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Nat Struct Mol Biol. 2020 Mar;27(3):240-248. doi: 10.1038/s41594-020-0380-1. Epub 2020 Feb 17.

FANCD2-FANCI is a clamp stabilized on DNA by monoubiquitination of FANCD2 during DNA repair.

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MRC Laboratory of Molecular Biology, Cambridge, UK.
Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany.
Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK.
MRC Laboratory of Molecular Biology, Cambridge, UK.


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.

[Available on 2020-08-17]

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