scholarly journals BCR-ABL1 kinase inhibits uracil DNA glycosylase UNG2 to enhance oxidative DNA damage and stimulate genomic instability

Leukemia ◽  
2012 ◽  
Vol 27 (3) ◽  
pp. 629-634 ◽  
Author(s):  
A Slupianek ◽  
R Falinski ◽  
P Znojek ◽  
T Stoklosa ◽  
S Flis ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genomic Instability ◽  
Oxidative Dna Damage ◽  
Dna Glycosylase ◽  
Uracil Dna Glycosylase

scholarly journals Obesity, oxidative DNA damage and vitamin D as predictors of genomic instability in children and adolescents

2021 ◽  
Author(s):  
Moonisah Usman ◽  
Maria Woloshynowych ◽  
Jessica Carrilho Britto ◽  
Ivona Bilkevic ◽  
Bethany Glassar ◽  
...  
Keyword(s):  
Vitamin D ◽  
Dna Damage ◽  
Genomic Instability ◽  
Oxidative Dna Damage ◽  
Nutritional Deficiencies ◽  
Aetiological Factor ◽  
Enzyme Linked Immunosorbent Assay ◽  
Childhood And Adolescence ◽  
Paediatric Obesity ◽  
Vitamin D Levels

Abstract Background/objectives Epidemiological evidence indicates obesity in childhood and adolescence to be an independent risk factor for cancer and premature mortality in adulthood. Pathological implications from excess adiposity may begin early in life. Obesity is concurrent with a state of chronic inflammation, a well-known aetiological factor for DNA damage. In addition, obesity has been associated with micro-nutritional deficiencies. Vitamin D has attracted attention for its anti-inflammatory properties and role in genomic integrity and stability. The aim of this study was to determine a novel approach for predicting genomic instability via the combined assessment of adiposity, DNA damage, systemic inflammation, and vitamin D status. Subjects/methods We carried out a cross-sectional study with 132 participants, aged 10–18, recruited from schools and paediatric obesity clinics in London. Anthropometric assessments included BMI Z-score, waist and hip circumference, and body fat percentage via bioelectrical impedance. Inflammation and vitamin D levels in saliva were assessed by enzyme-linked immunosorbent assay. Oxidative DNA damage was determined via quantification of 8-hydroxy-2′-deoxyguanosine in urine. Exfoliated cells from the oral cavity were scored for genomic instability via the buccal cytome assay. Results As expected, comparisons between participants with obesity and normal range BMI showed significant differences in anthropometric measures (p < 0.001). Significant differences were also observed in some measures of genomic instability (p < 0.001). When examining relationships between variables for all participants, markers of adiposity positively correlated with acquired oxidative DNA damage (p < 0.01) and genomic instability (p < 0.001), and negatively correlated with vitamin D (p < 0.01). Multiple regression analyses identified obesity (p < 0.001), vitamin D (p < 0.001), and oxidative DNA damage (p < 0.05) as the three significant predictors of genomic instability. Conclusions Obesity, oxidative DNA damage, and vitamin D deficiency are significant predictors of genomic instability. Non-invasive biomonitoring and predictive modelling of genomic instability in young patients with obesity may contribute to the prioritisation and severity of clinical intervention measures.

CML-CP Mouse Model of Genomic Instability.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1210-1210
Author(s):  
Elisabeth Bolton ◽  
Linda Kamp ◽  
Hardik Modi ◽  
Ravi Bhatia ◽  
Steffen Koschmieder ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Stem Cell ◽  
Mouse Model ◽  
Board Of Directors ◽  
Genomic Instability ◽  
Oxidative Dna Damage ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Dependent Effect

