The 1987 Walter Hubert lecture: Regulation and deficiencies in DNA repair

Lindahl, Tomas

doi:10.1038/bjc.1987.163

Cited by 30 publications

(8 citation statements)

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“…To avoid the deleterious effects of oxidative DNA damage, prokaryotes and eukaryotes have evolved the mechanism of DNA base excision repair initiated by the DNA glycosylases (15). 8-OxoG and FapyG residues are recognized and excised by the same DNA glycosylases, the bacterial formamidopyrimidine-DNA glycosylases (Fpg or MutM) and its eukaryote functional homologue, the Ogg1 proteins (5, 10, 11, 16 -19).…”

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confidence: 99%

Structural Basis for the Recognition of the FapydG Lesion (2,6-Diamino-4-hydroxy-5-formamidopyrimidine) by Formamidopyrimidine-DNA Glycosylase

Coste

Ober²,

Carell³

et al. 2004

Journal of Biological Chemistry

103

139

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Formamidopyrimidine-DNA glycosylase (Fpg) is a DNA repair enzyme that excises oxidized purines such as 7,8-dihydro-8-oxoguanine (8-oxoG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) from damaged DNA. Here, we report the crystal structure of the Fpg protein from Lactococcus lactis (LlFpg) bound to a carbocyclic FapydG (cFapydG)-containing DNA. The structure reveals that Fpg stabilizes the cFapydG nucleoside into an extrahelical conformation inside its substrate binding pocket. In contrast to the recognition of the 8-oxodG lesion, which is bound with the glycosidic bond in a syn conformation, the cFapydG lesion displays in the complex an anti conformation. Furthermore, Fpg establishes interactions with all the functional groups of the FapyG base lesion, which can be classified in two categories: (i) those specifying a purine-derived lesion (here a guanine) involved in the Watson-Crick face recognition of the lesion and probably contributing to an optimal orientation of the pyrimidine ring moiety in the binding pocket and (ii) those specifying the imidazole ring-opened moiety of FapyG and probably participating also in the rotameric selection of the FapydG nucleobase. These interactions involve strictly conserved Fpg residues and structural water molecules mediated interactions. The significant differences between the Fpg recognition modes of 8-oxodG and FapydG provide new insights into the Fpg substrate specificity.Reactive oxygen species generated in the cell during physiological processes or resulting from the cell exposure to exogenous chemical and physical agents can react with DNA to produce base lesions. The resulting DNA damages can interfere with both efficiency and fidelity of the DNA replication and transcription, thus participating in mutagenesis, carcinogenesis, and aging (1). Oxidation of guanine in DNA generates a plethora of oxidative bases lesions of which 7,8-dihydro-8-oxoguanine (8-oxoG) 1 and imidazole ring-opened purines (FapyG) are among the most abundant lesions (see Fig. 1) (2-4). FapyG lesions are also generated in DNA as by-products of N7-alkylated purines (5-9) (Fig. 1). 8-OxoG is a mutagenic DNA lesion because of alternative base-pairing possibility with dA, yielding G 3 T transversions in bacterial, yeast, and mammalian cells (10 -13). The FapyG lesion is potentially lethal and mutagenic (14).To avoid the deleterious effects of oxidative DNA damage, prokaryotes and eukaryotes have evolved the mechanism of DNA base excision repair initiated by the DNA glycosylases (15). 8-OxoG and FapyG residues are recognized and excised by the same DNA glycosylases, the bacterial formamidopyrimidine-DNA glycosylases (Fpg or MutM) and its eukaryote functional homologue, the Ogg1 proteins (5, 10, 11, 16 -19). Interestingly, the N7-Me-FapyG lesion is also efficiently repaired by DNA glycosylases that exhibit low and even undetectable capacity to release 8-oxoG such as the yeast Ntg1 and Ntg2 proteins (20). Fpg and Ogg1 proteins belong to the DNA glycosylases/abasic (AP) lyase family because the...

