scholarly journals Evidence that OGG1 Glycosylase Protects Neurons against Oxidative DNA Damage and Cell Death under Ischemic Conditions

2010 ◽  
Vol 31 (2) ◽  
pp. 680-692 ◽  
Author(s):  
Dong Liu ◽  
Deborah L Croteau ◽  
Nadja Souza-Pinto ◽  
Michael Pitta ◽  
Jingyan Tian ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cortical Neurons ◽  
Oxidative Dna Damage ◽  
Nuclear Dna ◽  
Excision Repair ◽  
Mitochondrial Fission ◽  
Metabolic Stress ◽  
Artery Occlusion ◽  
Dna Glycosylase ◽  
Base Excision

7,8-Dihydro-8-oxoguanine DNA glycosylase (OGG1) is a major DNA glycosylase involved in base-excision repair (BER) of oxidative DNA damage to nuclear and mitochondrial DNA (mtDNA). We used OGG1-deficient (OGG1−/–) mice to examine the possible roles of OGG1 in the vulnerability of neurons to ischemic and oxidative stress. After exposure of cultured neurons to oxidative and metabolic stress levels of OGG1 in the nucleus were elevated and mitochondria exhibited fragmentation and increased levels of the mitochondrial fission protein dynamin-related protein 1 (Drp1) and reduced membrane potential. Cortical neurons isolated from OGG1−/– mice were more vulnerable to oxidative insults than were OGG1+/+ neurons, and OGG1−/– mice developed larger cortical infarcts and behavioral deficits after permanent middle cerebral artery occlusion compared with OGG1+/+ mice. Accumulations of oxidative DNA base lesions (8-oxoG, FapyAde, and FapyGua) were elevated in response to ischemia in both the ipsilateral and contralateral hemispheres, and to a greater extent in the contralateral cortex of OGG1−/– mice compared with OGG1+/+ mice. Ischemia-induced elevation of 8-oxoG incision activity involved increased levels of a nuclear isoform OGG1, suggesting an adaptive response to oxidative nuclear DNA damage. Thus, OGG1 has a pivotal role in repairing oxidative damage to nuclear DNA under ischemic conditions, thereby reducing brain damage and improving functional outcome.

scholarly journals Oxygen-Dependent Accumulation of Purine DNA Lesions in Cockayne Syndrome Cells

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1671 ◽  
Author(s):  
Marios G. Krokidis ◽  
Mariarosaria D’Errico ◽  
Barbara Pascucci ◽  
Eleonora Parlanti ◽  
Annalisa Masi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Enzymatic Digestion ◽  
Cockayne Syndrome ◽  
Dna Lesions ◽  
Premature Aging ◽  
Neurological Features ◽  
Oxygen Tensions ◽  
Base Excision

Cockayne Syndrome (CS) is an autosomal recessive neurodegenerative premature aging disorder associated with defects in nucleotide excision repair (NER). Cells from CS patients, with mutations in CSA or CSB genes, present elevated levels of reactive oxygen species (ROS) and are defective in the repair of a variety of oxidatively generated DNA lesions. In this study, six purine lesions were ascertained in wild type (wt) CSA, defective CSA, wtCSB and defective CSB-transformed fibroblasts under different oxygen tensions (hyperoxic 21%, physioxic 5% and hypoxic 1%). In particular, the four 5′,8-cyclopurine (cPu) and the two 8-oxo-purine (8-oxo-Pu) lesions were accurately quantified by LC-MS/MS analysis using isotopomeric internal standards after an enzymatic digestion procedure. cPu levels were found comparable to 8-oxo-Pu in all cases (3–6 lesions/106 nucleotides), slightly increasing on going from hyperoxia to physioxia to hypoxia. Moreover, higher levels of four cPu were observed under hypoxia in both CSA and CSB-defective cells as compared to normal counterparts, along with a significant enhancement of 8-oxo-Pu. These findings revealed that exposure to different oxygen tensions induced oxidative DNA damage in CS cells, repairable by NER or base excision repair (BER) pathways. In NER-defective CS patients, these results support the hypothesis that the clinical neurological features might be connected to the accumulation of cPu. Moreover, the elimination of dysfunctional mitochondria in CS cells is associated with a reduction in the oxidative DNA damage.

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.

scholarly journals Base excision repair of oxidative DNA damage and association with cancer and aging

2008 ◽  
Vol 30 (1) ◽  
pp. 2-10 ◽  
Author(s):  
S. Maynard ◽  
S. H. Schurman ◽  
C. Harboe ◽  
N. C. de Souza-Pinto ◽  
V. A. Bohr
Keyword(s):  
Dna Damage ◽  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Base Excision

scholarly journals The Effect ofMsh2Knockdown on Toxicity Induced bytert-Butyl-hydroperoxide, Potassium Bromate, and Hydrogen Peroxide in Base Excision Repair Proficient and Deficient Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
N. Cooley ◽  
R. H. Elder ◽  
A. C. Povey
Keyword(s):  
Dna Damage ◽  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Shrna Expression ◽  
Cellular Toxicity ◽  
Dna Mismatch ◽  
Shrna Expression Vector ◽  
Repair Systems ◽  
Base Excision

The DNA mismatch repair (MMR) and base excision repair (BER) systems are important determinants of cellular toxicity following exposure to agents that cause oxidative DNA damage. To examine the interactions between these different repair systems, we examined whether toxicity, induced byt-BOOH and KBrO3, differs in BER proficient (Mpg+/+,Nth1+/+) and deficient (Mpg−/−,Nth1−/−) mouse embryonic fibroblasts (MEFs) followingMsh2knockdown of between 79 and 88% using an shRNA expression vector.Msh2knockdown inNth1+/+cells had no effect ont-BOOH and KBrO3induced toxicity as assessed by an MTT assay; knockdown inNth1−/−cells resulted in increased resistance tot-BOOH and KBrO3, a result consistent with Nth1 removing oxidised pyrimidines.Msh2knockdown inMpg+/+cells had no effect ont-BOOH toxicity but increased resistance to KBrO3; inMpg−/−cells,Msh2knockdown increased cellular sensitivity to KBrO3but increased resistance to t-BOOH, suggesting a role forMpgin removing DNA damage induced by these agents. MSH2 dependent and independent pathways then determine cellular toxicity induced by oxidising agents. A complex interaction between MMR and BER repair systems, that is, exposure dependent, also exists to determine cellular toxicity.

Roles of base excision repair enzymes Nth1p and Apn2p from Schizosaccharomyces pombe in processing alkylation and oxidative DNA damage

DNA Repair ◽  
2005 ◽  
Vol 4 (11) ◽  
pp. 1270-1280 ◽  
Author(s):  
Takanori Sugimoto ◽  
Emi Igawa ◽  
Haruna Tanihigashi ◽  
Mayumi Matsubara ◽  
Hiroshi Ide ◽  
...  
Keyword(s):  
Dna Damage ◽  
Schizosaccharomyces Pombe ◽  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Repair Enzymes ◽  
Base Excision

Mammalian DNA base excision repair proteins: their interactions and role in repair of oxidative DNA damage

Toxicology ◽  
2003 ◽  
Vol 193 (1-2) ◽  
pp. 43-65 ◽  
Author(s):  
Tadahide Izumi ◽  
Lee R. Wiederhold ◽  
Gargi Roy ◽  
Rabindra Roy ◽  
Arun Jaiswal ◽  
...  
Keyword(s):  
Dna Damage ◽  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Dna Base Excision Repair ◽  
Dna Base ◽  
Base Excision
Sign in / Sign up

Export Citation Format

Share Document