scholarly journals The Potential Role of 8-Oxoguanine DNA Glycosylase-Driven DNA Base Excision Repair in Exercise-Induced Asthma

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
KarryAnne K. Belanger ◽  
Bill T. Ameredes ◽  
Istvan Boldogh ◽  
Leopoldo Aguilera-Aguirre
Keyword(s):  
Base Excision Repair ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Dna Lesions ◽  
Dna Glycosylase ◽  
Airway Narrowing ◽  
Inflammatory Conditions ◽  
Base Excision ◽  
Exercise Induced

Asthma is characterized by reversible airway narrowing, shortness of breath, wheezing, coughing, and other symptoms driven by chronic inflammatory processes, commonly triggered by allergens. In 90% of asthmatics, most of these symptoms can also be triggered by intense physical activities and severely exacerbated by environmental factors. This condition is known as exercise-induced asthma (EIA). Current theories explaining EIA pathogenesis involve osmotic and/or thermal alterations in the airways caused by changes in respiratory airflow during exercise. These changes, along with existing airway inflammatory conditions, are associated with increased cellular levels of reactive oxygen species (ROS) affecting important biomolecules including DNA, although the underlying molecular mechanisms have not been completely elucidated. One of the most abundant oxidative DNA lesions is 8-oxoguanine (8-oxoG), which is repaired by 8-oxoguanine DNA glycosylase 1 (OGG1) during the base excision repair (BER) pathway. Whole-genome expression analyses suggest a cellular response to OGG1-BER, involving genes that may have a role in the pathophysiology of EIA leading to mast cell degranulation, airway hyperresponsiveness, and bronchoconstriction. Accordingly, this review discusses a potential new hypothesis in which OGG1-BER-induced gene expression is associated with EIA symptoms.

scholarly journals New perspectives in cancer biology from a study of canonical and non-canonical functions of base excision repair proteins with a focus on early steps

Mutagenesis ◽  
2019 ◽  
Vol 35 (1) ◽  
pp. 129-149 ◽  
Author(s):  
Matilde Clarissa Malfatti ◽  
Giulia Antoniali ◽  
Marta Codrich ◽  
Silvia Burra ◽  
Giovanna Mangiapane ◽  
...  
Keyword(s):  
Dna Repair ◽  
Base Excision Repair ◽  
Cancer Biology ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Dna Lesions ◽  
Cancer Development ◽  
Dna Repair Enzymes ◽  
Repair Enzymes ◽  
Base Excision

Abstract Alterations of DNA repair enzymes and consequential triggering of aberrant DNA damage response (DDR) pathways are thought to play a pivotal role in genomic instabilities associated with cancer development, and are further thought to be important predictive biomarkers for therapy using the synthetic lethality paradigm. However, novel unpredicted perspectives are emerging from the identification of several non-canonical roles of DNA repair enzymes, particularly in gene expression regulation, by different molecular mechanisms, such as (i) non-coding RNA regulation of tumour suppressors, (ii) epigenetic and transcriptional regulation of genes involved in genotoxic responses and (iii) paracrine effects of secreted DNA repair enzymes triggering the cell senescence phenotype. The base excision repair (BER) pathway, canonically involved in the repair of non-distorting DNA lesions generated by oxidative stress, ionising radiation, alkylation damage and spontaneous or enzymatic deamination of nucleotide bases, represents a paradigm for the multifaceted roles of complex DDR in human cells. This review will focus on what is known about the canonical and non-canonical functions of BER enzymes related to cancer development, highlighting novel opportunities to understand the biology of cancer and representing future perspectives for designing new anticancer strategies. We will specifically focus on APE1 as an example of a pleiotropic and multifunctional BER protein.

