Journal
Nature Communications
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms12124
Keywords
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Categories
Funding
- Royal Society [UF100717, ALRXNV0]
- Fell Fund [103/789]
- Cancer Research UK (CR-UK) through the CR-UK Oxford Centre [C5255/A18085]
- Medical Research Council [MR/N021002/1]
- Medical Research Fund
- Taiwanese Government
- Goodger Scholarship
- MRC-Clarendon Scholarship
- BBSRC grant
- MRC [MR/N021002/1] Funding Source: UKRI
- Royal Society [UF100717] Funding Source: Royal Society
- Medical Research Council [MR/N021002/1, 1514538] Funding Source: researchfish
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The Fanconi anaemia (FA) pathway is important for the repair of DNA interstrand crosslinks (ICL). The FANCD2-FANCI complex is central to the pathway, and localizes to ICLs dependent on its monoubiquitination. It has remained elusive whether the complex is recruited before or after the critical monoubiquitination. Here, we report the first structural insight into the human FANCD2-FANCI complex by obtaining the cryo-EM structure. The complex contains an inner cavity, large enough to accommodate a double-stranded DNA helix, as well as a protruding Tower domain. Disease-causing mutations in the Tower domain are observed in several FA patients. Our work reveals that recruitment of the complex to a stalled replication fork serves as the trigger for the activating monoubiquitination event. Taken together, our results uncover the mechanism of how the FANCD2-FANCI complex activates the FA pathway, and explains the underlying molecular defect in FA patients with mutations in the Tower domain.
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