FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway

Masamichi Ishiai, Hiroyuki Kitao, Agata Smogorzewska, Junya Tomida, Aiko Kinomura, Emi Uchida, Alihossein Saberi, Eiji Kinoshita, Emiko Kinoshita-Kikuta, Tohru Koike, Satoshi Tashiro, Stephen J. Elledge, Minoru Takata

研究成果: Contribution to journalArticle査読

180 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)1138-1146
ページ数9
ジャーナルNature Structural and Molecular Biology
15
11
DOI
出版ステータス出版済み - 11 27 2008

All Science Journal Classification (ASJC) codes

  • 構造生物学
  • 分子生物学

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