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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)624-637
Number of pages14
JournalMolecular Cell
Volume28
Issue number4
DOIs
Publication statusPublished - Nov 30 2007

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Molecular Biology

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    Zermati, Y., Mouhamad, S., Stergiou, L., Besse, B., Galluzzi, L., Boehrer, S., Pauleau, A. L., Rosselli, F., D'Amelio, M., Amendola, R., Castedo, M., Hengartner, M., Soria, J. C., Cecconi, F., & Kroemer, G. (2007). Nonapoptotic Role for Apaf-1 in the DNA Damage Checkpoint. Molecular Cell, 28(4), 624-637. https://doi.org/10.1016/j.molcel.2007.09.030