Differential functions of FANCI and FANCD2 ubiquitination stabilize ID2 complex on DNA
Open Access
- 8 June 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in EMBO Reports
- Vol. 21 (7), e50133
- https://doi.org/10.15252/embr.202050133
Abstract
The Fanconi anaemia (FA) pathway is a dedicated pathway for the repair of DNA interstrand crosslinks and is additionally activated in response to other forms of replication stress. A key step in the FA pathway is the monoubiquitination of each of the two subunits (FANCI and FANCD2) of the ID2 complex on specific lysine residues. However, the molecular function of these modifications has been unknown for nearly two decades. Here, we find that ubiquitination of FANCD2 acts to increase ID2's affinity for double‐stranded DNA via promoting a large‐scale conformational change in the complex. The resulting complex encircles DNA, by forming a secondary “Arm” ID2 interface. Ubiquitination of FANCI, on the other hand, largely protects the ubiquitin on FANCD2 from USP1‐UAF1 deubiquitination, with key hydrophobic residues of FANCI's ubiquitin being important for this protection. In effect, both of these post‐translational modifications function to stabilize a conformation in which the ID2 complex encircles DNA.Keywords
Funding Information
- H2020 European Research Council (ERC-2015-CoG-681582 ICLUb)
- Medical Research Council (MC_PC_17135)
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