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- Title
FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway.
- Authors
Ishiai, Masamichi; Kitao, Hiroyuki; Smogorzewska, Agata; Tomida, Junya; Kinomura, Aiko; Uchida, Emi; Saberi, Alihossein; Kinoshita, Eiji; Kinoshita-Kikuta, Emiko; Koike, Tohru; Tashiro, Satoshi; Elledge, Stephen J.; Takata, Minoru
- 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.
- Subjects
FANCONI'S anemia; DNA damage; DNA replication; CELLS; PROTEINS; ANEMIA; MOLECULAR biology
- Publication
Nature Structural & Molecular Biology, 2008, Vol 15, Issue 11, p1138
- ISSN
1545-9993
- Publication type
Article
- DOI
10.1038/nsmb.1504