The Fanconi anemia protein, FANCE, promotes the nuclear accumulation of FANCC.
Fanconi anemia is an autosomal recessive disorder characterized by aplastic anemia, cancer susceptibility, and cellular sensitivity to mitomycin C. The 6 known Fanconi anemia gene products (FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG proteins) interact in a common pathway. The monoubiquitination and nuclear foci formation of FANCD2 are essential for the function of this pathway. FANCA, FANCC, FANCG, and FANCF proteins form a multisubunit nuclear complex (FA complex) required for FANCD2 monoubiquitination. Because FANCE and FANCC interact in vitro and FANCE is required for FANCD2 monoubiquitination, we reasoned that FANCE is a component of the FA complex in vivo. Here we demonstrate that retroviral transduction of Fanconi anemia subtype E (FA-E) cells with the FANCE cDNA restores the nuclear accumulation of FANCC protein, FANCA-FANCC complex formation, monoubiquitination and nuclear foci formation of FANCD2, and mitomycin C resistance. Hemagglutinin (HA)-tagged FANCE protein localizes diffusely in the nucleus. In normal cells, HA-tagged FANCE protein coimmunoprecipitates with FANCA, FANCC, and FANCG but not with FANCD2. Our data indicate that FANCE is a component of the nuclear FA complex in vivo and is required for the monoubiquitination of FANCD2 and the downstream events in the FA pathway.
Taniguchi
Toshiyasu
T
Department of Pediatric Oncology, Dana-Farber Cancer Institute, and the Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
D'Andrea
Alan D
AD
D018797:Cell Cycle Proteins; D002458:Cell Fractionation; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure; D004268:DNA-Binding Proteins; D005199:Fanconi Anemia / Q000097:blood*; D052218:Fanconi Anemia Complementation Group C Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D052239:Fanconi Anemia Complementation Group E Protein; D051856:Fanconi Anemia Complementation Group Proteins; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; C499905:FANCD2 protein, human; C499907:FANCE protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D052239:Fanconi Anemia Complementation Group E Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D011506:Proteins