TY - JOUR
T1 - Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway
AU - Garcia-Higuera, Irene
AU - Taniguchi, Toshiyasu
AU - Ganesan, Shridar
AU - Meyn, M. Stephen
AU - Timmers, Cynthia
AU - Hejna, James
AU - Grompe, Markus
AU - D'Andrea, Alan D.
N1 - Funding Information:
We gratefully acknowledge Dr. Dirk Bohmann for the ubiquitin expression plasmids, Junjie Chen for BRCA1 −/− cells, and Joanne Sweasy for the anti-SCP3 antibody. We thank Hans Joenje for the cDNAs for FANCA, FANCG, and FANCF. We thank James DeCaprio, David Pellman, Xiaohua Wu, Dan Silver, David Livingston, and David Nathan for helpful discussions. We thank Bill Lane for performing the mass spectrometry. We thank Lisa Moreau for analysis of chromosome breakage and Wei Wang for preparation of the meiotic spreads. This work was supported by National Institutes of Health grants RO1HL52725-04, RO1DK43889-09, and PO1HL54785-04 (A. D. D.). I. G.-H. is a Special Fellow of the Leukemia and Lymphoma Society. T. T. was supported by a grant from the Naito Foundation.
PY - 2001
Y1 - 2001
N2 - Fanconi anemia (FA) is a human autosomal recessive cancer susceptibility disorder characterized by cellular sensitivity to mitomycin C and ionizing radiation. Although six FA genes (for subtypes A, C, D2, E, F, and G) have been cloned, their relationship to DNA repair remains unknown. In the current study, we show that a nuclear complex containing the FANCA, FANCC, FANCF, and FANCG proteins is required for the activation of the FANCD2 protein to a monoubiquitinated isoform. In normal (non-FA) cells, FANCD2 is monoubiquitinated in response to DNA damage and is targeted to nuclear foci (dots). Activated FANCD2 protein colocalizes with the breast cancer susceptibility protein, BRCA1, in ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes. The FANCD2 protein, therefore, provides the missing link between the FA protein complex and the cellular BRCA1 repair machinery. Disruption of this pathway results in the cellular and clinical phenotype common to all FA subtypes.
AB - Fanconi anemia (FA) is a human autosomal recessive cancer susceptibility disorder characterized by cellular sensitivity to mitomycin C and ionizing radiation. Although six FA genes (for subtypes A, C, D2, E, F, and G) have been cloned, their relationship to DNA repair remains unknown. In the current study, we show that a nuclear complex containing the FANCA, FANCC, FANCF, and FANCG proteins is required for the activation of the FANCD2 protein to a monoubiquitinated isoform. In normal (non-FA) cells, FANCD2 is monoubiquitinated in response to DNA damage and is targeted to nuclear foci (dots). Activated FANCD2 protein colocalizes with the breast cancer susceptibility protein, BRCA1, in ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes. The FANCD2 protein, therefore, provides the missing link between the FA protein complex and the cellular BRCA1 repair machinery. Disruption of this pathway results in the cellular and clinical phenotype common to all FA subtypes.
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U2 - 10.1016/S1097-2765(01)00173-3
DO - 10.1016/S1097-2765(01)00173-3
M3 - Article
C2 - 11239454
AN - SCOPUS:0035105291
SN - 1097-2765
VL - 7
SP - 249
EP - 262
JO - Molecular Cell
JF - Molecular Cell
IS - 2
ER -