The DNA-damage kinase ATR activates the FANCD2-FANCI clamp by priming it for ubiquitination

Tamara Sijacki, Pablo Alcón, Zhuo A. Chen, Stephen H. Mclaughlin, Shabih Shakeel, Juri Rappsilber, Lori A. Passmore

Research output: Contribution to journalArticlepeer-review


DNA interstrand cross-links are tumor-inducing lesions that block DNA replication and transcription. When cross-links are detected at stalled replication forks, ATR kinase phosphorylates FANCI, which stimulates monoubiquitination of the FANCD2–FANCI clamp by the Fanconi anemia core complex. Monoubiquitinated FANCD2–FANCI is locked onto DNA and recruits nucleases that mediate DNA repair. However, it remains unclear how phosphorylation activates this pathway. Here, we report structures of FANCD2–FANCI complexes containing phosphomimetic FANCI. We observe that, unlike wild-type FANCD2–FANCI, the phosphomimetic complex closes around DNA, independent of the Fanconi anemia core complex. The phosphomimetic mutations do not substantially alter DNA binding but instead destabilize the open state of FANCD2–FANCI and alter its conformational dynamics. Overall, our results demonstrate that phosphorylation primes the FANCD2–FANCI clamp for ubiquitination, showing how multiple posttranslational modifications are coordinated to control DNA repair.
Original languageEnglish
Pages (from-to)881-890
Number of pages10
JournalNature Structural & Molecular Biology
Issue number9
Early online date1 Sep 2022
Publication statusPublished - 1 Sep 2022


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