicals with Coenzyme Q10: An Educational Primer for Use with “Antioxidant CoQ10 Restores Fertility by Rescuing Bisphenol A-Induced Oxidative DNA Damage in the Caenorhabditis elegans Germline”

Genetics ◽

10.1534/genetics.120.303577 ◽

2020 ◽

Vol 216 (4) ◽

pp. 879-890

Author(s):

Beatrix R. Bradford ◽

Nicole E. Briand ◽

Nina Fassnacht ◽

Esabelle D. Gervasio ◽

Aidan M. Nowakowski ◽

...

Keyword(s):

Dna Damage ◽

Caenorhabditis Elegans ◽

Bisphenol A ◽

Coenzyme Q10 ◽

Oxidative Dna Damage ◽

Molecular Mechanisms ◽

Fluorescent Microscopy ◽

Environmental Chemicals ◽

Background Information ◽

Environmental Toxicants

Environmental toxicants are chemicals that negatively affect human health. Although there are numerous ways to limit exposure, the ubiquitous nature of certain environmental toxicants makes it impossible to avoid them entirely. Consequently, scientists are continuously working toward developing strategies for combating their harmful effects. Using the nematode Caenorhabditis elegans, a model with many genetic and physiological similarities to humans, researchers in the Colaiácovo laboratory have identified several molecular mechanisms by which the toxic agent bisphenol A (BPA) interferes with reproduction. Here, we address their recent discovery that a widely available compound, Coenzyme Q10 (CoQ10), can rescue BPA-induced damage. This work is significant in that it poses a low-cost method for improving reproductive success in humans. The goal of this primer is to assist educators and students with navigating the paper entitled “Antioxidant CoQ10 Restores Fertility by Rescuing Bisphenol A-Induced Oxidative DNA Damage in the Caenorhabditis elegans Germline.” It is ideally suited for integration into an upper-level undergraduate course such as Genetics, Cell and Molecular Biology, Developmental Biology, or Toxicology. The primer provides background information on the history of BPA, the utility of the C. elegans germ line as a model for studying reproductive toxicity, and research methods including assessment of programmed cell death, fluorescent microscopy applications, and assays to quantify gene expression. Questions for deeper exploration in-class or online are provided.Related article in GENETICS: Hornos Carneiro MF, Shin N, Karthikraj R, Barbosa F Jr, Kannan K, Colaiácovo MP. Antioxidant CoQ10 restores fertility by rescuing bisphenol A-induced oxidative DNA damage in the Caenorhabditis elegans Germline. Genetics 214:381–395.

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Testicular toxicity following chronic codeine administration is via oxidative DNA damage and up-regulation of NO and caspase 3

10.1101/796110 ◽

2019 ◽

Author(s):

RE Akhigbe ◽

A.F Ajayi

Keyword(s):

Dna Damage ◽

Oxidative Dna Damage ◽

Molecular Mechanisms ◽

Testicular Atrophy ◽

Marked Rise ◽

Oxidative Markers ◽

Inflammatory Parameters ◽

Testicular Weight ◽

Androgen Suppression

AbstractBackgroundCodeine, a 3-methylmorphine, and other related opioids have been implicated in androgen suppression, although the associated mechanisms remain unclear.AimTherefore, the objective of the current study was to elucidate the in vivo molecular mechanisms underlying codeine-induced androgen suppression.MethodsThis study made use of Twenty-one healthy male rabbits, distributed into three groups randomly, control and codeine-treated groups. The control had 1ml of normal saline daily p.o. The codeine-treated groups received either 4mg/kg b.w of codeine or 10mg/kg b.w of codeine p.o. for six weeks. Reproductive hormonal profile, testicular weight, enzymes, oxidative and inflammatory parameters, histological examination and apoptosis marker were evaluated to examine the effects of codeine use.Key findingsOral administration of codeine resulted in testicular atrophy and alterations in testicular histomorphology, elevated testicular enzymes, and suppression of circulatory and intra-testicular testosterone. These changes were associated with a marked rise in oxidative markers, including oxidative DNA damage, inflammatory response, and caspase-dependent apoptosis.SignificanceIn conclusion, chronic codeine use resulted in testicular degeneration and testosterone suppression, which may be attributable to nitric oxide-/oxidativestress-mediated caspase-dependent apoptotic testicular cell death.

