title: Sodium selenide toxicity is mediated by O2-dependent DNA breaks.
abstract: 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.
authors.affiliation: Ecole polytechnique, Laboratoire de Biochimie, CNRS, Palaiseau, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Peyroche
authors.forename: Cosmin
authors.initials: C
authors.lastname: Saveanu
authors.forename: Marc
authors.initials: M
authors.lastname: Dauplais
authors.forename: Myriam
authors.initials: M
authors.lastname: Lazard
authors.forename: François
authors.initials: F
authors.lastname: Beuneu
authors.forename: Laurence
authors.initials: L
authors.lastname: Decourty
authors.forename: Christophe
authors.initials: C
authors.lastname: Malabat
authors.forename: Alain
authors.initials: A
authors.lastname: Jacquier
authors.forename: Sylvain
authors.initials: S
authors.lastname: Blanquet
authors.forename: Pierre
authors.initials: P
authors.lastname: Plateau
mesh_terms: D000332:Aerobiosis; D000693:Anaerobiosis; D016923:Cell Death / Q000187:drug effects; D002869:Chromosome Aberrations / Q000187:drug effects; D053904:DNA Breaks, Single-Stranded / Q000187:drug effects*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D055786:Gene Knockout Techniques; D016681:Genome, Fungal; D006238:Haploidy; D059765:Homologous Recombination / Q000187:drug effects; D006967:Hypersensitivity; D008353:Mannitol / Q000494:pharmacology; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development; D018036:Selenium Compounds / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*
chemical_list: D018036:Selenium Compounds; C037341:sodium selenide; D008353:Mannitol; D010100:Oxygen; C026372:hydrogen selenide