Date Published: May 7, 2012
Publisher: Public Library of Science
Author(s): Gérald Peyroche, Cosmin Saveanu, Marc Dauplais, Myriam Lazard, François Beuneu, Laurence Decourty, Christophe Malabat, Alain Jacquier, Sylvain Blanquet, Pierre Plateau, Arun Rishi. http://doi.org/10.1371/journal.pone.0036343
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 (H2Se/HSe−/Se2−). Among the genes whose deletion caused hypresensitivity, 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 O2-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 O2. Finally we showed that, in vivo, toxicity strictly depended on the presence of O2. Therefore, by combining genome-wide and biochemical approaches, we demonstrated that, in yeast cells, hydrogen selenide induces toxic DNA breaks through an O2-dependent radical-based mechanism.
Selenium is mainly known as an essential micronutrient of many living species, including humans . At high doses, selenium is poisonous . In the recent years, selenium deserved considerable interest because of its possible protective effect against cancer at subtoxic doses . Beyond its role in chemoprevention, subtoxic administration of selenium appears to also have a promising potential in cancer therapy , , , . In all these medical applications, the gap between toxic and prophylactic or therapeutic doses is narrow. Although recent studies in a variety of model systems have increased our understanding of the anticarcinogenic mechanisms of selenium compounds, efforts still have to be made to complete our basic view of the underlying roles of selenium metabolites , .