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FANCD2–FANCI is a clamp stabilized on DNA by monoubiquitination of FANCD2 during DNA repair
DOI:
10.1038/s41594-020-0380-1
Authors:
Pablo
Alcon
(MRC Laboratory of Molecular Biology)
,
Shabih
Shakeel
(MRC Laboratory of Molecular Biology)
,
Zhuo A.
Chen
(Technische Universität Berlin)
,
Juri
Rappsilber
(Technische Universität Berlin)
,
Ketan J.
Patel
(MRC Laboratory of Molecular Biology)
,
Lori
Passmore
(MRC Laboratory of Molecular Biology)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Nature Structural & Molecular Biology
, VOL 493
State:
Published (Approved)
Published:
February 2020
Diamond Proposal Number(s):
17434
,
23268
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.
Journal Keywords: Cryoelectron microscopy; DNA damage and repair
Subject Areas:
Biology and Bio-materials
Diamond Offline Facilities:
Electron Bio-Imaging Centre (eBIC)
Instruments:
Krios I-Titan Krios I at Diamond