scholarly journals Impact of Single Nucleotide Polymorphisms of Base Excision Repair Genes on DNA Damage and Efficiency of DNA Repair in Recurrent Depression Disorder

2016 ◽  
Vol 54 (6) ◽  
pp. 4150-4159 ◽  
Author(s):  
Piotr Czarny ◽  
Dominik Kwiatkowski ◽  
Monika Toma ◽  
Joanna Kubiak ◽  
Agnieszka Sliwinska ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Nucleotide Polymorphisms ◽  
Recurrent Depression ◽  
Single Nucleotide ◽  
Base Excision ◽  
Repair Genes ◽  
Depression Disorder

Single nucleotide polymorphisms in base-excision repair genes hOGG1, APE1 and XRCC1 do not alter risk of Alzheimer's disease

2008 ◽  
Vol 442 (3) ◽  
pp. 287-291 ◽  
Author(s):  
Hande Parıldar-Karpuzoğlu ◽  
Semra Doğru-Abbasoğlu ◽  
Hasmet A. Hanagasi ◽  
Berrin Karadağ ◽  
Hakan Gürvit ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Nucleotide Polymorphisms ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Base Excision ◽  
Repair Genes

scholarly journals Dynamic Compartmentalization of Base Excision Repair Proteins in Response to Nuclear and Mitochondrial Oxidative Stress

2008 ◽  
Vol 29 (3) ◽  
pp. 794-807 ◽  
Author(s):  
Lyra M. Griffiths ◽  
Dan Swartzlander ◽  
Kellen L. Meadows ◽  
Keith D. Wilkinson ◽  
Anita H. Corbett ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Intracellular Localization ◽  
Genotoxic Stress ◽  
Mitochondrial Oxidative Stress ◽  
Base Excision

ABSTRACT DNAs harbored in both nuclei and mitochondria of eukaryotic cells are subject to continuous oxidative damage resulting from normal metabolic activities or environmental insults. Oxidative DNA damage is primarily reversed by the base excision repair (BER) pathway, initiated by N-glycosylase apurinic/apyrimidinic (AP) lyase proteins. To execute an appropriate repair response, BER components must be distributed to accommodate levels of genotoxic stress that may vary considerably between nuclei and mitochondria, depending on the growth state and stress environment of the cell. Numerous examples exist where cells respond to signals, resulting in relocalization of proteins involved in key biological transactions. To address whether such dynamic localization contributes to efficient organelle-specific DNA repair, we determined the intracellular localization of the Saccharomyces cerevisiae N-glycosylase/AP lyases, Ntg1 and Ntg2, in response to nuclear and mitochondrial oxidative stress. Fluorescence microscopy revealed that Ntg1 is differentially localized to nuclei and mitochondria, likely in response to the oxidative DNA damage status of the organelle. Sumoylation is associated with targeting of Ntg1 to nuclei containing oxidative DNA damage. These studies demonstrate that trafficking of DNA repair proteins to organelles containing high levels of oxidative DNA damage may be a central point for regulating BER in response to oxidative stress.

Potentiation of Melphalan-Induced Cytotoxicity through Targeting of the Base Excision Repair Pathway in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4799-4799
Author(s):  
April M. Reed ◽  
Melissa L. Fishel ◽  
Mark R. Kelley ◽  
Rafat Abonour
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Dna Repair ◽  
Side Effects ◽  
Small Molecule ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Chemotherapeutic Agents ◽  
Repair Pathways ◽  
Base Excision