Base excision repair mediated cascading triple-signal amplification for the sensitive detection of human alkyladenine DNA glycosylase

The Analyst ◽  
2019 ◽  
Vol 144 (9) ◽  
pp. 3064-3071 ◽  
Author(s):  
Huige Zhang ◽  
Lili Wang ◽  
Yi Xie ◽  
Xianwei Zuo ◽  
Hongli Chen ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Significant Role ◽  
Signal Amplification ◽  
Excision Repair ◽  
Dna Lesions ◽  
Sensitive Detection ◽  
Dna Glycosylase ◽  
Alkyladenine Dna Glycosylase ◽  
Base Excision

DNA glycosylase (DG) plays a significant role in repairing DNA lesions, and the dysregulation of DG activity is associated with a variety of human pathologies.

scholarly journals Molecular basis and functional consequences of the interaction between the Base Excision Repair DNA glycosylase NEIL1 and RPA

2021 ◽  
Author(s):  
Remy A Le Meur ◽  
Turner J Pecen ◽  
Kateryna V Le Meur ◽  
Zachary D Nagel ◽  
Walter J Chazin
Keyword(s):  
Base Excision Repair ◽  
Molecular Basis ◽  
Excision Repair ◽  
Dna Lesions ◽  
Dna Glycosylase ◽  
Scaffolding Protein ◽  
Duplex Dna ◽  
Ssdna Binding ◽  
Contact Points ◽  
Base Excision

NEIL1 is a DNA glycosylase that recognizes and initiates base excision repair of oxidized bases. The ubiquitous ssDNA binding scaffolding protein replication protein A (RPA) modulates NEIL1 activity in a manner that depends on DNA structure. Interaction between NEIL1 and RPA has been reported, but the molecular basis of this interaction has yet to be investigated. Using a combination of NMR spectroscopy and isothermal titration calorimetry (ITC), we show that NEIL1 interacts with RPA through two contact points. An interaction with the RPA32C protein recruitment domain was mapped to a motif in the common interaction domain (CID) of NEIL1 and a dissociation constant (Kd) of 200 nM was measured. A substantially weaker secondary interaction with the tandem RPA70AB ssDNA binding domains was also mapped to the CID. Together these two contact points reveal NEIL1 has a high overall affinity (Kd ~ 20 nM) for RPA. A homology model of the complex of RPA32C with the NEIL1 RPA binding motif in the CID was generated and used to design a set of mutations in NEIL1 to disrupt the interaction, which was confirmed by ITC. The mutant NEIL1 remains catalytically active against ionizing radiation-induced DNA lesions in duplex DNA in vitro. Testing the functional effect of disrupting the NEIL1-RPA interaction in vivo using a Fluorescence Multiplex-Host Cell Reactivation (FM-HCR) reporter assay revealed that RPA interaction is not required for NEIL1 activity against oxidative damage in duplex DNA, and furthermore revealed an unexpected role for NEIL1 in nucleotide excision repair. These findings are discussed in the context of the role of NEIL1 in replication-associated repair.

scholarly journals Chromatin recruitment of OGG1 requires cohesin and mediator and is essential for efficient 8-oxoG removal

2020 ◽  
Vol 48 (16) ◽  
pp. 9082-9097 ◽  
Author(s):  
Emilie Lebraud ◽  
Guillaume Pinna ◽  
Capucine Siberchicot ◽  
Jordane Depagne ◽  
Didier Busso ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Base Excision Repair ◽  
High Throughput ◽  
Excision Repair ◽  
Genomic Stability ◽  
Dna Lesions ◽  
Dna Glycosylase ◽  
Dna Glycosylases ◽  
Base Excision ◽  
Open Question

Abstract One of the most abundant DNA lesions induced by oxidative stress is the highly mutagenic 8-oxoguanine (8-oxoG), which is specifically recognized by 8-oxoguanine DNA glycosylase 1 (OGG1) to initiate its repair. How DNA glycosylases find small non-helix-distorting DNA lesions amongst millions of bases packaged in the chromatin-based architecture of the genome remains an open question. Here, we used a high-throughput siRNA screening to identify factors involved in the recognition of 8-oxoG by OGG1. We show that cohesin and mediator subunits are required for re-localization of OGG1 and other base excision repair factors to chromatin upon oxidative stress. The association of OGG1 with euchromatin is necessary for the removal of 8-oxoG. Mediator subunits CDK8 and MED12 bind to chromatin and interact with OGG1 in response to oxidative stress, suggesting they participate in the recruitment of the DNA glycosylase. The oxidative stress-induced association between the cohesin and mediator complexes and OGG1 reveals an unsuspected function of those complexes in the maintenance of genomic stability.

