Deregulated apoptosis is a hallmark of the Fanconi anemia syndrome.
Fanconi anemia (FA) is a genetic human disorder associated with bone marrow failure and predisposition to cancer. FA cells show poor growth capacity and spontaneous chromosomal anomalies as well as cellular and chromosomal hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC). Because it is likely that disruption of the apoptotic control would lead to such a phenotype, we investigated the implication of apoptosis in the FA syndrome. It is shown that, although demonstrating a high frequency of spontaneous apoptosis, FA cells from four genetic complementation groups are deficient in gamma-ray-induced apoptosis and their MMC hypersensitivity is not due to apoptosis. Fas is a cell surface receptor belonging to the tumor necrosis factor receptor family and is involved in apoptosis. We show that, independently of DNA damage, the alteration in the control of apoptosis in FA concerns also the pathway initiated by Fas activation. Finally, ectopic expression of the wild-type FAC gene corrects the MMC hypersensitivity and anomalies in apoptosis and cell cycle response in FA cells. Altogether, these findings strongly implicate the FA genes as playing a major role in the control of apoptosis. Thus, further studies with FA syndrome will be instrumental toward molecularly dissecting the apoptotic pathways.
Ridet
A
A
UMR218 du Centre National de la Recherche Scientifique, Institut Curie, Section de Recherche, LRC no. 1 du CEA, Paris, France.
Guillouf
C
C
Duchaud
E
E
Cundari
E
E
Fiore
M
M
Moustacchi
E
E
Rosselli
F
F
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins; D005199:Fanconi Anemia / Q000473:pathology*; D051856:Fanconi Anemia Complementation Group Proteins; D005720:Gamma Rays; D005796:Genes; D006801:Humans; D008214:Lymphocytes / Q000528:radiation effects; D016685:Mitomycin / Q000494:pharmacology; D009687:Nuclear Proteins; D011506:Proteins / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D011506:Proteins; D019014:fas Receptor; D016685:Mitomycin