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Chronic Oxidative DNA Damage Due to DNA Repair Defects Causes Chromosomal Instability in Saccharomyces cerevisiae

Molecular and Cellular Biology ◽

10.1128/mcb.00307-08 ◽

2008 ◽

Vol 28 (17) ◽

pp. 5432-5445 ◽

Cited By ~ 32

Author(s):

Natalya P. Degtyareva ◽

Lingling Chen ◽

Piotr Mieczkowski ◽

Thomas D. Petes ◽

Paul W. Doetsch

Keyword(s):

Saccharomyces Cerevisiae ◽

Dna Damage ◽

Chromosomal Instability ◽

Large Scale ◽

Oxidative Dna Damage ◽

Molecular Mechanisms ◽

Genotoxic Stress ◽

Growth Conditions ◽

High Frequencies ◽

The Relationship

ABSTRACT Oxidative DNA damage is likely to be involved in the etiology of cancer and is thought to accelerate tumorigenesis via increased mutation rates. However, the majority of malignant cells acquire a specific type of genomic instability characterized by large-scale genomic rearrangements, referred to as chromosomal instability (CIN). The molecular mechanisms underlying CIN are not entirely understood. We utilized Saccharomyces cerevisiae as a model system to delineate the relationship between genotoxic stress and CIN. It was found that elevated levels of chronic, unrepaired oxidative DNA damage caused chromosomal aberrations at remarkably high frequencies under both selective and nonselective growth conditions. In this system, exceeding the cellular capacity to appropriately manage oxidative DNA damage resulted in a “gain-of-CIN” phenotype and led to profound karyotypic instability. These results illustrate a novel mechanism for genome destabilization that is likely to be relevant to human carcinogenesis.

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Celastrol Alleviates Gamma Irradiation-Induced Damage by Modulating Diverse Inflammatory Mediators

International Journal of Molecular Sciences ◽

10.3390/ijms21031084 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1084 ◽

Cited By ~ 5

Author(s):

Hong Wang ◽

Kwang Seok Ahn ◽

Sulaiman Ali Alharbi ◽

Omar H. M. Shair ◽

Frank Arfuso ◽

...

Keyword(s):

Lipid Peroxidation ◽

Dna Damage ◽

Survival Rate ◽

Gamma Radiation ◽

Cell Viability ◽

Gamma Irradiation ◽

Oxidative Dna Damage ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Tnf Α

The present study aimed to explore the possible radioprotective effects of celastrol and relevant molecular mechanisms in an in vitro cell and in vivo mouse models exposed to gamma radiation. Human keratinocytes (HaCaT) and foreskin fibroblast (BJ) cells were exposed to gamma radiation of 20 Gy, followed by treatment with celastrol for 24 h. Cell viability, reactive oxygen species (ROS), nitric oxide (NO) and glutathione (GSH) production, lipid peroxidation, DNA damage, inflammatory cytokine levels, and NF-κB pathway activation were examined. The survival rate, levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in blood, and p65 and phospho-p65 expression were also evaluated in mice after exposure to gamma radiation and celastrol treatment. The gamma irradiation of HaCaT cells induced decreased cell viability, but treatment with celastrol significantly blocked this cytotoxicity. Gamma irradiation also increased free radical production (e.g., ROS and NO), decreased the level of GSH, and enhanced oxidative DNA damage and lipid peroxidation in cells, which were effectively reversed by celastrol treatment. Moreover, inflammatory responses induced by gamma irradiation, as demonstrated by increased levels of IL-6, TNF-α, and IL-1β, were also blocked by celastrol. The increased activity of NF-κB DNA binding following gamma radiation was significantly attenuated after celastrol treatment. In the irradiated mice, treatment with celastrol significantly improved overall survival rate, reduced the excessive inflammatory responses, and decreased NF-κB activity. As a NF-κB pathway blocker and antioxidant, celastrol may represent a promising pharmacological agent with protective effects against gamma irradiation-induced injury.

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‘Liver let die’: oxidative DNA damage and hepatotropic viruses

Journal of General Virology ◽

10.1099/vir.0.059485-0 ◽

2014 ◽

Vol 95 (5) ◽

pp. 991-1004 ◽

Cited By ~ 48

Author(s):