Abstract Melphalan (M) is an active agent against multiple myeloma (MM). One of the obstacles with M treatment is the patient’s ability to tolerate side effects such as mucositis and pancytopenia. This is especially true for those patients >70 years of age. We hypothesize that potentiation of M-induced cytotoxicity is possible in MM with agents that target, and therefore further imbalance, multiple DNA repair pathways. A key protein in the Base Excision Repair (BER) pathway, Apurinic/apyrimidinic endonuclease/ redox factor (APE1/Ref-1 or APE1) plays a major role in the repair of damage caused by chemotherapeutic agents including M and Temozolomide (TMZ), interacts with a number of transcription factors (HIF1-a, p53, AP1, NFkB, etc) to regulate their function through oxidation/reduction (redox) signaling, and is overexpressed in refractory/relapsed MM cells. Furthermore, a reduction in APE1 protein sensitizes MM cells to melphalan indicating that inhibition of this protein may have therapeutic potential in MM. In order to decipher the importance of APE1’s redox and repair functions in MM cells’ response to DNA damage via melphalan and TMZ, we have available to us small molecule APE1 inhibitors that affect only the repair activity or only the redox activity of APE1. The mechanism of action of MLP is primarily via monoadduct leading to DNA interstrand cross-link (ICL) formation which is processed by the Nucleotide Excision Repair (NER) pathway. MLP also causes N7methyl-G and N3methyl-A adduct formation which are repaired by the BER pathway. For these studies, we treated RPMI 8226 cells with several chemotherapeutic agents: M; TMZ, which creates primarily N7methyl-G and N3methyl-A adducts; Methoxyamine (MX), which has been shown to inhibit further processing by the BER pathway; and a small molecule which blocks the redox function of APE1. Our purpose was to overwhelm the DNA repair pathways by causing the accumulation of DNA repair intermediates and inducing apoptosis. M-induced cytotoxicity is enhanced by TMZ (CI=0.08), MX (CI=0.89), and E3330 (CI=0.06), and this effect was synergistic as determined by CalcuSyn software which generates median effect and combinational index (CI) values, with CI<1 indicative of synergy. Using MX to inhibit APE1 in combination with TMZ results in an increase in DNA damage and an increase in apoptosis in 8226 cells. Furthermore, the combination of the redox inhibitor + MX which blocks both functions of APE1 also results in an increase in apoptosis in the MM cells. Further studies include the addition of M to these combinations that are demonstrating an increase in efficacy in MM cells. These results indicate that using these DNA repair-targeted agents in addition to MLP may be a feasible way to increase the effect of the M on MM cells. The potential advantages to patients would be that they would be able to tolerate more treatments and that the combination treatments would be more effective than treatment with M alone. We anticipate that effective modulation of M and/or TMZ will overcome resistance without compromising efficacy and help to alleviate some of the side effects patients have to endure with melphalan treatment. This may be particularly advantageous to the more elderly patients.

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.

scholarly journals Base Excision Repair AP-Endonucleases-Like Genes Modulate DNA Damage Response and Virulence of the Human Pathogen Cryptococcus neoformans

2021 ◽  
Vol 7 (2) ◽  
pp. 133
Author(s):  
Rayssa Karla de Medeiros Oliveira ◽  
Fabián Andrés Hurtado ◽  
Pedro Henrique Gomes ◽  
Luiza Lassi Puglia ◽  
Fernanda Fonsêca Ferreira ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cryptococcus Neoformans ◽  
Dna Damage Response ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Antifungal Drugs ◽  
Host Immune System ◽  
Damage Response ◽  
Base Excision

Pathogenic microbes are exposed to a number of potential DNA-damaging stimuli during interaction with the host immune system. Microbial survival in this situation depends on a fine balance between the maintenance of DNA integrity and the adaptability provided by mutations. In this study, we investigated the association of the DNA repair response with the virulence of Cryptococcus neoformans, a basidiomycete that causes life-threatening meningoencephalitis in immunocompromised individuals. We focused on the characterization of C. neoformansAPN1 and APN2 putative genes, aiming to evaluate a possible role of the predicted Apurinic/apyrimidinic (AP) endonucleases 1 and 2 of the base excision repair (BER) pathway on C. neoformans response to stress conditions and virulence. Our results demonstrated the involvement of the putative AP-endonucleases Apn1 and Apn2 in the cellular response to DNA damage induced by alkylation and by UV radiation, in melanin production, in tolerance to drugs and in virulence of C. neoformans in vivo. We also pointed out the potential use of DNA repair inhibitor methoxy-amine in combination with conventional antifungal drugs, for the development of new therapeutic approaches against this human fungal pathogen. This work provides new information about the DNA damage response of the highly important pathogenic fungus C. neoformans.

