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Genotype-phenotype analysis of S326C OGG1 polymorphism: a risk factor for oxidative pathologies


Simonelli, Valeria; Camerini, Serena; Mazzei, Filomena; Van Loon, Barbara; Allione, Alessandra; D'Errico, Mariarosaria; Barone, Flavia; Minoprio, Anna; Ricceri, Fulvio; Guarrera, Simonetta; Russo, Alessia; Dalhus, Bjørn; Crescenzi, Marco; Hübscher, Ulrich; Bjørås, Magnar; Matullo, Giuseppe; Dogliotti, Eugenia (2013). Genotype-phenotype analysis of S326C OGG1 polymorphism: a risk factor for oxidative pathologies. Free Radical Biology & Medicine, 63:401-409.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Biochemistry and Molecular Biology
Dewey Decimal Classification:570 Life sciences; biology
Date:2013
Deposited On:28 Jan 2014 14:51
Last Modified:05 Apr 2016 17:25
Publisher:Elsevier
ISSN:0891-5849
Publisher DOI:https://doi.org/10.1016/j.freeradbiomed.2013.05.031
PubMed ID:23726996
Permanent URL: https://doi.org/10.5167/uzh-88950

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