title: Redox regulation of human OGG1 activity in response to cellular oxidative stress.
abstract: 8-Oxoguanine (8-oxoG), a common and mutagenic form of oxidized guanine in DNA, is eliminated mainly through base excision repair. In human cells its repair is initiated by human OGG1 (hOGG1), an 8-oxoG DNA glycosylase. We investigated the effects of an acute cadmium exposure of human lymphoblastoid cells on the activity of hOGG1. We show that coinciding with alteration of the redox cellular status, the 8-oxoG DNA glycosylase activity of hOGG1 was nearly completely inhibited. However, the hOGG1 activity returned to normal levels once the redox cellular status was normalized. In vitro, the activity of purified hOGG1 was abolished by cadmium and could not be recovered by EDTA. In cells, however, the reversible inactivation of OGG1 activity by cadmium was strictly associated with reversible oxidation of the protein. Moreover, the 8-oxoG DNA glycosylase activity of purified OGG1 and that from crude extracts were modulated by cysteine-modifying agents. Oxidation of OGG1 by the thiol oxidant diamide led to inhibition of the activity and a protein migration pattern similar to that seen in cadmium-treated cells. These results suggest that cadmium inhibits hOGG1 activity mainly by indirect oxidation of critical cysteine residues and that excretion of the metal from the cells leads to normalization of the redox cell status and restoration of an active hOGG1. The results presented here unveil a novel redox-dependent mechanism for the regulation of OGG1 activity.
authors.affiliation: Département de Radiobiologie et Radiopathologie, CEA, 18 route du Panorama, F-92265 Fontenay aux Roses, France. jpradicella@cea.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Bravard
authors.forename: Monique
authors.initials: M
authors.lastname: Vacher
authors.forename: Barbara
authors.initials: B
authors.lastname: Gouget
authors.forename: Alexandre
authors.initials: A
authors.lastname: Coutant
authors.forename: Florence Hillairet
authors.initials: FH
authors.lastname: de Boisferon
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Marsin
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chevillard
authors.forename: J Pablo
authors.initials: JP
authors.lastname: Radicella
mesh_terms: D002104:Cadmium / Q000494:pharmacology; D002478:Cells, Cultured; D003545:Cysteine / Q000378:metabolism; D045647:DNA Glycosylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress
chemical_list: D004791:Enzyme Inhibitors; D002104:Cadmium; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D003545:Cysteine