Abstract Abstract 1210 Background: BCR-ABL1 transforms hematopoietic stem cells to induce chronic myeloid leukemia in chronic phase (CML-CP). Although CML is stem cell-derived, it is a progenitor cell-driven disease. In CML-CP, leukemia stem cells (LSCs) are characterized by elevated BCR-ABL1 expression in comparison to leukemia progenitor cells (LPCs). Increased expression of BCR-ABL1 kinase is also associated with progression from CML-CP to CML-blast phase. Previously we showed that BCR-ABL1 kinase stimulates reactive oxygen species (ROS)-dependent DNA damage resulting in genomic instability in vitro, which was responsible for acquired imatinib-resistance and accumulation of chromosomal aberrations (Nowicki et al., Blood, 2005; Koptyra et al., Blood, 2006; Koptyra et al., Leukemia, 2008). Result: To examine the effects of BCR-ABL1 expression on genomic instability during in vivo leukemogenesis we employed an inducible transgenic mouse model of CML-CP with targeted expression of p210BCR-ABL1 in hematopoietic stem and progenitor cells (Koschmieder et al., Blood, 2005). Mice exhibiting CML-CP-like disease resulting from BCR-ABL1 induction demonstrated splenomegaly, leukocytosis, and Gr1+/CD11b+ myeloid expansion in bone marrow, spleen and peripheral blood, as detected by FACS analysis. BCR-ABL1 mRNA expression was higher in Lin-c-Kit+Sca1+ stem-enriched cells than in Lin-c-Kit+Sca1- progenitor-enriched cells, thus reminiscent of CML-CP (LSCs>LPCs). BCR-ABL1 increased levels of ROS (hydrogen peroxide, hydroxyl radical) and oxidative DNA lesions (8-oxoG) in LSC-enriched Lin-c-Kit+Sca1+ cells. Preliminary data also suggested that quiescent (CFSEmax) Lin-c-Kit+Sca1+ cells from BCR-ABL1-induced mice exhibited greater ROS (superoxide) production than non-induced counter parts. Moreover, higher levels of ROS were detected in BCR-ABL1-positive Lin-c-Kit+Sca1+ stem-enriched population in comparison to BCR-ABL1-positive Lin-c-Kit+Sca1- progenitor population, suggesting a dosage-dependent effect of BCR-ABL1. To confirm that BCR-ABL1 exerts a dosage-dependent effect on ROS-induced oxidative DNA damage, we showed that the levels of ROS, 8-oxoG and DNA double-strand breaks were proportional to BCR-ABL1 kinase expression in murine 32Dc13 and human CD34+ cells. Conclusion: In summary, this mouse model recapitulates the BCR-ABL1 expression profile attributed to stem and progenitor populations in human CML-CP. It also shows that the BCR-ABL1-positive, stem cell-enriched Lin-c-Kit+Sca1+ population displays elevated levels of ROS and oxidative DNA damage in comparison to normal counterparts, which makes it suitable to study the mechanisms of genomic instability in LSCs. Single nucleotide polymorphism (SNP) arrays will shed more light on the genomic instability of this BCR-ABL1-induced transgenic model of CML-CP. Disclosures: Koschmieder: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Genomic Instability Originates From Leukemia Stem Cells in a Mouse Model of CML-CP

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 445-445 ◽  
Author(s):  
Elisabeth Bolton ◽  
Mirle Schemionek ◽  
Hans-Ulrich Klein ◽  
Linda Kerstiens ◽  
Steffen Koschmieder ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Mouse Model ◽  
Progenitor Cells ◽  
Genomic Instability ◽  
Oxidative Dna Damage ◽  
Transgenic Mouse Model ◽  
Hematopoietic Stem ◽  
Genetic Aberrations ◽  
Stem And Progenitor Cells

