Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway.

Abstract	Monoubiquitination and deubiquitination of FANCD2:FANCI heterodimer is central to DNA repair in a pathway that is defective in the cancer predisposition syndrome Fanconi anemia (FA). The "FA core complex" contains the RING-E3 ligase FANCL and seven other essential proteins that are mutated in various FA subtypes. Here, we purified recombinant FA core complex to reveal the function of these other proteins. The complex contains two spatially separate FANCL molecules that are dimerized by FANCB and FAAP100. FANCC and FANCE act as substrate receptors and restrict monoubiquitination to the FANCD2:FANCI heterodimer in only a DNA-bound form. FANCA and FANCG are dispensable for maximal in vitro ubiquitination. Finally, we show that the reversal of this reaction by the USP1:UAF1 deubiquitinase only occurs when DNA is disengaged. Our work reveals the mechanistic basis for temporal and spatial control of FANCD2:FANCI monoubiquitination that is critical for chemotherapy responses and prevention of Fanconi anemia.
Authors	Sylvie van Twest, Vincent J Murphy, Charlotte Hodson, Winnie Tan, Paolo Swuec, Julienne J O'Rourke, Jörg Heierhorst, Wayne Crismani, Andrew J Deans
Journal	Molecular cell (Mol Cell) Vol. 65 Issue 2 Pg. 247-259 (Jan 19 2017) ISSN: 1097-4164 [Electronic] United States
PMID	27986371 (Publication Type: Journal Article)
Copyright	Copyright © 2017 Elsevier Inc. All rights reserved.
Chemical References	DNA-Binding Proteins FAAP100 protein, human FANCA protein, human FANCB protein, human FANCC protein, human FANCD2 protein, human FANCE protein, human FANCG protein, human FANCI protein, human Fanconi Anemia Complementation Group A Protein Fanconi Anemia Complementation Group C Protein Fanconi Anemia Complementation Group D2 Protein Fanconi Anemia Complementation Group E Protein Fanconi Anemia Complementation Group G Protein Fanconi Anemia Complementation Group Proteins ID2 protein, human Inhibitor of Differentiation Protein 2 Multiprotein Complexes Nuclear Proteins Recombinant Proteins USP1 associated factor 1, human DNA FANCL protein, human Fanconi Anemia Complementation Group L Protein USP1 protein, human Ubiquitin-Specific Proteases
Topics	Cell Line DNA (genetics, metabolism) DNA-Binding Proteins (metabolism) Fanconi Anemia (genetics, metabolism) Fanconi Anemia Complementation Group A Protein (metabolism) Fanconi Anemia Complementation Group C Protein (metabolism) Fanconi Anemia Complementation Group D2 Protein (genetics, metabolism) Fanconi Anemia Complementation Group E Protein (metabolism) Fanconi Anemia Complementation Group G Protein (metabolism) Fanconi Anemia Complementation Group L Protein (metabolism) Fanconi Anemia Complementation Group Proteins (genetics, metabolism) Humans Inhibitor of Differentiation Protein 2 (metabolism) Multiprotein Complexes Nuclear Proteins (metabolism) Protein Binding Protein Multimerization Recombinant Proteins (metabolism) Substrate Specificity Time Factors Transfection Ubiquitin-Specific Proteases (metabolism) Ubiquitination

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