scholarly journals A Dual Face of APE1 in the Maintenance of Genetic Stability in Monocytes: An Overview of the Current Status and Future Perspectives

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 643
Author(s):  
Gabriela Betlej ◽  
Ewelina Bator ◽  
Antoni Pyrkosz ◽  
Aleksandra Kwiatkowska
Keyword(s):  
Genetic Stability ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Biological Significance ◽  
Dna Lesions ◽  
Current Status ◽  
Dna Breaks ◽  
Antioxidant Genes ◽  
Double Strand Dna Breaks ◽  
Base Excision

Monocytes, which play a crucial role in the immune system, are characterized by an enormous sensitivity to oxidative stress. As they lack four key proteins responsible for DNA damage response (DDR) pathways, they are especially prone to reactive oxygen species (ROS) exposure leading to oxidative DNA lesions and, consequently, ROS-driven apoptosis. Although such a phenomenon is of important biological significance in the regulation of monocyte/macrophage/dendritic cells’ balance, it also a challenge for monocytic mechanisms that have to provide and maintain genetic stability of its own DNA. Interestingly, apurinic/apyrimidinic endonuclease 1 (APE1), which is one of the key proteins in two DDR mechanisms, base excision repair (BER) and non-homologous end joining (NHEJ) pathways, operates in monocytic cells, although both BER and NHEJ are impaired in these cells. Thus, on the one hand, APE1 endonucleolytic activity leads to enhanced levels of both single- and double-strand DNA breaks (SSDs and DSBs, respectively) in monocytic DNA that remain unrepaired because of the impaired BER and NHEJ. On the other hand, there is some experimental evidence suggesting that APE1 is a crucial player in monocytic genome maintenance and stability through different molecular mechanisms, including induction of cytoprotective and antioxidant genes. Here, the dual face of APE1 is discussed.

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.

scholarly journals Reduced Levels of DNA Polymerase δ Induce Chromosome Fragile Site Instability in Yeast

2008 ◽  
Vol 28 (17) ◽  
pp. 5359-5368 ◽  
Author(s):  
Francene J. Lemoine ◽  
Natasha P. Degtyareva ◽  
Robert J. Kokoska ◽  
Thomas D. Petes
Keyword(s):  
Dna Polymerase ◽  
Cancer Biology ◽  
Molecular Mechanisms ◽  
Fragile Site ◽  
Fragile Sites ◽  
Dna Lesions ◽  
Catalytic Subunit ◽  
Dna Breaks ◽  
Dna Polymerase Δ ◽  
Double Strand Dna Breaks

ABSTRACT Specific regions of genomes (fragile sites) are hot spots for the chromosome rearrangements that are associated with many types of cancer cells. Understanding the molecular mechanisms regulating the stability of chromosome fragile sites, therefore, has important implications in cancer biology. We previously identified two chromosome fragile sites in Saccharomyces cerevisiae that were induced in response to the reduced expression of Pol1p, the catalytic subunit of DNA polymerase α. In the study presented here, we show that reduced levels of Pol3p, the catalytic subunit of DNA polymerase δ, induce instability at these same sites and lead to the generation of a variety of chromosomal aberrations. These findings demonstrate that a change in the stoichiometry of replicative DNA polymerases results in recombinogenic DNA lesions, presumably double-strand DNA breaks.

scholarly journals Endonuclease IV Is the Main Base Excision Repair Enzyme Involved in DNA Damage Induced by UVA Radiation and Stannous Chloride

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Ellen S. Motta ◽  
Paulo Thiago Souza-Santos ◽  
Tuany R. Cassiano ◽  
Flávio J. S. Dantas ◽  
Adriano Caldeira-de-Araujo ◽  
...  
Keyword(s):  
Stannous Chloride ◽  
Excision Repair ◽  
Dna Lesions ◽  
Dna Breaks ◽  
Strand Breaks ◽  
E Coli ◽  
Dna Lesion ◽  
Base Excision ◽  
Dna Strand ◽  
Uva Radiation

Stannous chloride (SnCl2) and UVA induce DNA lesions through ROS. The aim of this work was to study the toxicity induced by UVA preillumination, followed bySnCl2treatment.E. coliBER mutants were used to identify genes which could play a role in DNA lesion repair generated by these agents. The survival assays showed (i) Thenfomutant was the most sensitive toSnCl2; (ii) lethal synergistic effect was observed after UVA pre-illumination, plusSnCl2incubation, thenfomutant being the most sensitive; (iii) wild type andnfomutants, transformed with pBW21 plasmid (nfo+) had their survival increased following treatments. The alkaline agarose gel electrophoresis assays pointed that (i) UVA induced DNA breaks andfpgmutant was the most sensitive; (ii)SnCl2-induced DNA strand breaks were higher than those from UVA andnfomutant had the slowest repair kinetics; (iii)UVA+SnCl2promoted an increase in DNA breaks thanSnCl2and, again,nfomutant displayed the slowest repair kinetics. In summary, Nfo protectsE. colicells against damage induced bySnCl2andUVA+SnCl2.

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.