Abstract Abstract 445 For decades, chronic myeloid leukemia (CML) has served not only as a paradigm for understanding the evolution and multi-step process of carcinogenesis but also for studying cancer stem and progenitor cells responsible for the initiation and/or maintenance of the disease. CML is initiated by BCR-ABL1 tyrosine kinase transformation of hematopoietic stem cells into leukemia stem cells (LSCs) to induce CML-chronic phase (CML-CP). The deregulated growth of LSC-derived leukemia progenitor cells (LPCs) leads to manifestation of the disease. It is unclear if LSCs and/or LPCs are able to acquire additional genetic changes that confer resistance to tyrosine kinase inhibitors (TKIs) and induce more aggressive CML blast phase (CML-BP). In addition, the mechanisms and consequences of genomic instability may differ substantially among these cells. For example, the effects of genetic aberrations acquired in quiescent LSCs may be dormant, but if the aberrations induce proliferation or appear in LSCs that are already cycling, they may generate TKI-resistant and/or more malignant clones. Alternatively, genomic instability in LPCs must be accompanied by the acquisition of LSC-like properties to prevent mutations from disappearing before they undergo terminal maturation. Previously, we reported that BCR-ABL1–transformed cell lines accumulate reactive oxygen species (ROS)-induced oxidative DNA damage [8-oxoguanine (8oxoG), double strand breaks (DSBs)] resulting in genomic instability in vitro, which was responsible for acquired imatinib-resistance and accumulation of chromosomal aberrations (Nowicki et al., Blood, 2005; Koptyra et al., Blood, 2006; Koptyra et al., Leukemia, 2008). To determine which populations of CML-CP cells, LSCs and/or LPCs, accumulate genomic instability we employed the SCLtTA/BCR-ABL1 tetracycline-inducible (tet-off) transgenic mouse model of CML-CP with targeted expression of p210BCR-ABL1 in hematopoietic stem and progenitor cells (Koschmieder et al., Blood, 2005). Mice exhibiting CML-CP-like disease resulting from BCR-ABL1 induction demonstrated splenomegaly and Gr1+/CD11b+ myeloid expansion in bone marrow, spleen and peripheral blood. BCR-ABL1 mRNA expression was higher in the Lin−c-Kit+Sca1+ murine leukemia stem cell–enriched population (muLSCs) than in the Lin−c-Kit+Sca1− murine leukemia progenitor cell–enriched population (muLPCs), thus reminiscent of human CML-CP (Lin−CD34+CD38− LSCs > Lin−CD34+CD38+ LPCs). BCR-ABL1 induction increased levels of ROS (hydrogen peroxide, hydroxyl radical) and oxidative DNA damage (8-oxoG, DSBs) in muLSCs, but not in muLPCs. In addition, CFSEmax/eFluor670max quiescent muLSCs displayed more ROS (superoxide, hydrogen peroxide) and oxidative DNA damage (8oxoG, DSBs) than non-induced counterparts. Currently, we are examining genomic instability in the most primitive long-term muLSCs (Lin−c-Kit+Sca1+CD34−Flt3−). Lastly, single nucleotide polymorphism (SNP) arrays detected a variety of genetic aberrations (addition, deletions) in BCR-ABL1–induced Lin− BM cells. Individual mice displayed a great degree of diversity in the intensity of genetic instability accumulating between 31 to 826 aberrations, which recapitulate heterogeneity of sporadic aberrations detected in CML-CP patients. These aberrations include deletions in Trp53 and Ikzf1, and additions in Zfp423 and Idh1 genes, which have been linked to progression from CML-CP to CML-BP. In summary, by using the SCLtTA/BCR-ABL1 inducible transgenic mouse model of CML-CP we showed that muLSCs, but not muLPCs, displayed elevated levels of ROS-induced oxidative DNA damage likely resulting in the accumulation of extensive genetic aberrations. This observation supports the hypothesis that genomic instability in CML-CP originates in LSCs. Current analysis of microarrays may shed some light on the mechanisms leading to enhanced ROS production and accumulation of oxidative DNA damage in muLSCs. Disclosures: Koschmieder: Novartis, Bristol-Myers Squibb: Consultancy.

ROS-Induced DNA Damage Causing Genomic Instability in CML Stem and/or Progenitor Cells and in Quiescent and/or Proliferating Cells: Role of Mitochondrial Respiratory Chain Complex III.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3268-3268
Author(s):  
Margaret Nieborowska-Skorska ◽  
Mateusz Koptyra ◽  
Elisabeth Bolton ◽  
Regina Ray ◽  
Danielle Ngaba ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genomic Instability ◽  
Respiratory Chain ◽  
Chromosomal Aberrations ◽  
Oxidative Dna Damage ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Abl Kinase ◽  
Mitochondrial Respiratory

