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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.

Author information

1
MRC Laboratory of Molecular Biology, Cambridge, UK.
2
Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany.
3
Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK.
4
MRC Laboratory of Molecular Biology, Cambridge, UK. passmore@mrc-lmb.cam.ac.uk.

Abstract

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.

PMID:
32066963
PMCID:
PMC7067600
[Available on 2020-08-17]
DOI:
10.1038/s41594-020-0380-1

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