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

Autor: Tamara Sijacki, Pablo Alcón, Zhuo A. Chen, Stephen H. McLaughlin, Shabih Shakeel, Juri Rappsilber, Lori A. Passmore
Rok vydání: 2022
Předmět:
Zdroj: Nat Struct Mol Biol
Sijacki, T, Alcón, P, Chen, Z A, Mclaughlin, S H, Shakeel, S, Rappsilber, J & Passmore, L A 2022, ' The DNA-damage kinase ATR activates the FANCD2-FANCI clamp by priming it for ubiquitination ', Nature Structural & Molecular Biology, vol. 29, no. 9, pp. 881-890 . https://doi.org/10.1038/s41594-022-00820-9
ISSN: 1545-9985
1545-9993
Popis: DNA interstrand crosslinks are tumor-inducing lesions that block DNA replication and transcription. When crosslinks are detected at stalled replication forks, ATR kinase phosphorylates FANCI, which stimulates monoubiquitination of the FANCD2-FANCI clamp by the Fanconi anemia (FA) 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 FA core complex. Surprisingly, 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 reveal that phosphorylation primes the FANCD2-FANCI clamp for ubiquitination, showing how multiple post-translational modifications are coordinated to control DNA-repair.
Databáze: OpenAIRE
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