期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 27, 期 3, 页码 240-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41594-020-0380-1
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资金
- Medical Research Council, as part of United Kingdom Research and Innovation [MC_U105192715, MC_U105178811]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [329673113]
- Wellcome Trust [203149, EM17434, BI23268]
- EMBO Long-Term Fellowship [ALTF 692-2018]
- MRC [EM17434, BI23268]
- Biotechnology and Biological Sciences Research Council [EM17434, BI23268]
- MRC [MC_U105192715, MC_U105178811, MC_PC_15065] Funding Source: UKRI
Structural analysis of the DNA crosslink repair factors FANCD2 and FANCI demonstrates that a complex of both factors adopts a closed conformation upon ubiquitination of FANCD2, trapping the complex on DNA. Vertebrate DNA crosslink repair excises toxic replication-blocking DNA crosslinks. Numerous factors involved in crosslink repair have been identified, and mutations in their corresponding genes cause Fanconi anemia (FA). A key step in crosslink repair is monoubiquitination of the FANCD2-FANCI heterodimer, which then recruits nucleases to remove the DNA lesion. Here, we use cryo-EM to determine the structures of recombinant chicken FANCD2 and FANCI complexes. FANCD2-FANCI adopts a closed conformation when the FANCD2 subunit is monoubiquitinated, creating a channel that encloses double-stranded DNA (dsDNA). Ubiquitin is positioned at the interface of FANCD2 and FANCI, where it acts as a covalent molecular pin to trap the complex on DNA. In contrast, isolated FANCD2 is a homodimer that is unable to bind DNA, suggestive of an autoinhibitory mechanism that prevents premature activation. Together, our work suggests that FANCD2-FANCI is a clamp that is locked onto DNA by ubiquitin, with distinct interfaces that may recruit other DNA repair factors.
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