Cloning of a yeast 8-oxoguanine DNA glycosylase reveals the existence of a base-excision DNA-repair protein superfamily

Nash, Huw M.; Bruner, Steven D.; Schärer, Orlando D.; Kawate, Tomohiko; Addona, Theresa A.; Spooner, Eric; Lane, William S.; Verdine, Gregory L.

doi:10.1016/s0960-9822(02)00641-3

Cited by 444 publications

(427 citation statements)

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“…In both enzymes a catalytically essential Asp residue protrudes into the cleft, and this Asp is invariant among the HhH\GPD-containing glycosylases (Figure 8). These observations, as well as other results, suggest a related mechanism for substrate recognition for monofunctional glycosylases and glycosylases\β-lyases, although the catalytic mechanisms are somewhat different [158,161] (Figure 9). For both glycosylases the target base is apparently flipped out of the dsDNA helix and accommodated in a substrate-binding pocket, which in AlkA is rich in hydrophobic residues and thus ideally suited to interact with a wide range of electron-deficient bases via Π-donor-acceptor interactions.…”

Section: The Conserved Hhh Motif and A Unified Catalytic Mechanism Fosupporting

confidence: 77%

“…The HhH motif has also been identified in several other DNA glycosylases [91,161,162] (Figure 8) and other DNA-binding proteins [163]. In both AlkA and EndoIII this HhH\GPD motif is located in the interdomain cleft, which is lined in AlkA with hydrophobic residues and in EndoIII with polar residues.…”

Section: The Conserved Hhh Motif and A Unified Catalytic Mechanism Fomentioning

confidence: 82%

“…Recent studies have provided compelling evidence that the HhH motif, together with a Pro\Gly-rich stretch and a conserved Asp residue C-terminal to it (GPD motif) [161], comprise the active site both in AlkA [158] and the bifunctional EndoIII [162]. The HhH motif has also been identified in several other DNA glycosylases [91,161,162] (Figure 8) and other DNA-binding proteins [163].…”

Section: The Conserved Hhh Motif and A Unified Catalytic Mechanism Fomentioning

confidence: 99%

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DNA glycosylases in the base excision repair of DNA

Krokan

Standal

Slupphaug

1997

Biochemical Journal

763

566

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A wide range of cytotoxic and mutagenic DNA bases are removed by different DNA glycosylases, which initiate the base excision repair pathway. DNA glycosylases cleave the Nglycosylic bond between the target base and deoxyribose, thus releasing a free base and leaving an apurinic\apyrimidinic (AP) site. In addition, several DNA glycosylases are bifunctional, since they also display a lyase activity that cleaves the phosphodiester backbone 3h to the AP site generated by the glycosylase activity. Structural data and sequence comparisons have identified common features among many of the DNA glycosylases. Their active sites have a structure that can only bind extrahelical target bases, as observed in the crystal structure of human uracil-DNA glycosylase in a complex with double-stranded DNA. Nucleotide flipping is apparently actively facilitated by the enzyme. With bacteriophage T4 endonuclease V, a pyrimidine-

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Section: The Conserved Hhh Motif and A Unified Catalytic Mechanism Fosupporting

confidence: 77%

Section: The Conserved Hhh Motif and A Unified Catalytic Mechanism Fomentioning

confidence: 82%

Section: The Conserved Hhh Motif and A Unified Catalytic Mechanism Fomentioning

confidence: 99%

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DNA glycosylases in the base excision repair of DNA

Krokan

Standal

Slupphaug

1997

Biochemical Journal

763

566

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“…To prevent the mutagenic e ect of oh 8 Gua, three DNA repair enzymes (MutM, MutY and MutT proteins) exist in Escherichia coli (E. coli) (Tchou et al, 1991;Boiteux et al, 1992;Au et al, 1989;Michaels et al, 1991Maki and Sekiguchi, 1992). Recently, the OGG1 gene of Saccharomyces cerevisiae (yOGG1) was cloned as being a functional yeast homologue of the bacterial mutM gene (van der Nash et al, 1996). Subsequently, a human homologue of the yeast OGG1 gene, hOGG1, was isolated based on the homology search of expressed sequence tags (Aburatani et al, 1997;Arai et al, 1997;Lu et al, 1997;Radicella et al, 1997;Roldan-Arjona et al, 1997;Rosenquist et al, 1997).…”

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confidence: 99%

Genetic polymorphisms and alternative splicing of the hOGG1 gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA

Kohno¹,

Shinmura

Tosaka³

et al. 1998

Oncogene

387

309

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The hOGG1 gene encodes a DNA glycosylase that excises 8-hydroxyguanine (oh 8 Gua) from damaged DNA. Structural analyses of the hOGG1 gene and its transcripts were performed in normal and lung cancer cells. Due to a genetic polymorphism at codon 326, hOGG1-Ser 326 and hOGG1-Cys 326 proteins were produced in human cells. Activity in the repair of oh 8 Gua was greater in hOGG1-Ser 326 protein than in hOGG1-Cys 326 protein in the complementation assay of an E. coli mutant defective in the repair of oh 8 Gua. Two isoforms of hOGG1 transcripts produced by alternative splicing encoded distinct hOGG1 proteins: one with and the other without a putative nuclear localization signal. Loss of heterozygosity at the hOGG1 locus was frequently (15/ 23, 62.2%) detected in lung cancer cells, and a cell line NCI-H526 had a mutation leading to the formation of the transcripts encoding a truncated hOGG1 protein. However, the oh 8 Gua levels in nuclear DNA were similar among lung cancer cells and leukocytes irrespective of the type of hOGG1 proteins expressed. These results suggest that the oh 8 Gua levels are maintained at a steady level, even though multiple hOGG1 proteins are produced due to genetic polymorphisms, mutations and alternative splicing of the hOGG1 gene.

