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Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability

DOI: 10.1016/j.molcel.2018.02.023 DOI Help

Authors: Dominika Kwasna (University of Dundee) , Syed Arif Abdul Rehman (University of Dundee) , Jayaprakash Natarajan (University of Dundee) , Stephen Matthews (University of Dundee) , Ross Madden (University of Dundee) , Virginia De Cesare (University of Dundee) , Simone Weidlich (University of Dundee) , Satpal Virdee (University of Dundee) , Ivan Ahel (Sir William Dunn School of Pathology, University of Oxford) , Ian Gibbs-seymour (Sir William Dunn School of Pathology, University of Oxford) , Yogesh Kulathu (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Cell

State: Published (Approved)
Published: March 2018
Diamond Proposal Number(s): 16778

Open Access Open Access

Abstract: Deubiquitinating enzymes (DUBs) are important regulators of ubiquitin signaling. Here, we report the discovery of deubiquitinating activity in ZUFSP/C6orf113. High-resolution crystal structures of ZUFSP in complex with ubiquitin reveal several distinctive features of ubiquitin recognition and catalysis. Our analyses reveal that ZUFSP is a novel DUB with no homology to any known DUBs, leading us to classify ZUFSP as the seventh DUB family. Intriguingly, the minimal catalytic domain does not cleave polyubiquitin. We identify two ubiquitin binding domains in ZUFSP: a ZHA (ZUFSP helical arm) that binds to the distal ubiquitin and an atypical UBZ domain in ZUFSP that binds to polyubiquitin. Importantly, both domains are essential for ZUFSP to selectively cleave K63-linked polyubiquitin. We show that ZUFSP localizes to DNA lesions, where it plays an important role in genome stability pathways, functioning to prevent spontaneous DNA damage and also promote cellular survival in response to exogenous DNA damage.

Journal Keywords: deubiquitinating enzyme; DUB; uniquitin binding domain; DNA repair; DNA damage response; ubiquitin signaling; polyubiquitin; Lys63 chains

Subject Areas: Biology and Bio-materials


Instruments: B23-Circular Dichroism , I04-Macromolecular Crystallography

Other Facilities: European Synchrotron Radiation Facility

Documents:
1-s2.0-S1097276518301424-main.pdf