Differential functions of FANCI and FANCD2 ubiquitination stabilize ID2 complex on DNA

Rennie, M. L. , Lemonidis, K. , Arkinson, C., Chaugule, V. K. , Clarke, M. , Streetley, J. , Spagnolo, L. and Walden, H. (2020) Differential functions of FANCI and FANCD2 ubiquitination stabilize ID2 complex on DNA. EMBO Reports, 21(7), e50133. (doi: 10.15252/embr.202050133) (PMID:32510829) (PMCID:PMC7332966)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Spagnolo, Dr Laura and Clarke, Dr Mairi and Chaugule, Dr Viduth and Streetley, Dr James and Lemonidis, Dr Kimon and Arkinson, Connor and Rennie, Dr Martin and Walden, Professor Helen
Authors: Rennie, M. L., Lemonidis, K., Arkinson, C., Chaugule, V. K., Clarke, M., Streetley, J., Spagnolo, L., and Walden, H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:EMBO Reports
ISSN (Online):1469-3178
Published Online:08 June 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in EMBO Reports 21(7): e50133
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301445The Scottish Macromolecular Imaging Centre (SMIC)David BhellaMedical Research Council (MRC)MC_PC_17135III - Centre for Virus Research
301474The purchase and maintenance of a cryo-electron microscopeDavid BhellaScottish Funding Council (SFC)H17007III - Centre for Virus Research