scholarly journals Link between Base Excision Repair (BER), Reactive Oxygen Species (ROS), and Cancer

2021 ◽  
Author(s):  
Nour Fayyad ◽  
Farah Kobaisi ◽  
Mohammad Fayyad-Kazan ◽  
Ali Nasrallah ◽  
Hussein Fayyad-Kazan ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Base Excision

scholarly journals Kinetic Modeling Reveals the Roles of Reactive Oxygen Species Scavenging and DNA Repair Processes in Shaping the Dose-Response Curve of KBrO3-Induced DNA Damage

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Maria A. Spassova ◽  
David J. Miller ◽  
Alexander S. Nikolov
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Dose Response ◽  
Excision Repair ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Repair Processes ◽  
Base Excision

We have developed a kinetic model to investigate how DNA repair processes and scavengers of reactive oxygen species (ROS) can affect the dose-response shape of prooxidant induced DNA damage. We used as an example chemicalKBrO3which is activated by glutathione and forms reactive intermediates that directly interact with DNA to form 8-hydroxy-2-deoxyguanosine DNA adducts (8-OH-dG). The single strand breaks (SSB) that can result from failed base excision repair of these adducts were considered as an effect downstream from 8-OH-dG. We previously demonstrated that, in the presence of effective base excision repair, 8-OH-dG can exhibit threshold-like dose-response dependence, while the downstream SSB can still exhibit a linear dose-response. Here we demonstrate that this result holds for a variety of conditions, including low levels of GSH, the presence of additional SSB repair mechanisms, or a scavenger. It has been shown that melatonin, a terminal scavenger, inhibitsKBrO3-caused oxidative damage. Our modeling revealed that sustained exposure toKBrO3can lead to fast scavenger exhaustion, in which case the dose-response shapes for both endpoints are not substantially affected. The results are important to consider when forming conclusions on a chemical’s toxicity dose dependence based on the dose-response of early genotoxic events.

AML1/ETO Confers a Mutator Phenotype In Acute Myeloid Leukemia Associated with Downregulation of the Base-Excision-Repair Gene OGG1,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3441-3441
Author(s):  
Victoria J Forster ◽  
Andrea Beyerle ◽  
Olaf Heidenreich ◽  
James M Allan
Keyword(s):  
Base Excision Repair ◽  
Myeloid Leukemia ◽  
Excision Repair ◽  
Oxygen Species ◽  
Leukemic Transformation ◽  
Repair Gene ◽  
Mutator Phenotype ◽  
Hematopoietic Precursor ◽  
Base Excision ◽  
Tk6 Cells

Abstract Abstract 3441 The translocation t(8;21)(q22;q22) is the most common cytogenetic abnormality in acute myeloid leukemia (AML), detected in around 15% of all cases. The translocation fuses the DNA binding domain of AML1 (RUNX1) to the almost full-length ETO (RUNX1T1, MTG8) protein converting a transcriptional modulator essential for hematopoiesis into a constitutive repressor. Expression of AML1/ETO in animal models is not sufficient for leukemogenesis, and further mutations are required. AML1/ETO has been detected in the Guthrie cards of pediatric patients who subsequently developed t(8;21) AML, suggesting that AML1/ETO+ hematopoietic precursor cells remain latent for many years before leukemic transformation. The mechanisms by which additional mutations are acquired are not well characterised. AML1/ETO affects DNA repair gene expression and is associated with lower levels of 8-oxoguanine DNA glycosylase (OGG1) in patient samples and transduced primary CD34+ cells. OGG1 removes oxidatively damaged guanine bases from the DNA strand as an initial step of the base-excision repair pathway. Taken together, these observations suggest the existence of a pre-leukemic, AML1/ETO-expressing hematopoietic precursor which is susceptible to the acquisition of further DNA mutations by virtue of compromised DNA repair function. In order to test this hypothesis we investigated the effect of AML1/ETO expression on susceptibility to spontaneous and exposure driven mutation in TK6 cells. TK6 lymphoblastoid cells have one functional copy of the thymidine kinase (TK) gene, allowing for quantification of mutant cells by functionally screening for the TK−/− phenotype. TK6 cells were lentivirally transduced with the pHR-SINcPPT-SIEW vector containing AML1/ETO; and EGFP as an expression marker. Expression was confirmed by flow cytometry, western blotting and qRT-PCR. Serial dilution assays were performed to generate AML1/ETO+ TK6 clonal populations with AML1/ETO expression varying from 10–150% of that found in Kasumi-1; a t(8;21)+ patient-derived cell line. We also used the PIGA gene as a second mutational target. Loss of this glycosyl-phosphatidylinositol (GPI) anchor results in an absence of GPI-linked proteins from the cell membrane, including CD55 and CD59. Cells that are simultaneously negative for two or more GPI-linked proteins are considered to be PIGA mutants and are detected using fluorochrome-conjugated antibodies. Preliminary mutation results on AML1/ETO+ TK6 clones revealed that the fusion gene conferred an approximate 2 fold higher background TK−/− mutation frequency (MF) (2.1 × 10−6−2.6 × 10−6) compared to controls (0.9 × 10−61.1 × 10−6), and a 2–4 fold higher PIGA MF (Controls: 0.32 × 10−4−1.4 × 10−4 and AML1/ETO+ Clones: 2.7 × 10−4– 5.7 × 10−4), suggesting that AML1/ETO confers a moderate mutator phenotype even without exposure to genotoxic agents. Furthermore, spontaneous MF was proportional to AML1/ETO expression, with higher-expressing clones displaying a higher MF than lower expressers and control cells. When treated with low-dose doxorubicin (a chemotherapeutic anthracyline that induces strand breaks in DNA but can also generate reactive oxygen species (ROS)), AML1/ETO+ TK6 clones had a substantially higher TK−/− MF (0.5 × 10−5– 1.2 × 10−5) in comparison to controls; wild-type TK6 and backbone vector-alone transduced TK6 (1.8x 10−6−3.2 × 10−6) (p<0.001). Quantitative PCR revealed a significant 2-fold reduction in OGG1 levels in TK6 lentivirally transduced with AML1/ETO (p<0.05). Furthermore, siRNA mediated knockdown of AML1/ETO in the t(8;21)+ cell lines Kasumi-1 and SKNO-1 resulted in a substantial increase of OGG1, providing strong evidence that AML1/ETO directly regulates OGG1 expression. Consistent with downregulation of OGG1 and susceptibility to ROS-induced mutation, AML1/ETO+ clones had a 2–4 fold higher PIGA MF (0.6 × 10−3−1.3 × 10−3) compared to controls (1.6 × 10−4−3.3 × 10−4) when treated with hydrogen peroxide. We have shown that AML1/ETO confers a mutator phenotype on cells that is associated with downregulation of OGG1, providing a plausible explanation for the particular susceptibility of AML1/ETO+ cells to mutation induction by agents that generate reactive oxygen species. This work suggests a mechanism by which AML1/ETO translocated pre-leukemic hematopoetic cells acquire additional mutations, ultimately leading to leukemic transformation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Role for Nucleotide Excision Repair in Virulence of Mycobacterium tuberculosis

