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

Research output: Contribution to journalArticle

151 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1138-1146
Number of pages9
JournalNature Structural and Molecular Biology
Volume15
Issue number11
DOIs
Publication statusPublished - Nov 27 2008

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Fanconi Anemia
Phosphorylation
Chromosome Breakage
Mutation
DNA Replication
DNA Repair
Alanine
DNA Damage
Chickens
DNA

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

Cite this

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

In: Nature Structural and Molecular Biology, Vol. 15, No. 11, 27.11.2008, p. 1138-1146.

Research output: Contribution to journalArticle

Ishiai, M, Kitao, H, Smogorzewska, A, Tomida, J, Kinomura, A, Uchida, E, Saberi, A, Kinoshita, E, Kinoshita-Kikuta, E, Koike, T, Tashiro, S, Elledge, SJ & Takata, M 2008, 'FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway', Nature Structural and Molecular Biology, vol. 15, no. 11, pp. 1138-1146. https://doi.org/10.1038/nsmb.1504
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. / FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. In: Nature Structural and Molecular Biology. 2008 ; Vol. 15, No. 11. pp. 1138-1146.
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