title: Genotype-phenotype analysis of S326C OGG1 polymorphism: a risk factor for oxidative pathologies.
abstract: 8-Oxoguanine DNA glycosylase (OGG) activity was measured by an in vitro assay in lymphocytes of healthy volunteers genotyped for various OGG1 polymorphisms. Only homozygous carriers of the polymorphic C326 allele showed a significantly lower OGG activity compared to the homozygous S326 genotype. The purified S326C OGG1 showed a decreased ability to complete the repair synthesis step in a base excision repair reaction reconstituted in vitro. The propensity of this variant to dimerize as well as its catalytic impairment were shown to be enhanced under oxidizing conditions. Mass spectrometry revealed that the extra cysteine of the variant protein is involved in disulfide bonds compatible with significant conformational changes and/or dimerization. We propose that the S326C OGG1 catalytic impairment and its susceptibility to dimerization and disulfide bond formation in an oxidizing environment all concur to decrease repair capacity. Consequently, the C326 homozygous carriers may be at increased risk of oxidative pathologies.
authors.affiliation: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Simonelli
authors.forename: Serena
authors.initials: S
authors.lastname: Camerini
authors.forename: Filomena
authors.initials: F
authors.lastname: Mazzei
authors.forename: Barbara
authors.initials: B
authors.lastname: Van Loon
authors.forename: Alessandra
authors.initials: A
authors.lastname: Allione
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: D'Errico
authors.forename: Flavia
authors.initials: F
authors.lastname: Barone
authors.forename: Anna
authors.initials: A
authors.lastname: Minoprio
authors.forename: Fulvio
authors.initials: F
authors.lastname: Ricceri
authors.forename: Simonetta
authors.initials: S
authors.lastname: Guarrera
authors.forename: Alessia
authors.initials: A
authors.lastname: Russo
authors.forename: Bjørn
authors.initials: B
authors.lastname: Dalhus
authors.forename: Marco
authors.initials: M
authors.lastname: Crescenzi
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hübscher
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matullo
authors.forename: Eugenia
authors.initials: E
authors.lastname: Dogliotti
mesh_terms: D000328:Adult; D000483:Alleles; D004249:DNA Damage / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006720:Homozygote; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human
keywords: DNA repair; Disulfide bond profile; Free radicals; Genotype–phenotype analysis; Single-nucleotide polymorphisms