Abstract
Seven Fanconi anemia–associated proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCL) form a nuclear Fanconi anemia core complex that activates the monoubiquitination of FANCD2, targeting FANCD2 to BRCA1-containing nuclear foci. Cells from individuals with Fanconi anemia of complementation groups D1 and J (FA-D1 and FA-J) have normal FANCD2 ubiquitination. Using genetic mapping, mutation identification and western-blot data, we identify the defective protein in FA-J cells as BRIP1 (also called BACH1), a DNA helicase that is a binding partner of the breast cancer tumor suppressor BRCA1.
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Acknowledgements
We thank the affected individuals and their families for providing tissue samples for these studies; the many physicians who referred their patients to the IFAR and helped in sending the tissue samples for their contributions; A. Dawson, B. Chodirker and G. Graham for providing samples from the Inuit families, which were instrumental to the success of the mapping experiments; S. Cantor for the monopool BRIP1 antibody; Myriad Genetic Laboratories for sequencing BRCA2 in IFAR samples; F. Lach, S. Arama, B. Zhang and Y. Flit for technical assistance; and J. Morales, C. Zhao and J. Lowe for advice. This work was supported in part by grants from the US National Institutes of Health (to A.D.A. and to J.P.), by the Joel and Joan Smilow Initiative (J.P.); by Kinderkrebsklinik Duesseldorf e. V. (H.H.); by CIEMAT and the Marcelino Botin Foundation (P.R.); by the Schroeder-Kurth Fund and the Deutsche Fanconi-Anamie-Hilfe (K.N., R.K. and D.S.); and by the Fanconi Anemia Research Fund (H.H.).
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Supplementary Fig. 1
Chromatograms displaying the wild type and mutation c.2533C>T in exon 17 of BRIP1, and illustration of the creation of a premature stop codon R798X. (PDF 106 kb)
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Levran, O., Attwooll, C., Henry, R. et al. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet 37, 931–933 (2005). https://doi.org/10.1038/ng1624
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DOI: https://doi.org/10.1038/ng1624
