Sodium selenide toxicity is mediated by O2-dependent DNA breaks.

Gerald Peyroche (1) , Cosmin Saveanu (2) , Marc Dauplais (1) , Myriam Lazard (1) , Francois Beuneu (3) , Laurence Decourty (2) , Christophe Malabat (2) , Alain Jacquier (2) , Sylvain Blanquet (1) , Pierre Plateau (1)

1 BIOC - Laboratoire de Biochimie de l'Ecole polytechnique
2 Génétique des Interactions Macromoléculaires
3 LSI - Laboratoire des Solides Irradiés - Irradiated Solids Laboratory

Hydrogen selenide is a recurrent metabolite of selenium compounds. However, few experiments studied the direct link between this toxic agent and cell death. To address this question, we first screened a systematic collection of Saccharomyces cerevisiae haploid knockout strains for sensitivity to sodium selenide, a donor for hydrogen selenide (H(2)Se/HSe(-/)Se(2-)). Among the genes whose deletion caused hypersensitivity, homologous recombination and DNA damage checkpoint genes were over-represented, suggesting that DNA double-strand breaks are a dominant cause of hydrogen selenide toxicity. Consistent with this hypothesis, treatment of S. cerevisiae cells with sodium selenide triggered G2/M checkpoint activation and induced in vivo chromosome fragmentation. In vitro, sodium selenide directly induced DNA phosphodiester-bond breaks via an O(2)-dependent reaction. The reaction was inhibited by mannitol, a hydroxyl radical quencher, but not by superoxide dismutase or catalase, strongly suggesting the involvement of hydroxyl radicals and ruling out participations of superoxide anions or hydrogen peroxide. The (*)OH signature could indeed be detected by electron spin resonance upon exposure of a solution of sodium selenide to O(2). Finally we showed that, in vivo, toxicity strictly depended on the presence of O(2). Therefore, by combining genome-wide and biochemical approaches, we demonstrated that, in yeast cells, hydrogen selenide induces toxic DNA breaks through an O(2)-dependent radical-based mechanism.

Domaines: Biochimie, Biologie Moléculaire

Gerald Peyroche, Cosmin Saveanu, Marc Dauplais, Myriam Lazard, Francois Beuneu, et al.. Sodium selenide toxicity is mediated by O2-dependent DNA breaks.. PLoS ONE, 2012, 7 (5), pp.e36343. ⟨10.1371/journal.pone.0036343⟩. ⟨hal-00764441⟩