Abstract Abstract 3268 Poster Board III-1 BCR/ABL kinase transforms hematopoietic stem cells to induce chronic myelogenous leukemia (CML). CML in chronic phase (CML-CP) is a leukemia stem cell (LSC)-derived but leukemia progenitor cell (LPC)-driven disease, which is, in most cases, sensitive to ABL tyrosine kinase inhibitors (TKIs) monotherapy. TKIs do not eradicate the leukemia but instead usually render the disease ‘inactive', since the residual quiescent LSCs are intrinsically insensitive to BCR-ABL inhibition and, in a significant cohort of CML patients, LPCs are also refractory or acquire resistance to TKIs due to mutations in BCR/ABL kinase. In the post-imatinib era, these cells may eventually undergo transformation and initiate fatal CML blast crisis (CML-BC). The malignant progression is usually associated with enhanced expression of BCR/ABL and accumulation of additional genetic aberrations, such as TKI-resistant mutations and chromosomal aberrations. In CML-CP, LSCs and LPCs reside in the CD34+CD38- and CD34+CD38+ populations, respectively, whereas in CML-BC, LSCs are also found in the CD34+CD38+ population. In addition, LSCs and LPCs usually belong to quiescent (CFSEmax) and proliferative (CFSElow) populations, respectively. However, the origin of CML-BC clone and the role of BCR/ABL “dosage” are not known. Since genomic instability usually results from DNA damage, we investigated the mechanisms responsible for enhanced DNA damage in CML cells. Much endogenous DNA damage arises from free radicals such as reactive oxygen species (ROS). Here we show that LSCs-enriched CD34+CD38- and quiescent (CFSEmax) CML cells and LPCs-enriched CD34+CD38+ cells contain higher levels of ROS (superoxide anion, hydrogen peroxide, and hydroxyl radical) than corresponding cells from normal donors (CML-BC>CML-CP>Normal). Interestingly, CFSEmax and CFSElow CML cells displayed similar elevation of ROS indicating that the presence of BCR/ABL and not the proliferative status enhances ROS. In addition, total cellular ROS and mitochondrial ROS levels were proportional to the expression of BCR/ABL kinase implicating the role of BCR/ABL kinase “dosage”. Higher levels of ROS caused more oxidative DNA lesions, such as 8-oxoG and DNA double-strand breaks (DSBs) in CD34+ and also in CD34+CD38- CML cells than in normal counterparts (CML-BC>CML-CP>Normal). Inhibition of BCR/ABL kinase with imatinib partially reduced ROS and oxidative DNA damage in CD34+ CML-CP cells, implicating BCR/ABL-dependent and -;independent mechanisms. Our previous studies showed that elevated levels of oxidative DNA damage in BCR/ABL-transformed cells were responsible for accumulation of TKI-resistant BCR/ABL mutants and chromosomal aberrations (Blood, 2006; Leukemia, 2008), highlighting the importance of identification of the sources of ROS in CML. Mitochondrial respiratory chain (MRC) is a major site of ATP production via oxidative phosphorylation, which is associated with electron flux through MRC. Some of the electrons may escape and react with molecular oxygen to form ROS. To shut down MRC, cells were depleted of mitochondrial DNA (mtDNA) by long-term exposure to ethidium bromide in the presence of uridine and pyruvate as confirmed by RT-PCR showing the absence/reduction of mtDNA-coded Cox II gene transcript. The absence of functional MRC reduced the level of ROS by 40% and 20% in CD34+ CML-CP cells and normal counterparts, respectively, suggesting that MRC is an important source of ROS in leukemia cells. Using selective inhibitors of various MRC complexes we identified complex III as major producer of ROS in LSCs and LPCs in CML-CP. The role of complex III in CML-BC cells is somehow diminished in concordance with the observation that prolonged exposure of MRC to elevated levels of ROS results in “mitochondrial injury” and reduction of MRC activity in advanced stages of cancer. In summary, we postulate that BCR/ABL kinase generates ROS and oxidative DNA damage in a dose-dependent manner not only in LPCs-enriched CD34+CD38+ and CFSElow cells, but also in LSCs-enriched CD34+CD38- and CFSEmax cells, and that MRC complex III generates significant amount of ROS in CML-CP cells. Thus, genomic instability causing TKI resistance and progression to CML-BC may originate in LSCs as well as in LPCs. Disclosures: No relevant conflicts of interest to declare.

