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A threshold of endogenous stress is required to engage cellular response to protect against mutagenesis.
Saintigny, Yannick; Chevalier, François; Bravard, Anne; Dardillac, Elodie; Laurent, David; Hem, Sonia; Dépagne, Jordane; Radicella, J Pablo; Lopez, Bernard S.
Afiliación
  • Saintigny Y; Institute of Cellular and Molecular Radiobiology -Commissariat à l'Energie Atomique et aux Energies Alternatives, Fontenay aux Roses, F-92265, France.
  • Chevalier F; Institute of Cellular and Molecular Radiobiology -Commissariat à l'Energie Atomique et aux Energies Alternatives, Fontenay aux Roses, F-92265, France.
  • Bravard A; Institute of Cellular and Molecular Radiobiology -Commissariat à l'Energie Atomique et aux Energies Alternatives, Fontenay aux Roses, F-92265, France.
  • Dardillac E; UMR967 INSERM/CEA/Universités Paris Diderot et Paris Saclay, Fontenay aux Roses, F-92265, France.
  • Laurent D; Institute of Cellular and Molecular Radiobiology -Commissariat à l'Energie Atomique et aux Energies Alternatives, Fontenay aux Roses, F-92265, France.
  • Hem S; UMR 8200 CNRS, Institut de cancérologie Gustave Roussy, Université Paris-Saclay, équipe labélisée par la Ligue bationale contre le Cancer "LIGUE 2014", Villejuif, F-94805, France.
  • Dépagne J; Institute of Cellular and Molecular Radiobiology -Commissariat à l'Energie Atomique et aux Energies Alternatives, Fontenay aux Roses, F-92265, France.
  • Radicella JP; Plateforme de spectrométrie de masse protéomique - MSPP, Biochimie et physiologie moléculaire des plantes, CNRS, INRA, Montpellier Supagro, Univ. Montpellier, 34060 Montpellier, France.
  • Lopez BS; Institute of Cellular and Molecular Radiobiology -Commissariat à l'Energie Atomique et aux Energies Alternatives, Fontenay aux Roses, F-92265, France.
Sci Rep ; 6: 29412, 2016 07 11.
Article en En | MEDLINE | ID: mdl-27406380
ABSTRACT
Endogenous stress represents a major source of genome instability, but is in essence difficult to apprehend. Incorporation of labeled radionuclides into DNA constitutes a tractable model to analyze cellular responses to endogenous attacks. Here we show that incorporation of [(3)H]thymidine into CHO cells generates oxidative-induced mutagenesis, but, with a peak at low doses. Proteomic analysis showed that the cellular response differs between low and high levels of endogenous stress. In particular, these results confirmed the involvement of proteins implicated in redox homeostasis and DNA damage signaling pathways. Induced-mutagenesis was abolished by the anti-oxidant N-acetyl cysteine and plateaued, at high doses, upon exposure to L-buthionine sulfoximine, which represses cellular detoxification. The [(3)H]thymidine-induced mutation spectrum revealed mostly base substitutions, exhibiting a signature specific for low doses (GC > CG and AT > CG). Consistently, the enzymatic activity of the base excision repair protein APE-1 is induced at only medium or high doses. Collectively, the data reveal that a threshold of endogenous stress must be reached to trigger cellular detoxification and DNA repair programs; below this threshold, the consequences of endogenous stress escape cellular surveillance, leading to high levels of mutagenesis. Therefore, low doses of endogenous local stress can jeopardize genome integrity more efficiently than higher doses.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Daño del ADN / Mutagénesis / Estrés Oxidativo / Inestabilidad Genómica Límite: Animals Idioma: En Revista: Sci Rep Año: 2016 Tipo del documento: Article País de afiliación: Francia

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Daño del ADN / Mutagénesis / Estrés Oxidativo / Inestabilidad Genómica Límite: Animals Idioma: En Revista: Sci Rep Año: 2016 Tipo del documento: Article País de afiliación: Francia