Mechanism, specificity and function of FANCD2‐FANCI ubiquitination and deubiquitination

Lemonidis, K. , Arkinson, C., Rennie, M. L. and Walden, H. (2021) Mechanism, specificity and function of FANCD2‐FANCI ubiquitination and deubiquitination. FEBS Journal, (doi: 10.1111/febs.16077) (Early Online Publication)

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Abstract

Fanconi anemia (FA) is a rare genetic disorder caused by mutations in any of the currently 22 known FA genes. The products of these genes, along with other FA associated proteins, participate in a biochemical pathway, known as the FA pathway. This pathway is responsible for the repair of DNA inter-stand crosslinks (ICL) and the maintenance of genomic stability in response to replication stress. At the centre of the pathway is the mono-ubiquitination of two FA proteins, FANCD2 and FANCI, on two specific lysine residues. This is achieved by the combined action of the UBE2T ubiquitin-conjugating enzyme and a large multicomponent E3 ligase, known as the FA-core complex. This E2-E3 pair specifically targets the FANCI-FANCD2 heterodimer (ID2 complex) for ubiquitination on DNA. Deubiquitination of both FANCD2 and FANCI, which is also critical for ICL repair, is achieved by the USP1-UAF1 complex. Recent work suggests that FANCD2 ubiquitination transforms the ID2 complex into a sliding DNA clamp. Further ID2 ubiquitination on FANCI does not alter the closed ID2 conformation observed upon FANCD2 ubiquitination, and the associated with this, high DNA affinity. However, the resulting di-mono-ubiquitinated complex is highly resistant to USP1-UAF1 deubiquitination. This review will provide an update on recent work focusing on how specificity in FANCD2 ubiquitination and de-ubiquitination is achieved. Recent findings shedding light to the mechanisms, molecular functions and biological roles of FANCI/FANCD2 ubiquitination and deubiquitination will be also discussed.

Item Type:Articles
Status:Early Online Publication
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lemonidis, Dr Kimon and Rennie, Dr Martin and Arkinson, Connor and Walden, Professor Helen
Authors: Lemonidis, K., Arkinson, C., Rennie, M. L., and Walden, H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:FEBS Journal
Publisher:Wiley
ISSN:1742-464X
ISSN (Online):1742-4658
Published Online:17 June 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in FEBS Journal 2021
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
302391Regulation of DNA interstrand crosslink repair by ubiquitin.Helen WaldenEuropean Research Council (ERC)681506Institute of Molecular, Cell & Systems Biology