BCR-ABL1 Kinase Inhibits DNA Glycosylases to Enhance Oxidative DNA Damage and Stimulate Genomic Instability

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 520-520
Author(s):  
Artur Slupianek ◽  
Rafal Falinski ◽  
Pawel Znojek ◽  
Tomasz Stoklosa ◽  
Sylwia Flis ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genomic Instability ◽  
Oxidative Dna Damage ◽  
Conflicts Of Interest ◽  
Point Mutations ◽  
Specific Inhibitor ◽  
Chronic Phase ◽  
Dna Lesions ◽  
Dna Bases ◽  
Transformed Cell Lines

Abstract Abstract 520 Tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib and nilotinib revolutionized the treatment of BCR-ABL1 kinase-positive chronic myeloid leukemia in chronic phase (CML-CP). Unfortunately, 15–25% of patients initially responding favorably to imatinib will develop acquired drug resistance, which in 40–90% of cases is caused by genomic instability resulting in the appearance of clones expressing TKI resistant BCR-ABL1 kinase mutants. We reported that CML-CP leukemia stem and progenitor cell populations accumulate high amounts of reactive oxygen species (ROS) resulting in excessive oxidative DNA damage such as oxidized DNA bases (8-oxoguanine and 5-hydroxycytosine→uracil) (Nieborowska-Skorska et al., Blood, 2012). Unfaithful and/or inefficient repair of these lesions generates TKI resistant point mutations in BCR-ABL1 kinase. Oxidative DNA lesions may be removed by base excision repair (BER) or, if not removed, will create mismatches, which are repaired by mismatch repair (MMR). Since we found that MMR is inhibited in CML-CP (Stoklosa et al., Cancer Res., 2008), the activity of BER is critical to prevent the accumulation of point mutations. Using an array of specific substrates and inhibitors/blocking antibodies we found that two major glycosylases, uracil-DNA glycosylase UNG2 and 8-oxoguanine glycosylase (OGG1) responsible for the excision of uracil (product of oxidation of cytosine) and 8-oxoguanine (8-oxoG) from DNA, respectively, were inhibited in BCR-ABL1 –transformed cell lines and CD34+ CML cells. The inhibitory effect was even more pronounced in CML blast phase (CML-BP) in comparison to CML-CP, it depended on BCR-ABL1 kinase activity and was not accompanied by deregulation of nuclear expression and/or chromatin association of these glycosylases. The effect was BCR-ABL1 kinase-specific because several other fusion tyrosine kinases such as TEL-ABL1, TEL-PDGFbetaR and NPM-ALK did not reduce UNG2 activity. Using UNG2-specific inhibitor UGI we found that UNG2 activity diminished the number of oxidized DNA bases detected by modified comet assay and prevented accumulation of point mutations in reporter gene Na+/K+ATPase, which encode resistance to ouabain. In conclusion, we hypothesize that inhibition of UNG2 and OGG1, accompanied by reduced MMR activity is responsible for accumulation of TKI-resistant BCR-ABL1 kinase point mutations and perhaps also other point mutations facilitating malignant progression of CML. Disclosures: No relevant conflicts of interest to declare.

Genomic Instability in CML-CP originates From the Most Primitive Imatinib-Refractory Leukemia Stem Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 909-909
Author(s):  
Elisabeth Bolton ◽  
Mirle Schemionek ◽  
Hans-Urlich Klein ◽  
Grazyna Hoser ◽  
Sylwia Flis ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Board Of Directors ◽  
Genomic Instability ◽  
Research Funding ◽  
Oxidative Dna Damage ◽  
Dna Lesions ◽  
Leukemia Stem Cells ◽  
Human Leukemia ◽  
Advisory Committees

