Article abstract
Nature Structural & Molecular Biology 15, 1138 - 1146 (2008)
Published online: 19 October 2008 | doi:10.1038/nsmb.1504
FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway
Masamichi Ishiai1,8, Hiroyuki Kitao1,2,7,8, Agata Smogorzewska3,4, Junya Tomida1, Aiko Kinomura2, Emi Uchida1, Alihossein Saberi1,7, Eiji Kinoshita5, Emiko Kinoshita-Kikuta5, Tohru Koike5, Satoshi Tashiro6, Stephen J Elledge3 & Minoru Takata1,2
Abstract
In response to DNA damage or replication fork stress, the Fanconi anemia pathway is activated, leading to monoubiquitination of FANCD2 and FANCI and their colocalization in foci. Here we show that, in the chicken DT40 cell system, multiple alanine-substitution mutations in six conserved and clustered Ser/Thr-Gln motifs of FANCI largely abrogate monoubiquitination and focus formation of both FANCI and FANCD2, resulting in loss of DNA repair function. Conversely, FANCI carrying phosphomimic mutations on the same six residues induces constitutive monoubiquitination and focus formation of FANCI and FANCD2, and protects against cell killing and chromosome breakage by DNA interstrand cross-linking agents. We propose that the multiple phosphorylation of FANCI serves as a molecular switch in activation of the Fanconi anemia pathway. Mutational analysis of putative phosphorylation sites in human FANCI indicates that this switch is evolutionarily conserved.
- Laboratory of DNA Damage Signaling, Department of Late Effect Studies, Radiation Biology Center, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
- Department of Human Genetics, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
- Department of Genetics, Howard Hughes Medical Institute, Center for Genetics and Genomics, Brigham and Women's Hospital, Harvard Medical School, Room 158D, NRB, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
- Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, WRN 225, Boston, Massachusetts 02114, USA.
- Department of Functional Molecular Science, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
- Department of Cellular Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
- Present addresses: Department of Molecular Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan (H.K.); Department of Genetics, School of Medicine, Ahwaz Jondishapoor of Medical Sciences, Golestan Street, Ahwaz 61357-15749, Iran (A. Saberi).
- These authors contributed equally to this work.
Correspondence to: Minoru Takata1,2 e-mail: mtakata@house.rbc.kyoto-u.ac.jp
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