scholarly journals Non-muscle invasive bladder cancer tissues have increased base excision repair capacity

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Berna Somuncu ◽  
Selcuk Keskin ◽  
Fatma Merve Antmen ◽  
Yesim Saglican ◽  
Aysegul Ekmekcioglu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Base Excision Repair ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Dna Glycosylase ◽  
Low Grade ◽  
Repair Capacity ◽  
Significant Difference ◽  
Base Excision ◽  
Muscle Invasive

Abstract The molecular mechanisms underlying the development and progression of bladder cancer (BC) are complex and have not been fully elucidated. Alterations in base excision repair (BER) capacity, one of several DNA repair mechanisms assigned to preserving genome integrity, have been reported to influence cancer susceptibility, recurrence, and progression, as well as responses to chemotherapy and radiotherapy. We report herein that non-muscle invasive BC (NMIBC) tissues exhibit increased uracil incision, abasic endonuclease and gap-filling activities, as well as total BER capacity in comparison to normal bladder tissue from the same patient (p < 0.05). No significant difference was detected in 8-oxoG incision activity between cancer and normal tissues. NMIBC tissues have elevated protein levels of uracil DNA glycosylase, 8-oxoguanine DNA glycosylase, AP endonuclease 1 and DNA polymerase β protein. Moreover, the fold increase in total BER and the individual BER enzyme activities were greater in high-grade tissues than in low-grade NMIBC tissues. These findings suggest that enhanced BER activity may play a role in the etiology of NMIBC and that BER proteins could serve as biomarkers in disease prognosis, progression or response to genotoxic therapeutics, such as Bacillus Calmette–Guérin.

Response of Base Excision Repair Enzymes to Complex DNA Lesions

2001 ◽  
Vol 156 (5) ◽  
pp. 584-589 ◽  
Author(s):  
M. Weinfeld ◽  
A. Rasouli-Nia ◽  
M. A. Chaudhry ◽  
R. A. Britten
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Lesions ◽  
Repair Enzymes ◽  
Base Excision

scholarly journals Multiprobe RNase Protection Assay Analysis of mRNA Levels for the Escherichia coli Oxidative DNA Glycosylase Genes under Conditions of Oxidative Stress

2000 ◽  
Vol 182 (19) ◽  
pp. 5416-5424 ◽  
Author(s):  
Christine M. Gifford ◽  
Jeffrey O. Blaisdell ◽  
Susan S. Wallace
Keyword(s):  
Escherichia Coli ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Glycosylase ◽  
Mrna Levels ◽  
Aerobic Growth ◽  
Rnase Protection ◽  
Transcript Levels ◽  
Endonuclease Iii ◽  
Base Excision

ABSTRACT Escherichia coli formamidopyrimidine DNA glycosylase (Fpg), MutY DNA glycosylase, endonuclease VIII, and endonuclease III are oxidative base excision repair DNA glycosylases that remove oxidized bases from DNA, or an incorrect base paired with an oxidized base in the case of MutY. Since genes encoding other base excision repair proteins have been shown to be part of adaptive responses inE. coli, we wanted to determine whether the oxidative DNA glycosylase genes are induced in response to conditions that cause the type of damage their encoded proteins remove. The genesfpg, mutY, nei, and nthencode Fpg, MutY, endonuclease VIII, and endonuclease III, respectively. Multiprobe RNase protection assays were used to examine the transcript levels of these genes under conditions that induce the SoxRS, OxyR, and SOS regulons after a shift from anaerobic to aerobic growth and at different stages along the growth curve. Transcript levels for all four genes decreased as cells progressed from log-phase growth to stationary phase and increased after cells were shifted from anaerobic to aerobic growth. None of the genes were induced by hydrogen peroxide, paraquat, X rays, or conditions that induce the SOS response.

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