期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 29, 期 9, 页码 881-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41594-022-00820-9
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资金
- Wellcome Trust [BI23268, 203149]
- MRC
- Biotechnology and Biological Sciences Research Council
- MRC as part of UK Research and Innovation
- MRC [MC_U105192715]
- Cambridge Trust
- EMBO Long-Term Fellowship [ALTF 692-2018]
- Deutsche Forschungsgemeinschaft (German Research Foundation) [329673113]
This study reveals that phosphorylation of FANCI by the ATR DNA damage kinase primes the FANCD2-FANCI clamp for ubiquitination, facilitating the initiation of DNA cross-link repair.
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. Sijacki et al. show how phosphorylation of FANCI by the ATR DNA damage kinase primes the FANCD2-FANCI clamp for ubiquitination. Phosphorylation promotes closure of the clamp, exposing a lysine for ubiquitination to initiate DNA cross-link repair.
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