Nonapoptotic role for Apaf-1 in the DNA damage checkpoint

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

来源：Molecular Cell, 2007, 28(4): 624-637.

DOI：10.1016/j.molcel.2007.09.030

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.

• 出版日期2007-11-30