RRC ID 4194
Author Zermati Y, Mouhamad S, Stergiou L, Besse B, Galluzzi L, Boehrer S, Pauleau AL, Rosselli F, D'Amelio M, Amendola R, Castedo M, Hengartner M, Soria JC, Cecconi F, Kroemer G.
Title Nonapoptotic role for Apaf-1 in the DNA damage checkpoint.
Journal Mol. Cell
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.
Volume 28(4)
Pages 624-37
Published 2007-11-30
DOI 10.1016/j.molcel.2007.09.030
PII S1097-2765(07)00743-5
PMID 18042457
MeSH Animals Apoptosis* / drug effects Apoptotic Protease-Activating Factor 1 / deficiency Apoptotic Protease-Activating Factor 1 / metabolism* Caenorhabditis elegans / cytology Caenorhabditis elegans / drug effects Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / metabolism Calcium-Binding Proteins / metabolism Carcinoma, Non-Small-Cell Lung / enzymology Cell Cycle / drug effects Cell Line, Tumor Cell Nucleus / metabolism Checkpoint Kinase 1 Cisplatin / pharmacology Conserved Sequence DNA Damage* Embryo, Mammalian / cytology Embryo, Mammalian / drug effects Embryo, Mammalian / metabolism Humans Lung Neoplasms / enzymology Mice Phosphorylation / drug effects Phylogeny Protein Kinases / metabolism Protein Transport / drug effects
IF 14.248
Times Cited 76
C.elegans tm853