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FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway
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FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway
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Journal Article
FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway
2008
Overview
The Fanconi anemia pathway is involved in the signaling of DNA damage. Several Fanconi anemia proteins have been identified, but how the pathway is actually activated was unclear. Now, work on chicken DT40 cells indicates that phosphorylation of FANCI at multiple sites triggers FANCD2 monoubiquitination and DNA-damage repair.
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Ataxia Telangiectasia Mutated Proteins
/ Biomedical and Life Sciences
/ Cell Cycle Proteins - antagonists & inhibitors
/ Cell Cycle Proteins - genetics
/ Cell Cycle Proteins - metabolism
/ Chickens
/ DNA
/ Fanconi Anemia Complementation Group D2 Protein - genetics
/ Fanconi Anemia Complementation Group D2 Protein - metabolism
/ Fanconi Anemia Complementation Group Proteins - genetics
/ Fanconi Anemia Complementation Group Proteins - metabolism
/ Humans
/ Mutation
/ Phosphodiesterase Inhibitors - metabolism
/ Protein Serine-Threonine Kinases - antagonists & inhibitors
/ Protein Serine-Threonine Kinases - genetics
/ Protein Serine-Threonine Kinases - metabolism
/ Recombinant Fusion Proteins - genetics
/ Recombinant Fusion Proteins - metabolism
