<i>In vitro</i>
            repair of oxidative DNA damage by human nucleotide excision repair system: Possible explanation for neurodegeneration in Xeroderma  pigmentosum patients

Reardon, Joyce T.; Bessho, Tadayoshi; Kung, Hsiang Chuan; Bolton, Philip H.; Sancar, Aziz

doi:10.1073/pnas.94.17.9463

Cited by 338 publications

(231 citation statements)

References 52 publications

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“…The large parts of these nonbulky adducts are repaired by the base excision repair (BER) mechanism, 5,10 with possible participation from nuclear excision repair. 11 DNA glycosylases, of which there are several types, recognize damaged DNA bases and catalyze hydrolytic cleavage of the N-glycosyl bond linking the base to the sugar. A DNA polymerase then fills the resulting gap.…”

Section: Introductionmentioning

confidence: 99%

Human 8-oxoguanine DNA glycosylase increases resistance to hyperoxic cytotoxicity in lung epithelial cells and involvement with altered MAPK activity

et al. 2005

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It is unknown whether base excision DNA repair (BER) proteins interact with mitogen-activated protein kinases (MAPK) under oxidation. Here, we explored roles of BER proteins in signaling transduction involving MAPK during hyperoxia. We demonstrated that ERK1/2 phosphorylation in A549 cells was increased in 95% O 2 . p38 activity in A549 cells was also increased by exposure to 95% O 2 . To evaluate regulatory roles of MAPK, we have transduced A549 cells and primary alveolar epithelial type II cells (AECII) to overexpress 8-oxoguanine DNA glycosylase (hOgg1). Overexpression of hOgg1 reduced hyperoxic toxicity in A549 and AECII cells. Furthermore, protection by BER against hyperoxia appeared to involve an upregulation of ERK1/2 and downregulation of p38. These observations demonstrate, for the first time, that reduction of hyperoxic toxicity by BER proteins may be involved with MAPK activity, thereby impacting cell survival. Furthermore, our studies suggest that modulation of MAPK may be used in combination with BER proteins to counteract hyperoxic toxicity.

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Section: Introductionmentioning

confidence: 99%

Human 8-oxoguanine DNA glycosylase increases resistance to hyperoxic cytotoxicity in lung epithelial cells and involvement with altered MAPK activity

et al. 2005

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“…However, in vivo studies revealed a role for NER in the repair of methylated DNA base lesions that do not cause major helical distortions and in providing cellular resistance to simple methylating agents (38,48,49). Indeed, biochemical studies confirmed that subtle types of DNA damage can be substrates for NER, including thymine glycols, 8-oxoguanine, O 4 -ethylthymine, O 4 -methylthymine, O 6 -methylguanine, AP sites, and N 6 -methyladenine (17,22,26,36,38,46). Thus, NER may play a role in alkylation resistance larger than was originally thought.…”

mentioning

confidence: 99%

Contribution of Base Excision Repair, Nucleotide Excision Repair, and DNA Recombination to Alkylation Resistance of the Fission Yeast Schizosaccharomyces pombe

Memişoğlu

Samson

2000

J Bacteriol

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DNA damage is unavoidable, and organisms across the evolutionary spectrum possess DNA repair pathways that are critical for cell viability and genomic stability. To understand the role of base excision repair (BER) in protecting eukaryotic cells against alkylating agents, we generated Schizosaccharomyces pombe strains mutant for the mag1 3-methyladenine DNA glycosylase gene. We report that S. pombe mag1 mutants have only a slightly increased sensitivity to methylation damage, suggesting that Mag1-initiated BER plays a surprisingly minor role in alkylation resistance in this organism. We go on to show that other DNA repair pathways play a larger role than BER in alkylation resistance. Mutations in genes involved in nucleotide excision repair (rad13) and recombinational repair (rhp51) are much more alkylation sensitive than mag1 mutants. In addition, S. pombe mutant for the flap endonuclease rad2 gene, whose precise function in DNA repair is unclear, were also more alkylation sensitive than mag1 mutants. Further, mag1 and rad13 interact synergistically for alkylation resistance, and mag1 and rhp51 display a surprisingly complex genetic interaction. A model for the role of BER in the generation of alkylation-induced DNA strand breaks in S. pombe is discussed.DNA damage emanates from the inherent chemical instability of nucleic acids, from errors made by DNA polymerase during DNA replication, and from exposure to DNA-damaging agents present in the environment or produced by certain endogenous cellular processes (reviewed in reference 15). All organisms possess a panel of DNA repair mechanisms to repair damaged DNA. DNA excision repair pathways recognize and remove damaged segments from one DNA strand and then resynthesize new DNA, using the opposing undamaged strand as a template. Excision repair includes base excision repair (BER) and nucleotide excision repair (NER). An alternative approach to handling damaged DNA is by recombinational repair. These DNA repair pathways have been best characterized in Escherichia coli, but analogous pathways have been found in all organisms examined to date (15).BER initiation occurs by the action of DNA glycosylases that recognize specific types of damaged or abnormal DNA bases and cleave the glycosylic bond linking the base to the sugarphosphate backbone. DNA glycosylases recognize bases such as uracil, deaminated adenine (hypoxanthine), and certain alkylated and oxidized purines and pyrimidines (reviewed in references 10, 15, 21, 31, and 47). Releasing a damaged base from the DNA produces an apurinic/apyrimidinic (AP) site, and it is worth noting that AP sites are themselves a form of DNA damage. In addition to being generated by DNA glycosylases, AP sites can be formed spontaneously. AP endonucleases (which cleave 5Ј to the AP site) or AP lyases (which cleave 3Ј to the AP site) cleave the DNA backbone adjacent to the AP site. AP endonuclease produces a 5Ј-deoxyribose phosphate moiety, which must be removed to allow subsequent DNA ligation; removal occurs by the action of deoxyr...

