Abstract
Activation of the Fanconi anemia (FA) DNA damage–response pathway results in the monoubiquitination of FANCD2, which is regulated by the nuclear FA core ubiquitin ligase complex. A FANCD2 protein sequence–based homology search facilitated the discovery of FANCI, a second monoubiquitinated component of the FA pathway. Biallelic mutations in the gene coding for this protein were found in cells from four FA patients, including an FA-I reference cell line.
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Acknowledgements
We thank the affected individuals and their families and the many physicians that have referred families to the International Fanconi Anemia Registry for participation in the research. We thank H. Joenje (VU University Medical Center) for providing the FA-I reference cell line EUFA592, K. Nakanishi, M. Jasin (Memorial Sloan-Kettering Cancer Center), T. Taniguchi (Fred Hutchinson Cancer Research Center) and A. D'Andrea (Dana-Farber Cancer Institute) for cell lines and reagents, Deutsche FA-Hilfe and R. Dietrich for research support, members of T.T.H.'s, D.Bar-Sagi and D. Reinberg laboratories (New York University) for technical assistance, equipment and helpful discussions, and H. Wang (SeqWright) for providing technical expertise. This work was supported in part by Deutsche Forschungsgemeinschaft grant Ha2322/2-1 and German Jose Carreras Leukemia Foundation R06/21 (H.H.), US National Institutes of Health grant R37HL32987 (A.D.A.) and New York University School of Medicine start-up funding (T.T.H.).
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Supplementary information
Supplementary Fig. 1
Top candidates from sequence-based homology search using the conserved FANCD2 monoubiquitination site LVIRK (PDF 1946 kb)
Supplementary Fig. 2
Protein sequence alignment of human FANCI and FANCD2 (PDF 953 kb)
Supplementary Fig. 3
Determining the monoubiquitination status of FANCI in FA patients with low FANCD2 protein levels (PDF 464 kb)
Supplementary Fig. 4
Sequence traces for patients F010191 and EUFA592 (PDF 425 kb)
Supplementary Table 1
FANCI genomic primers (PDF 13 kb)
Supplementary Table 2
KIAA1794 cDNA primers (PDF 10 kb)
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Sims, A., Spiteri, E., Sims, R. et al. FANCI is a second monoubiquitinated member of the Fanconi anemia pathway. Nat Struct Mol Biol 14, 564–567 (2007). https://doi.org/10.1038/nsmb1252
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DOI: https://doi.org/10.1038/nsmb1252
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