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Instruments / Technical Area	Publication Details	Published	Actions
B21-High Throughput SAXS I04-Macromolecular Crystallography	Structural basis of FANCD2 deubiquitination by USP1−UAF1 Martin L. Rennie , Connor Arkinson , Viduth K. Chaugule , Rachel Toth , Helen Walden Nature Structural & Molecular Biology 18 DOI: 10.1038/s41594-021-00576-8 Diamond Proposal Number(s): [14980, 19844] Show Abstract ▼ Abstract: Ubiquitin-specific protease 1 (USP1) acts together with the cofactor UAF1 during DNA repair processes to specifically remove monoubiquitin signals. One substrate of the USP1−UAF1 complex is the monoubiquitinated FANCI−FANCD2 heterodimer, which is involved in the repair of DNA interstrand crosslinks via the Fanconi anemia pathway. Here we determine structures of human USP1−UAF1 with and without ubiquitin and bound to monoubiquitinated FANCI−FANCD2. The crystal structures of USP1−UAF1 reveal plasticity in USP1 and key differences to USP12−UAF1 and USP46−UAF1, two related proteases. A cryo-EM reconstruction of USP1−UAF1 in complex with monoubiquitinated FANCI−FANCD2 highlights a highly orchestrated deubiquitination process, with USP1−UAF1 driving conformational changes in the substrate. An extensive interface between UAF1 and FANCI, confirmed by mutagenesis and biochemical assays, provides a molecular explanation for the requirement of both proteins, despite neither being directly involved in catalysis. Overall, our data provide molecular details of USP1−UAF1 regulation and substrate recognition.	Apr 2021
Krios IV-Titan Krios IV at Diamond	Differential functions of FANCI and FANCD2 ubiquitination stabilize ID2 complex on DNA Martin L. Rennie , Kimon Lemonidis , Connor Arkinson , Viduth K Chaugule , Mairi Clarke , James Streetley , Laura Spagnolo , Helen Walden Embo Reports 21 DOI: 10.15252/embr.202050133 Diamond Proposal Number(s): [16637] Open Access Show Abstract ▼ 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.	Jul 2020

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