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

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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. © 2007 Elsevier Inc. All rights reserved.
Original languageEnglish
Pages (from-to)624 - 637
Number of pages14
JournalMolecular Cell
Volume28
Issue number4
DOIs
Publication statusPublished - 30 Nov 2007
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Molecular Biology

Cite this

Zermati, Y., Mouhamad, S., Stergiou, L., Besse, B., Galluzzi, L., Boehrer, S., ... 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