Martin R. Higgs ◽

Philippe Chouteau ◽

Hervé Lerat

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Cellular Response ◽

Oxidative Dna Damage ◽

Molecular Mechanisms ◽

Large Body ◽

Clinical Importance ◽

Dna Lesions ◽

Chronic Infections ◽

The Impact

Chronic infections by the hepatotropic viruses hepatitis B virus (HBV) and hepatitis C virus (HCV) are major risk factors for the development of hepatocellular carcinoma (HCC). It is estimated that more than 700 000 individuals per year die from HCC, and around 80 % of HCC is attributable to HBV or HCV infection. Despite the clear clinical importance of virus-associated HCC, the underlying molecular mechanisms remain largely elusive. Oxidative stress, in particular DNA lesions associated with oxidative damage, play a major contributory role in carcinogenesis, and are strongly linked to the development of many cancers, including HCC. A large body of evidence demonstrates that both HBV and HCV induce hepatic oxidative stress, with increased oxidative DNA damage being observed both in infected individuals and in murine models of infection. Here, we review the impact of HBV and HCV on the incidence and repair of oxidative DNA damage. We begin by giving a brief overview of oxidative stress and the repair of DNA lesions induced by oxidative stress. We then review in detail the evidence surrounding the mechanisms by which both viruses stimulate oxidative stress, before focusing on how the viral proteins themselves may perturb the cellular response to oxidative DNA damage, impacting upon genome stability and thus hepatocarcinogenesis.

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Acrylamide Exposure and Oxidative DNA Damage, Lipid Peroxidation and Fasting Plasma Glucose Alteration: Association and Mediation Analyses in Chinese Urban Adults

10.2337/figshare.12076134 ◽

2020 ◽

Author(s):

Bin Wang ◽

Weihong Qiu ◽

Shijie Yang ◽

Limin Cao ◽

Chunmei Zhu ◽

...

Keyword(s):

Lipid Peroxidation ◽

Dna Damage ◽

Plasma Glucose ◽

Fasting Plasma Glucose ◽

Oxidative Dna Damage ◽

Adult Population ◽

Prostaglandin F2α ◽

Mediation Analyses ◽

Mediating Role ◽

Fasting Plasma

<a>OBJECTIVE: </a>Acrylamide exposure from daily-consumed food has raised global concern. We aimed to assess the exposure-response relationships of internal acrylamide exposure with oxidative DNA damage, lipid peroxidation and fasting plasma glucose (FPG) alteration, and investigate the mediating role of oxidative DNA damage and lipid peroxidation in the association of internal acrylamide exposure with FPG. RESEARCH DESIGN AND METHODS: FPG and urinary biomarkers of oxidative DNA damage (8-hydroxy-deoxy-guanosine, 8-OHdG), lipid peroxidation (8-iso-prostaglandin-F2α, 8-iso-PGF2α) and acrylamide exposure (N-acetyl-S-(2-carbamoylethyl)-L-cysteine, AAMA; N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine, GAMA) were measured for 3,270 general adults from the Wuhan-Zhuhai cohort. The associations of urinary acrylamide metabolites with 8-OHdG, 8-iso-PGF2α and FPG were assessed by linear mixed models. The mediating roles of 8-OHdG and 8-iso-PGF2α were evaluated by mediation analysis. RESULTS: We found significant linear positive dose-response relationships of urinary acrylamide metabolites with 8-OHdG, 8-iso-PGF2α and FPG (except GAMA with FPG), and 8-iso-PGF2α with FPG. Each 1-unit increase in log-transformed level of AAMA, ΣUAAM (AAMA+GAMA) or 8-iso-PGF2α was associated with a 0.17-, 0.15- or 0.23-mmol/L increase in FPG, respectively (P or/and P trend<0.05). Each 1% increase in AAMA, GAMA or ΣUAAM was associated with a 0.19%, 0.27% or 0.22% increase in 8-OHdG, respectively, and a 0.40%, 0.48% or 0.44% increase in 8-iso-PGF2α, respectively (P and P trend<0.05). Increased 8-iso-PGF2α rather than 8-OHdG significantly mediated 64.29% and 76.92% of the AAMA and ΣUAAM associated-FPG increases, respectively. CONCLUSIONS: Exposure of general adult population to acrylamide was associated with FPG elevation, oxidative DNA damage and lipid peroxidation, which in turn partly mediated acrylamide-associated FPG elevation.

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Serum of 8-OHdG as a potential biomarker of oxidative DNA damage in workers exposed to harmful working environments

Russian Journal of Occupational Health and Industrial Ecology ◽

10.31089/1026-9428-2019-59-9-783-784 ◽

2020 ◽

pp. 783-783

Author(s):

I. A. Umnyagina ◽

L. A. Strakhova ◽

T. V. Blinova

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Blood Serum ◽

Oxidative Dna Damage ◽

Working Environment ◽

Working Environments ◽

Potential Biomarker ◽

High Level ◽

Damage Marker

In the blood serum of 70% individuals exposed to harmful factors of the working environment, a high level of oxidative stress and the DNA damage marker 8-Hydroxy-2’-Deoxyguanosine (8-OHdG) were detected.

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