Structural basis of FANCD2 deubiquitination by USP1-UAF1

Rennie, M. L. , Arkinson, C., Chaugule, V. K. , Toth, R. and Walden, H. (2021) Structural basis of FANCD2 deubiquitination by USP1-UAF1. Nature Structural and Molecular Biology, 28(4), pp. 356-364. (doi: 10.1038/s41594-021-00576-8) (PMID:33795880)

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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.

Item Type:Articles
Additional Information:This work was supported by the European Research Council (ERC-2015-CoG-681582) ICLUb consolidator grant to H.W. and the Medical Research Council (MC_UU_120164/12).
Glasgow Author(s) Enlighten ID:Chaugule, Dr Viduth and Arkinson, Connor and Rennie, Dr Martin and Walden, Professor Helen
Authors: Rennie, M. L., Arkinson, C., Chaugule, V. K., Toth, R., and Walden, H.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Nature Structural and Molecular Biology
Publisher:Nature Research
ISSN (Online):1545-9985
Published Online:01 April 2021
Copyright Holders:Copyright © 2021 Springer Nature Ltd
First Published:First published in Nature Structural and Molecular Biology 28(4): 356-364
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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