2005 ◽  
Vol 73 (8) ◽  
pp. 4581-4587 ◽  
Author(s):  
K. Heran Darwin ◽  
Carl F. Nathan
Keyword(s):  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Mycobacterium Tuberculosis ◽  
Excision Repair ◽  
Uv Light ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Phagocyte Oxidase ◽  
Nitric Oxide Synthase 2

ABSTRACT Mutations in Mycobacterium tuberculosis uvrB result in severe sensitivity to acidified nitrite, a source of nitric oxide (6). In this study, we show that a uvrB mutant is exquisitely sensitive to UV light but not to several sources of reactive oxygen species in vitro. Furthermore, a uvrB mutant was attenuated in mice as judged by an extension of life span. Attenuation in mice was partially reversed by genetic inactivation of nitric oxide synthase 2 (iNOS) and almost completely reversed in mice lacking both iNOS and phagocyte oxidase. Thus, a gene predicted to encode a key element of DNA repair is required for resistance of M. tuberculosis to both reactive nitrogen and reactive oxygen species in mice.

scholarly journals OGG1 protects mouse spermatogonial stem cells from reactive oxygen species in culture†

2020 ◽  
Author(s):  
Yoshifumi Mori ◽  
Narumi Ogonuki ◽  
Ayumi Hasegawa ◽  
Mito Kanatsu-Shinohara ◽  
Atsuo Ogura ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Hydrogen Peroxide ◽  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Excision Repair ◽  
Point Mutations ◽  
Reactive Oxygen ◽  
Functional Screening ◽  
Oxygen Species ◽  
Self Renewal

Abstract Although reactive oxygen species (ROS) are required for spermatogonial stem cell (SSC) self-renewal, they induce DNA damage and are harmful to SSCs. However, little is known about how SSCs protect their genome during self-renewal. Here, we report that Ogg1 is essential for SSC protection against ROS. While cultured SSCs exhibited homologous recombination-based DNA double-strand break repair at levels comparable with those in pluripotent stem cells, they were significantly more resistant to hydrogen peroxide than pluripotent stem cells or mouse embryonic fibroblasts, suggesting that they exhibit high levels of base excision repair (BER) activity. Consistent with this observation, cultured SSCs showed significantly lower levels of point mutations than somatic cells, and showed strong expression of BER-related genes. Functional screening revealed that Ogg1 depletion significantly impairs survival of cultured SSCs upon hydrogen peroxide exposure. Thus, our results suggest increased expression of BER-related genes, including Ogg1, protects SSCs from ROS-induced damage.

Mitochondria as a source of reactive oxygen species

2009 ◽  
pp. c3 ◽  
Author(s):  
Helena M. Cochemé ◽  
Michael P. Murphy
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Oxygen Species

Clinical aspects of reactive oxygen and nitrogen species

2004 ◽  
Vol 71 ◽  
pp. 121-133 ◽  
Author(s):  
Ascan Warnholtz ◽  
Maria Wendt ◽  
Michael August ◽  
Thomas Münzel
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Risk Factor ◽  
Endothelial Dysfunction ◽  
Vascular Tissue ◽  
Rapid Development ◽  
Reactive Oxygen ◽  
Clinical Aspects ◽  
No Production ◽  
Oxygen Species

Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes mellitus and chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species in endothelial and/or smooth muscle cells and the adventitia, and the subsequent decrease in vascular bioavailability of NO. Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include NAD(P)H-oxidase, xanthine oxidase and endothelial nitric oxide synthase in an uncoupled state. Recent studies indicate that endothelial dysfunction of peripheral and coronary resistance and conductance vessels represents a strong and independent risk factor for future cardiovascular events. Ways to reduce endothelial dysfunction include risk-factor modification and treatment with substances that have been shown to reduce oxidative stress and, simultaneously, to stimulate endothelial NO production, such as inhibitors of angiotensin-converting enzyme or the statins. In contrast, in conditions where increased production of reactive oxygen species, such as superoxide, in vascular tissue is established, treatment with NO, e.g. via administration of nitroglycerin, results in a rapid development of endothelial dysfunction, which may worsen the prognosis in patients with established coronary artery disease.

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