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“…In Saccharomyces cerevisiae the OGG1 gene was cloned as the functional eukaryotic homologue of the bacterial fpg gene (Au ret van der Kemp et al, 1996). The yeast Ogg1 protein is a DNA glycosylase/AP lyase which excises 8-OxoG, formamidopyrimidines and incizes apurinic/apyrimidinic (AP) sites in damaged DNA (Au ret van der Kemp et al, 1996;Nash et al, 1996;Girard et al, 1997;Karahalil et al, 1998). Furthermore, inactivation of the OGG1 gene in yeast creates a mutator phenotype that is also speci®c for the generation of the GC to TA transversions (Thomas et al, 1997).…”

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confidence: 99%

Mutations in OGG1, a gene involved in the repair of oxidative DNA damage, are found in human lung and kidney tumours

et al. 1998

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The human OGG1 gene encodes a DNA glycosylase activity catalysing the excision of the mutagenic lesion 7,8-dihydro-8-oxoguanine from oxidatively damaged DNA. The OGG1 gene was localized to chromosome 3p25, a region showing frequent loss of heterozygosity (LOH) in lung and kidney tumours. In this study, we have analysed by RT ± PCR the expression of OGG1 in 25 small cell lung cancers, in 15 kidney carcinomas and the 15 normal kidney counterparts. The results show that OGG1 messenger RNA can be detected in all tumours tested and that no signi®cant di erence was observed in the level of expression between normal and tumoral kidney tissues. Denaturing gradient gel electrophoresis (DGGE) was used to screen this series of human tumours for alterations in the OGG1 cDNA. The study revealed homozygous mutations in three tumours, two from lung and one from kidney. Sequencing analysis of the mutants identi®ed a single base substitution in each of the three cases: two tranversions (GC to TA and TA to AT) and one transition (GC to AT). All three substitutions cause an amino acid change in the hOgg1 protein. For the mutant kidney tumour, the normal tissue counterpart shows a wild-type pro®le. These results suggest a role for OGG1 mutations in the course of the multistage process of carcinogenesis in lung or kidney.Keywords: oxidative DNA damage; DNA repair; missense mutations of OGG1 gene; human lung and kidney cancer; tumour suppressor gene Damage to DNA by oxygen-free radicals is postulated to cause mutations that are associated with the initiation or the progression of human cancers (Breimer, 1990;Loeb, 1997;Beckman and Ames, 1997). Oxidative damage-induced mutations can activate oncogenes or inactivate tumour suppressor genes altering the cell growth control (Fearon, 1997). An oxidatively damaged guanine, 7,, is abundantly produced in DNA as a consequence of the cellular oxidative metabolism or the exposure to ionizing radiation or chemical carcinogens (Dizdaroglu, 1991;Cadet et al., 1997). The presence of 8-OxoG in DNA has been shown to be mutagenic since, while this lesion does not impede DNA chain elongation, it preferentially pairs with adenine during in vitro DNA synthesis (Shibutani et al., 1991). The biological incidence of the presence of 8-OxoG in DNA has been unveiled by the study of two genes in E. coli, fpg (mutM) and mutY (micA) which code for DNA glycosylases that cooperate to prevent the mutagenic e ects of 8-OxoG in DNA (Boiteux et al., 1987;Cabrera et al., 1988;Radicella et al., 1988;Nghiem et al., 1988;Au et al., 1989). Inactivation of either gene leads to a spontaneous mutator phenotype characterized by the exclusive increase in GC to TA transversions (Michaels and Miller, 1992;Grollman and Moriya, 1993;Boiteux and Laval, 1997). In Saccharomyces cerevisiae the OGG1 gene was cloned as the functional eukaryotic homologue of the bacterial fpg gene (Au ret van der Kemp et al., 1996). The yeast Ogg1 protein is a DNA glycosylase/AP lyase which excises 8-OxoG, formamidopyrimidines and incizes apurinic/apyrimid...

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Cloning of a yeast 8-oxoguanine DNA glycosylase reveals the existence of a base-excision DNA-repair protein superfamily

Cited by 444 publications

References 49 publications

DNA glycosylases in the base excision repair of DNA

DNA glycosylases in the base excision repair of DNA

Genetic polymorphisms and alternative splicing of the hOGG1 gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA

Mutations in OGG1, a gene involved in the repair of oxidative DNA damage, are found in human lung and kidney tumours

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