Inactivation of mammalian 8-oxoguanine-DNA glycosylase by cadmium(II): implications for cadmium genotoxicity

Abstract

Cadmium(II) is a toxic, mutagenic and carcinogenic metal (IARC Class 1 human carcinogen). It causes damage to eukaryotic cells both in acute and chronic modes of exposure via multiple biochemical mechanisms. In particular, Cd diminishes the capacity of cells to repair oxidative DNA damage. Oxidative DNA lesions are important precursors to mutations and ultimately may lead to neoplastic transformation of human cells. We investigated interactions of Cd with murine Ogg1 (mOgg1), an enzyme that removes 8-oxoguanine (8-oxoG), an abundant oxidative lesion, from DNA. Cd 2+ and Zn 2+, but not other divalent cations tested, suppressed mOgg1-catalyzed reactions. The apparent inhibition by Cd consisted of at least two independent processes: irreversible, DNA-independent first-order inactivation of mOgg1 and DNA-dependent inhibition. Irreversibly inactivated mOgg1 has nearly normal affinity for damaged DNA and a normal catalytic rate constant but is defective in formation of the covalent reaction intermediate. When both modes of inhibition are in effect, the catalytic rate constant is dramatically lowered, while affinity to damaged DNA is decreased moderately. Potential sites for Cd binding in mOgg1 and mOgg1-DNA complex are identified. Inactivation of Ogg1 may play a role in the mutagenic and carcinogenic action of Cd.