Redox regulation of human OGG1 activity in response to cellular oxidative stress
Tim
Redox regulation of human OGG1 activity in response to cellular
oxidative stress.Bravard A, Vacher M, Gouget B, Coutant A, de
Boisferon FH, Marsin S, Chevillard S, Radicella JP.
Département de Radiobiologie et Radiopathologie, CEA, 18 route du
Panorama, F-92265 Fontenay aux Roses, France. jprad...@cea.fr.
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.
PMID: 16923968 [PubMed - indexed for MEDLINE]
PMCID: PMC1636869