S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51.
Fanconi anemia (FA) is a human autosomal recessive cancer susceptibility disorder characterized by cellular sensitivity to mitomycin C and defective cell-cycle progression. Six FA genes (corresponding to subtypes A, C, D2, E, F, and G) have been cloned, and the encoded FA proteins interact in a common pathway. DNA damage activates this pathway, leading to monoubiquitination of the downstream FANCD2 protein and targeting to nuclear foci containing BRCA1. In the current study, we demonstrate that FANCD2 also undergoes monoubiquitination during S phase of the cell cycle. Monoubiquitinated FANCD2 colocalizes with BRCA1 and RAD51 in S-phase-specific nuclear foci. Monoubiquitination of FANCD2 is required for normal cell-cycle progression following cellular exposure to mitomycin C. Our data indicate that the monoubiquitination of FANCD2 is highly regulated, and they suggest that FANCD2/BRCA1 complexes and FANCD2/RAD51 complexes participate in an S-phase-specific cellular process, such as DNA repair by homologous recombination.
Taniguchi
Toshiyasu
T
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Garcia-Higuera
Irene
I
Andreassen
Paul R
PR
Gregory
Richard C
RC
Grompe
Markus
M
D'Andrea
Alan D
AD
D019313:BRCA1 Protein / Q000378:metabolism*; D002453:Cell Cycle / Q000528:radiation effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D052236:Fanconi Anemia Complementation Group D2 Protein; D016195:G2 Phase; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D008938:Mitosis; D009687:Nuclear Proteins / Q000378:metabolism*; D051135:Rad51 Recombinase; D011994:Recombinant Proteins / Q000378:metabolism; D016196:S Phase / Q000528:radiation effects; D014162:Transfection; D014466:Ultraviolet Rays
D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D009687:Nuclear Proteins; D011994:Recombinant Proteins; C495153:RAD51 protein, human; D051135:Rad51 Recombinase