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mentioning

confidence: 99%

Structural Basis for the Recognition of the FapydG Lesion (2,6-Diamino-4-hydroxy-5-formamidopyrimidine) by Formamidopyrimidine-DNA Glycosylase

Coste

Ober²,

Carell³

et al. 2004

Journal of Biological Chemistry

103

139

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“…They had repair abilities which were 20% of controls at 2 h and 50% at 8 h (No. 4), and 40% at 2 h and 90% at 8 h (No. 8).…”

Section: Discussionmentioning

confidence: 99%

“…A number of hu man genetic disorders with cellular defects in DNA repair arc known [1][2][3][4], DNA repair became of great importance when it was established that cancer pa tients and also high-risk family members have defi ciencies in their repair systems [5][6][7][8], These investiga tions are generally based on a comparison of the statistical differences in repair ability between two populations (e.g. controls and cancer or cancerprone).…”

Section: Introductionmentioning

confidence: 99%

Differences in the Kinetics of DNA Repair in Cancer Patients and Healthy Controls

Kovács

Langemann²

1991

Oncology

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The time course of DNA repair, using (³H)thymidine uptake as parameter, was measured during 8h after a single exposure to 2, 8, and 16 UV-C J/m² in lymphocytes of 8 cancer patients, 1 xeroderma pigmentosum patient and 10 controls. All patients had reduced repair, and all controls normal repair, as calculated 2 h after a single exposure. Six patients reached normal levels with a delay of 2–6 h, whereas 2 patients and the xeroderma pigmentosum patient did not. Although the kinetic curves in controls and patients had a similar form, those for 8 and 16 J/m² in patients were shifted so that they corresponded to that of 2 J/m² in controls. Additionally the ability to repair repeated damage (cells irradiated twice or three times at 2-hour intervals with doses of 2 or 8 J/m²) was investigated in 6 patients and in 7 controls. The incorporation values showed significant differences between patients and controls at each dose and time point. Cancer patients tend to repair repeated damage less efficiently than controls. Using these parameters subtle differences between the repair ability of individuals might be identified. Because of the known connection between reduced DNA repair and carcinogenesis, this might help to distinguish cancer-prone individuals.

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“…DNA glycosylases, endonucleases, and exonucleases have been reported to preferentially cleave oxidatively modified bases from damaged DNA. Following this, DNA polymerase replaces the excised bases and DNA ligases seal new 3' and 5' ends (Teebor et al, 1988;Lindahl, 1987). Modified bases such as thymine glycol and 8-hydroxy guanosine can be measured in urine and have been used to monitor oxidative damage to DNA in vivo.…”

Section: Oxidative Modification Of Proteinsmentioning

confidence: 99%

Toxicity of oxygen from naturally occurring redox‐active pro‐oxidants

Pardini

1995

Arch Insect Biochem Physiol

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The survival of all aerobic life forms requires the ground-state of molecular oxygen, O2. However, the activation of O2 to reactive oxygen species (ROS) is responsible for universal toxicity. ROS are responsible in deleterious intracellular reactions associated with oxidative stress including membrane lipid peroxidation, and the oxidation of proteins and DNA. Redox-active allelochemicals such as quinones and phenolic compounds are involved in activating O2 to its deleterious forms including superoxide anion free radical, O2.-, hydrogen peroxide, H2O2, and hydroxyl radical, OH. Molecular oxygen is also activated in biologically relevant photosensitizing reactions to the singlet form, 1O2. The insect lifestyle exposes them to a broad diversity of pro-oxidant allelochemicals and, like mammalian species, they have developed an elaborate antioxidant system comprised of chemical antioxidants and a bank of anti-oxidant enzymes. We have found that an insect's antioxidant adaptation to a particular food correlates well with its risk of exposure to potential pro-oxidants.

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The 1987 Walter Hubert lecture: Regulation and deficiencies in DNA repair

Cited by 30 publications

References 60 publications

Structural Basis for the Recognition of the FapydG Lesion (2,6-Diamino-4-hydroxy-5-formamidopyrimidine) by Formamidopyrimidine-DNA Glycosylase

Structural Basis for the Recognition of the FapydG Lesion (2,6-Diamino-4-hydroxy-5-formamidopyrimidine) by Formamidopyrimidine-DNA Glycosylase

Differences in the Kinetics of DNA Repair in Cancer Patients and Healthy Controls

Toxicity of oxygen from naturally occurring redox‐active pro‐oxidants

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