Chemistry of Glycosylases and Endonucleases Involved in Base-Excision Repair

David, Sheila S.; Williams, S. D.

doi:10.1021/cr980321h

Cited by 492 publications

(614 citation statements)

References 287 publications

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“…This spectrum corresponds well not to the guanine radical but to a [4Fe-4S] 3+/2+ difference spectrum, which also has an absorption maximum near 405 nm [37,69]. As observed in the EPR experiments, these transient absorption data then also support formation first of a guanine radical upon oxidative flash quench of [Ru(phen) 2 We further examined a more defined system where the photooxidant Ru(dppz)(phen)(bpy ′) 2+ , (bpy′ = 4-butyric acid-4′-methyl bipyridine) is covalently linked to DNA at the 5′ end. Upon annealing to a complementary strand, the ruthenium complex specifically intercalates 3-4 bases from the 5′-end of the DNA duplex [70]; MutY is capable of binding non-specifically to this designed duplex.…”

Section: Redox Activation Of Muty By Guanine Radicalsupporting

confidence: 71%

“…In base excision repair (BER), glycosylase enzymes are responsible for searching the genome for chemically modified bases and catalyzing their excision [2]. These enzymes must first locate their substrate in a vast excess of undamaged DNA, flip the substrate into the active site of the protein, and catalyze scission of the N-glycosidic bond between the errant base and the sugar-phosphate backbone.…”

Section: Introductionmentioning

confidence: 99%

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DNA repair glycosylases with a [4Fe–4S] cluster: A redox cofactor for DNA-mediated charge transport?

Boal

Yavin

Barton

2007

Journal of Inorganic Biochemistry

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The [4Fe-4S] cluster is ubiquitous to a class of base excision repair enzymes, in organisms ranging from bacteria to man, and was first considered as a structural element, owing to its redox stability under physiological conditions. When studied bound to DNA, two of these repair proteins (MutY and Endonuclease III from Escherichia coli) display DNA-dependent reversible electron transfer with characteristics typical of high potential iron proteins. These results have inspired a reexamination of the role of the [4Fe-4S] cluster in this class of enzymes. Might the [4Fe-4S] cluster be used as a redox cofactor to search for damaged sites using DNA-mediated charge transport, a process well known to be highly sensitive to lesions and mismatched bases? Described here are experiments demonstrating the utility of DNA-mediated charge transport in characterizing these DNA-binding metalloproteins, as well as efforts to elucidate this new function for DNA as an electronic signaling medium among the proteins.

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Section: Redox Activation Of Muty By Guanine Radicalsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

DNA repair glycosylases with a [4Fe–4S] cluster: A redox cofactor for DNA-mediated charge transport?

Boal

Yavin

Barton

2007

Journal of Inorganic Biochemistry

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“…[Fapy]-DNA glycosylase removes ring-opened imidazole derivatives of purines such as 7-methyl-fapy-guanine, FAPY-guanine, FAPY-adenine, and 7,8-dihydro-8 oxoguanine (42). In an alkaline buffer, strand breaks will be generated due to helimination of abasic DNA lesions, making it detectable by the SCGE assay.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Induces Direct Radical-Associated DNA Damage

Attene‐Ramos

Wagner

Gaskins

et al. 2007

Molecular Cancer Research

239

172

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Hydrogen sulfide (H 2 S) is produced by indigenous sulfate-reducing bacteria in the large intestine and represents an environmental insult to the colonic epithelium. Clinical studies have linked the presence of either sulfate-reducing bacteria or H 2 S in the colon with chronic disorders such as ulcerative colitis and colorectal cancer, although at this point, the evidence is circumstantial and underlying mechanisms remain undefined. We showed previously that sulfide at concentrations similar to those found in the human colon induced genomic DNA damage in mammalian cells. The present study addressed the nature of the DNA damage by determining if sulfide is directly genotoxic or if genotoxicity requires cellular metabolism. We also questioned if sulfide genotoxicity is mediated by free radicals and if DNA base oxidation is involved. Naked nuclei from untreated Chinese hamster ovary cells were treated with sulfide; DNA damage was induced by concentrations as low as 1 Mmol/L. This damage was effectively quenched by cotreatment with butylhydroxyanisole. Furthermore, sulfide treatment increased the number of oxidized bases recognized by formamidopyrimidine [fapy]-DNA glycosylase. These results confirm the genotoxicity of sulfide and strongly implicate that this genotoxicity is mediated by free radicals. These observations highlight the possible role of sulfide as an environmental insult that, given a predisposing genetic background, may lead to genomic instability or the cumulative mutations characteristic of colorectal cancer. (Mol Cancer Res 2007;5(5):455 -9)

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“…NaBH 4 reduces and stabilizes the AP-site so that no βelimination product forms (43). NaBH 4 does not interfere with the glycosylase because UNG has no lyase activity (7,30,31). Furthermore, the β-elimination product of an AP-site inhibits enzymatic activity (43).…”

Section: Preparation Of Substratementioning

confidence: 99%

Role of active site tyrosines in dynamic aspects of DNA binding by AP endonuclease☆

et al. 2007

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AP endonuclease (AP endo), a key enzyme in repair of abasic sites in DNA, makes a single nick 5′ to the phosphodeoxyribose of an abasic site (AP-site). We recently proposed a novel mechanism, whereby the enzyme uses a key tyrosine (Tyr 171 ) to directly attack the scissile phosphate of the APsite. We showed that loss of the tyrosyl hydroxyl from Tyr 171 resulted in dramatic diminution in enzymatic efficiency. Here we extend the previous work to compare binding/recognition of AP endo to oligomeric DNA with and without an AP-site by wild type enzyme and several tyrosine mutants including Tyr 128 , Tyr 171 and Tyr 269 . We used single turnover and electrophoretic mobility shift assays. As expected, binding to DNA with an AP-site is more efficient than binding to DNA without one. Unlike catalytic cleavage by AP endo, which requires both hydroxyl and aromatic moieties of Tyr 171 , the ability to bind DNA efficiently without an AP-site is independent of an aromatic moiety at position 171. However, the ability to discriminate efficiently between DNA with and without an AP-site requires tyrosine at position 171. Thus, AP endo requires a tyrosine at the active site for the properties that enable it to behave as an efficient, processive endonuclease.

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Chemistry of Glycosylases and Endonucleases Involved in Base-Excision Repair

Cited by 492 publications

References 287 publications

DNA repair glycosylases with a [4Fe–4S] cluster: A redox cofactor for DNA-mediated charge transport?

DNA repair glycosylases with a [4Fe–4S] cluster: A redox cofactor for DNA-mediated charge transport?

Hydrogen Sulfide Induces Direct Radical-Associated DNA Damage

Role of active site tyrosines in dynamic aspects of DNA binding by AP endonuclease☆

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