scholarly journals Targeted DNA Damage Repair CRISPR/Cas9 Knockout Screen Identifies Novel Classification of Poly-ADP Ribose Polymerase Inhibitors Based on Key Base Excision Repair Proteins

2020 ◽  
Author(s):  
Gregory A. Breuer ◽  
Jonathan Bezney ◽  
Nathan R. Fons ◽  
Ranjini K. Sundaram ◽  
Wanjuan Feng ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Parp Inhibition ◽  
Brca1 And Brca2 ◽  
Damage Repair ◽  
Base Excision

ABSTRACTDNA repair deficiencies have become an increasingly promising target for novel therapeutics within the realm of clinical oncology. Recently, a number of inhibitors of Poly(ADP-ribose) Polymerases (PARPs) have received approval for the treatment of ovarian cancers with and without deleterious mutations in the homologous recombination proteins BRCA1 and BRCA2. Unfortunately, as over a hundred clinical trials are actively underway testing the utility of PARP inhibition across dozens of unique cancers, the mechanism of action for such inhibitors remains unclear. While many believe PARP trapping to be the most important determinant driving the cytotoxicity found in such inhibitors, clinically effective inhibitors exist which possess both strong and weak PARP-trapping qualities. Such results indicate that characterization of inhibitors as strong and weak trappers does not properly capture the intra-class characteristics of such small molecule inhibitors. Using a novel, targeted DNA damage repair and response (DDR) CRISPR/Cas9 screening library, we describe a new classification scheme for PARP inhibitors that revolves around sensitivity to key modulators of the base excision repair (BER) pathway, unrelated to trapping ability or catalytic inhibition of PARP. These findings demonstrate that inhibition of PARylation and induction of PARP trapping are not the only factors responsible for the clinical response of DDR-deficient cancers to PARP inhibition, and provide insight into the optimal choice of PARP inhibitor to be used in the setting of additional DNA repair deficiencies.

scholarly journals The senescence-accelerated mouse prone 8 as a model for oxidative stress and impaired DNA repair in the male germ line

Reproduction ◽  
2013 ◽  
Vol 146 (3) ◽  
pp. 253-262 ◽  
Author(s):  
T B Smith ◽  
G N De Iuliis ◽  
T Lord ◽  
R J Aitken
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Reactive Oxygen Species Generation ◽  
Control Strain ◽  
Base Excision ◽  
High Level ◽  
Senescence Accelerated Mouse

The discovery of a truncated base excision repair pathway in human spermatozoa mediated by OGG1 has raised questions regarding the effect of mutations in critical DNA repair genes on the integrity of the paternal genome. The senescence-accelerated mouse prone 8 (SAMP8) is a mouse model containing a suite of naturally occurring mutations resulting in an accelerated senescence phenotype largely mediated by oxidative stress, which is further enhanced by a mutation in theOgg1gene, greatly reducing the ability of the enzyme to excise 8-hydroxy,2′-deoxyguanosine (8OHdG) adducts. An analysis of the reproductive phenotype of the SAMP8 males revealed a high level of DNA damage in caudal epididymal spermatozoa as measured by the alkaline Comet assay. Furthermore, these lesions were confirmed to be oxidative in nature, as demonstrated by significant increases in 8OHdG adduct formation in the SAMP8 testicular tissue (P<0.05) as well as in mature spermatozoa (P<0.001) relative to a control strain (SAMR1). Despite this high level of oxidative DNA damage in spermatozoa, reactive oxygen species generation was not elevated and motility of spermatozoa was found to be similar to that for the control strain with the exception of progressive motility, which exhibited a slight but significant decline with advancing age (P<0.05). When challenged with Fenton reagents (H2O2and Fe2+), the SAMP8 spermatozoa demonstrated a highly increased susceptibility to formation of 8OHdG adducts compared with the controls (P<0.001). These data highlight the role of oxidative stress and OGG1-dependent base excision repair mechanisms in defining the genetic integrity of mammalian spermatozoa.

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