Abstract Abstract 909 Genomic instability is a hallmark of chronic myeloid leukemia in chronic phase (CML-CP) resulting in the appearance of clones carrying BCR-ABL1 kinase mutations encoding resistance to tyrosine kinase inhibitors (TKIs) and/or those harboring additional chromosomal aberrations, eventually leading to disease relapse and/or malignant progression to blast phase (CML-BP) [Skorski, T., Leukemia and Lymphoma, 2011]. We found that Lin−CD34+CD38− human leukemia stem cells (huLSCs), including the quiescent sub-population, and Lin−CD34+CD38+ human leukemia progenitor cells (huLPCs) accumulate high levels of reactive oxygen species (ROS) resulting in numerous oxidative DNA lesions such as 8-oxoguanine (8-oxoG) and DNA double-strand breaks (DSBs) [Nieborowska-Skorska, Blood, 2012]. huLSCs and huLPCs treated with TKIs continue to exhibit ROS-induced oxidative DNA damage suggesting the persistence of genomic instability in TKI-treated patients. Furthermore, genomic instability in TKI-refractory huLSCs and TKI-sensitive huLPCs may have a varying impact on disease progression and determining novel treatment modalities. To determine if TKI-refractory huLSCs are a source of genomic instability we employed a tetracycline-inducible murine model of CML-CP: SCLtTA/p210BCR-ABL1. Mice exhibiting CML-CP -like disease demonstrated splenomegaly, leukocytosis, and expansion of mature Gr1+/CD11b+ cells. ROS were elevated in Lin−c-Kit+Sca-1+ cells (muLSCs), but not Lin−c-Kit+Sca-1− cells (muLPCs), which was associated with higher mRNA expression of BCR-ABL1 in muLSCs. In addition, ROS levels were directly proportional to BCR-ABL1 kinase expression in transduced CD34+ human hematopoietic cells, thus confirming the “dosage-dependent” effect of BCR-ABL1 on ROS. Among the Lin−c-Kit+Sca-1+ cells, enhanced ROS were detected in TKI-refractory quiescent muLSCs, in CD34−Flt3− long-term and CD34+Flt3− short-term muLSCs, and also in CD34+Flt3+ multipotent progenitors. High levels of ROS in muLSCs were accompanied by aberrant expression of genes regulating ROS metabolism (mitochondrial electron transport, oxidative phosphorylation, hydrogen peroxide synthesis, and detoxification). In addition, muLSCs, including the quiescent sub-population, displayed high levels of oxidative DNA lesions (8-oxoG, and DSBs). ROS-induced oxidative DNA damage in muLSCs was accompanied by genomic instability in CML-CP –like mice, which accumulated a broad range of genetic aberrations recapitulating the heterogeneity of sporadic mutations detected in TKI-naive CML-CP patients. These aberrations include TKI-resistant BCR-ABL1 kinase mutations, deletions in Ikzf1 and Trp53 and additions in Zfp423 and Idh1 genes, which have been associated with CML-CP relapse and progression to CML-BP. Imatinib caused only modest inhibition of ROS and oxidative DNA damage in TKI-refractory muLSCs. In concordance, CML-CP –like mice treated with imatinib continued to accumulate genomic aberrations. Since BCR-ABL1(K1172R) kinase-dead mutant expressed in CD34+ human hematopoietic cells did not enhance ROS, it suggests that BCR-ABL1 kinase-independent mechanisms contribute to genomic instability. In summary, we postulate that ROS-induced oxidative DNA damage resulting in genetic instability may originate in the most primitive TKI-refractory huLSCs in TKI-naive and TKI-treated patients. Disclosures: Lange: Novartis: Honoraria, Research Funding. Müller:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Koschmieder:Novartis / Novartis Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

A fission yeast homologue of the human uracil-DNA-glycosylase and their roles in causing DNA damage after overexpression

2003 ◽  
Vol 306 (3) ◽  
pp. 693-700 ◽  
Author(s):  
Robert T Elder ◽  
Xudong Zhu ◽  
Stephane Priet ◽  
Mingzhong Chen ◽  
Min Yu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Fission Yeast ◽  
Dna Glycosylase ◽  
Uracil Dna Glycosylase

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.

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