Nonapoptotic role for Apaf-1 in the DNA damage checkpoint.
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.
INSERM, U848, 94805 Villejuif, France.
Yael
Y
Zermati
Shahul
S
Mouhamad
Lilli
L
Stergiou
Benjamin
B
Besse
Lorenzo
L
Galluzzi
Simone
S
Boehrer
Anne-Laure
AL
Pauleau
Filippo
F
Rosselli
Marcello
M
D'Amelio
Roberto
R
Amendola
Maria
M
Castedo
Michael
M
Hengartner
Jean-Charles
JC
Soria
Francesco
F
Cecconi
Guido
G
Kroemer
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053477:Apoptotic Protease-Activating Factor 1 / Q000172:deficiency / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D002945:Cisplatin / Q000494:pharmacology; D017124:Conserved Sequence; D004249:DNA Damage; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D010802:Phylogeny; D011494:Protein Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects
D053477:Apoptotic Protease-Activating Factor 1; D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; C089224:Ced-4 protein, C elegans; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C000605876:chk-1 protein, C elegans; D002945:Cisplatin