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“…Some adducts are subject to multiple repair pathways (i.e., 8-oxo-dG is repaired by BER and, presumably, NER machinery (23,24)). Etheno adducts bearing structural similarity to M 1 dG (e.g., 1,N 2 -ethenodG, 1,N 6 -etheno-deoxyadenosine, and 3,N 4 -etheno-deoxycytidine) are substrates for BER enzymes and DNA glycosylases (25)(26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

Metabolism in Vitro and in Vivo of the DNA Base Adduct, M₁G

Knutson

Akingbade

Crews

et al. 2007

Chem. Res. Toxicol.

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Oxidative damage is considered a major contributing factor to genetic diseases including cancer. Our laboratory is evaluating endogenously formed DNA adducts as genomic biomarkers of oxidative injury. Recent efforts have focused on investigating the metabolic stability of adducts in vitro and in vivo. Here, we demonstrate that the base adduct, M 1 G, undergoes oxidative metabolism in vitro in rat liver cytosol (RLC, K m ) 105 µM and V max /K m ) 0.005 min -1 mg -1 ) and in vivo when administered intravenously to male Sprague Dawley rats. LC-MS analysis revealed two metabolites containing successive additions of 16 amu. One-and two-dimensional NMR experiments showed that oxidation occurred first at the 6-position of the pyrimido ring, forming 6-oxo-M 1 G, and then at the 2-position of the imidazole ring, yielding 2,6-dioxo-M 1 G. Authentic 6-oxo-M 1 G was chemically synthesized and observed to undergo metabolism to 2,6-dioxo-M 1 G in RLC (K m ) 210 µM and V max /K m ) 0.005 min -1 mg -1 ). Allopurinol partially inhibited M 1 G metabolism (75%) and completely inhibited 6-oxo-M 1 G metabolism in RLC. These inhibition studies suggest that xanthine oxidase is the principal enzyme acting on M 1 G in RLC and the only enzyme that converts 6-oxo-M 1 G to 2,6-dioxo-M 1 G. Both M 1 G and 6-oxo-M 1 G are better substrates (5-fold) for oxidative metabolism in RLC than the deoxynucleoside, M 1 dG. Alternative repair pathways or biological processing of M 1 dG makes the fate of M 1 G of interest as a potential marker of oxidative damage in vivo.

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In vitro repair of oxidative DNA damage by human nucleotide excision repair system: Possible explanation for neurodegeneration in Xeroderma pigmentosum patients

Cited by 338 publications

References 52 publications

Human 8-oxoguanine DNA glycosylase increases resistance to hyperoxic cytotoxicity in lung epithelial cells and involvement with altered MAPK activity

Human 8-oxoguanine DNA glycosylase increases resistance to hyperoxic cytotoxicity in lung epithelial cells and involvement with altered MAPK activity

Contribution of Base Excision Repair, Nucleotide Excision Repair, and DNA Recombination to Alkylation Resistance of the Fission Yeast Schizosaccharomyces pombe

Metabolism in Vitro and in Vivo of the DNA Base Adduct, M₁G

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In vitro repair of oxidative DNA damage by human nucleotide excision repair system: Possible explanation for neurodegeneration in Xeroderma pigmentosum patients

Cited by 338 publications

References 52 publications

Human 8-oxoguanine DNA glycosylase increases resistance to hyperoxic cytotoxicity in lung epithelial cells and involvement with altered MAPK activity

Human 8-oxoguanine DNA glycosylase increases resistance to hyperoxic cytotoxicity in lung epithelial cells and involvement with altered MAPK activity

Contribution of Base Excision Repair, Nucleotide Excision Repair, and DNA Recombination to Alkylation Resistance of the Fission Yeast Schizosaccharomyces pombe

Metabolism in Vitro and in Vivo of the DNA Base Adduct, M1G

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Metabolism in Vitro and in Vivo of the DNA Base Adduct, M₁G