Nonapoptotic Role for Apaf-1 in the DNA Damage Checkpoint

Yael Zermati, Shahul Mouhamad, Lilli Stergiou, Benjamin Besse, Lorenzo Galluzzi, Simone Boehrer, Anne Laure Pauleau, Filippo Rosselli, Marcello D'Amelio, Roberto Amendola, Maria Castedo, Michael Hengartner, Jean Charles Soria, Francesco Cecconi, Guido Kroemer

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    97 Citations (Scopus)

    Résumé

    Apaf-1 is an essential factor for cytochrome c-driven caspase activation during mitochondrial apoptosis but has also an apoptosis-unrelated function. Knockdown of Apaf-1 in human cells, knockout of apaf-1 in mice, and loss-of-function mutations in the Caenorhabditis elegans apaf-1 homolog ced-4 reveal the implication of Apaf-1/CED-4 in DNA damage-induced cell-cycle arrest. Apaf-1 loss compromised the DNA damage checkpoints elicited by ionizing irradiation or chemotherapy. Apaf-1 depletion reduced the activation of the checkpoint kinase Chk1 provoked by DNA damage, and knockdown of Chk1 abrogated the Apaf-1-mediated cell-cycle arrest. Nuclear translocation of Apaf-1, induced in vitro by exogenous DNA-damaging agents, correlated in non-small cell lung cancer (NSCLC) with the endogenous activation of Chk-1, suggesting that this pathway is clinically relevant. Hence, Apaf-1 exerts two distinct, phylogenetically conserved roles in response to mitochondrial membrane permeabilization and DNA damage. These data point to a role for Apaf-1 as a bona fide tumor suppressor.

    langue originaleAnglais
    Pages (de - à)624-637
    Nombre de pages14
    journalMolecular Cell
    Volume28
    Numéro de publication4
    Les DOIs
    étatPublié - 30 nov. 2007

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