A new DNA breaks repair pathway involving PARP3 and base excision repair proteins

2018 ◽  
Vol 482 (1) ◽  
pp. 96-100
Author(s):  
E. Belousova ◽  
◽  
M. Kutuzov ◽  
P. Ivankina ◽  
A. Ishchenko ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Repair Pathway ◽  
Dna Breaks ◽  
Base Excision

scholarly journals Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology

Cell Reports ◽  
2021 ◽  
Vol 36 (10) ◽  
pp. 109668
Author(s):  
Tanima SenGupta ◽  
Konstantinos Palikaras ◽  
Ying Q. Esbensen ◽  
Georgios Konstantinidis ◽  
Francisco Jose Naranjo Galindo ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Breaks ◽  
Single Stranded Dna ◽  
Age Dependent ◽  
Base Excision

Roles of Caenorhabditis elegans WRN Helicase in DNA Damage Responses, and a Comparison with Its Mammalian Homolog: A Mini-Review

Gerontology ◽  
2015 ◽  
Vol 62 (3) ◽  
pp. 296-303 ◽  
Author(s):  
Jin-Sun Ryu ◽  
Hyeon-Sook Koo
Keyword(s):  
Dna Damage ◽  
Caenorhabditis Elegans ◽  
Werner Syndrome ◽  
Model Organisms ◽  
Current Status ◽  
Helicase Domain ◽  
Replication Forks ◽  
Dna Breaks ◽  
Double Strand Dna Breaks ◽  
Double Strand Dna

Werner syndrome protein (WRN) is unusual among RecQ family DNA helicases in having an additional exonuclease activity. WRN is involved in the repair of double-strand DNA breaks via the homologous recombination and nonhomologous end joining pathways, and also in the base excision repair pathway. In addition, the protein promotes the recovery of stalled replication forks. The helicase activity is thought to unwind DNA duplexes, thereby moving replication forks or Holliday junctions. The targets of the exonuclease could be the nascent DNA strands at a replication fork or the ends of double-strand DNA breaks. However, it is not clear which enzyme activities are essential for repairing different types of DNA damage. Model organisms such as mice, flies, and worms deficient in WRN homologs have been investigated to understand the physiological results of defects in WRN activity. Premature aging, the most remarkable characteristic of Werner syndrome, is also seen in the mutant mice and worms, and hypersensitivity to DNA damage has been observed in WRN mutants of all three model organisms, pointing to conservation of the functions of WRN. In the nematode Caenorhabditis elegans, the WRN homolog contains a helicase domain but no exonuclease domain, so that this animal is very useful for studying the in vivo functions of the helicase without interference from the activity of the exonuclease. Here, we review the current status of investigations of C. elegans WRN-1 and discuss its functional differences from the mammalian homologs.

scholarly journals Molecular Mechanisms of the Whole DNA Repair System: A Comparison of Bacterial and Eukaryotic Systems

2010 ◽  
Vol 2010 ◽  
pp. 1-32 ◽  
Author(s):  
Rihito Morita ◽  
Shuhei Nakane ◽  
Atsuhiro Shimada ◽  
Masao Inoue ◽  
Hitoshi Iino ◽  
...  
Keyword(s):  
Dna Repair ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Thermus Thermophilus ◽  
Repair System ◽  
System A ◽  
Recombination Repair ◽  
Repair Mechanisms ◽  
Repair Pathways ◽  
Base Excision

DNA is subjected to many endogenous and exogenous damages. All organisms have developed a complex network of DNA repair mechanisms. A variety of different DNA repair pathways have been reported: direct reversal, base excision repair, nucleotide excision repair, mismatch repair, and recombination repair pathways. Recent studies of the fundamental mechanisms for DNA repair processes have revealed a complexity beyond that initially expected, with inter- and intrapathway complementation as well as functional interactions between proteins involved in repair pathways. In this paper we give a broad overview of the whole DNA repair system and focus on the molecular basis of the repair machineries, particularly inThermus thermophilusHB8.

scholarly journals Molecular mechanisms associated with clustered lesion-induced impairment of 8-oxoG recognition by the human glycosylase OGG1

2021 ◽  
Author(s):  
Tao Jiang ◽  
Antonio MONARI ◽  
Elise Dumont ◽  
Emmanuelle Bignon
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Structural Features ◽  
Repair Pathway ◽  
Dna Lesion ◽  
Damage Response ◽  
Base Excision ◽  
Structural Signature ◽  
Dynamics Simulations

The 8-oxo-7,8-dihydroguanine, referred to as 8-oxoG, is a highly mutagenic DNA lesion that can provoke the appearance of mismatches if it escapes the DNA Damage Response. The specific recognition of its structural signature by the hOGG1 glycosylase is the first step along the Base Excision Repair pathway, that ensures the integrity of the genome by preventing the emergence of mutations. 8-oxoG formation, structural features and repair have been the matter of extensive research and more recently this active field of research expended to the more complicated case of 8-oxoG within clustered lesions. Indeed, the presence of a second lesion within 1 or 2 helix turns can dramatically impact the repair yields of 8-oxoG by glycosylases. In this work, we use mu-range molecular dynamics simulations and machine learning-based post-analysis to explore the molecular mechanisms associated with the recognition of 8-oxoG by hOGG1 when embedded in a multiple lesions site with a mismatch in 5' or 3'. We delineate the stiffening of the DNA-protein interactions upon the presence of the mismatches, and rationalize the much lower repair yields reported with a 5' mismatch by describing the perturbation of 8-oxoG structural features upon addition of an adjacent lesion.

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