TY  - BOOK
AU  - Sijacki,Tamara
AU  - Alcón,Pablo
AU  - Chen,Zhuo A.
AU  - McLaughlin,Stephen H.
AU  - Shakeel,Shabih
AU  - Rappsilber,Juri
AU  - Passmore,Lori A.
TI  - The DNA-damage kinase ATR activates the FANCD2-FANCI clamp by priming it for ubiquitination
PY  - 2022///-09
KW  - Text
KW  - local
N1  - /pmc/articles/PMC7613635; /pubmed/36050501
N2  - 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
UR  - http://dx.doi.org/10.1038/s41594-022-00820-9
ER  -