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

Dominika Kwasna; Syed Arif Abdul Rehman; Jayaprakash Natarajan; Stephen Matthews; Ross Madden; Virginia De Cesare; Simone Weidlich; Satpal Virdee; Ivan Ahel; Ian Gibbs-Seymour; Yogesh Kulathu

doi:10.1016/j.molcel.2018.02.023

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

Dominika Kwasna, Syed Arif Abdul Rehman, Jayaprakash Natarajan, Stephen Matthews, Ross Madden, Virginia De Cesare, Simone Weidlich, Satpal Virdee, Ivan Ahel, Ian Gibbs-Seymour (Lead / Corresponding author), Yogesh Kulathu (Lead / Corresponding author)

MRC PPU

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	150-164.e6
Number of pages	15
Journal	Molecular Cell
Volume	70
Issue number	1
Early online date	22 Mar 2018
DOIs	https://doi.org/10.1016/j.molcel.2018.02.023
Publication status	Published - 5 Apr 2018

Keywords

Ubiquitin signaling
signal transduction
deubiquitinases
DNA damage
replication stress
ubiquitin binding domain
polyubiquitin
deubiquitinating enzyme
DNA damage response
ubiquitin signaling
DNA repair
DUB
Lys63 chains
uniquitin binding domain

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2018.02.023Licence: CC BY

Final Published VersionFinal published version, 5.53 MBLicence: CC BY

Activity Based Proteomics of E3 Ligases
Virdee, S. (Investigator)
Biotechnology and Biological Sciences Research Council
1/07/17 → 30/06/21
Project: Research
Regulation of Lymphocyte Biology by Ubiquitin and Ubiquitin like Modifiers RELYUBL (Starting Grant)
Kulathu, Y. (Investigator)
COMMISSION OF THE EUROPEAN COMMUNITIES
1/06/16 → 31/12/21
Project: Research

Discovery and characterization of a novel Deubiquitinase ZUP1
Kwasna, D. B. (Author), Kulathu, Y. (Supervisor), 2021
Student thesis: Doctoral Thesis › Doctor of Philosophy
Quantitative Deubiquitinase (DUB) Interactomics to Dissect the Biology of Cancer Associated DUBs
Natarajan, J. (Author), Kulathu, Y. (Supervisor), 2019
Student thesis: Doctoral Thesis › Doctor of Philosophy

Kulathu, Yogesh
- MRC PPU - Professor (Teaching and Research) of Cellular Biochemistry
Person: Academic

Cite this

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

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.",

keywords = "Ubiquitin signaling, signal transduction, deubiquitinases, DNA damage, replication stress, ubiquitin binding domain, polyubiquitin, deubiquitinating enzyme, DNA damage response, ubiquitin signaling, DNA repair, DUB, Lys63 chains, uniquitin binding domain",

author = "Dominika Kwasna and Rehman, {Syed Arif Abdul} and Jayaprakash Natarajan and Stephen Matthews and Ross Madden and {De Cesare}, Virginia and Simone Weidlich and Satpal Virdee and Ivan Ahel and Ian Gibbs-Seymour and Yogesh Kulathu",

note = "Research in the Kulathu lab is supported by the Medical Research Council UK (MC_UU_12016/6), European Research Council (677623), the EMBO Young Investigator Programme, and the pharmaceutical companies supporting the Division of Signal Transduction Therapy. YK is a Lister Institute Prize Fellow. IG-S acknowledges funding from the European Commission through a Marie Sk{\l}odowska-Curie Fellowship (701319) and is a recipient of a Kurti Junior Research Fellowship from Brasenose College, University of Oxford. IA is supported by the Wellcome Trust (101794), Cancer Research UK (C35050/A22284) and the European Research Council (281739).",

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month = apr,

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doi = "10.1016/j.molcel.2018.02.023",

language = "English",

volume = "70",

pages = "150--164.e6",

journal = "Molecular Cell",

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T1 - Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability

AU - Kwasna, Dominika

AU - Rehman, Syed Arif Abdul

AU - Natarajan, Jayaprakash

AU - Matthews, Stephen

AU - Madden, Ross

AU - De Cesare, Virginia

AU - Weidlich, Simone

AU - Virdee, Satpal

AU - Ahel, Ivan

AU - Gibbs-Seymour, Ian

AU - Kulathu, Yogesh

N1 - Research in the Kulathu lab is supported by the Medical Research Council UK (MC_UU_12016/6), European Research Council (677623), the EMBO Young Investigator Programme, and the pharmaceutical companies supporting the Division of Signal Transduction Therapy. YK is a Lister Institute Prize Fellow. IG-S acknowledges funding from the European Commission through a Marie Skłodowska-Curie Fellowship (701319) and is a recipient of a Kurti Junior Research Fellowship from Brasenose College, University of Oxford. IA is supported by the Wellcome Trust (101794), Cancer Research UK (C35050/A22284) and the European Research Council (281739).

PY - 2018/4/5

Y1 - 2018/4/5

N2 - 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.

AB - 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.

KW - Ubiquitin signaling

KW - signal transduction

KW - deubiquitinases

KW - DNA damage

KW - replication stress

KW - ubiquitin binding domain

KW - polyubiquitin

KW - deubiquitinating enzyme

KW - DNA damage response

KW - ubiquitin signaling

KW - DNA repair

KW - DUB

KW - Lys63 chains

KW - uniquitin binding domain

U2 - 10.1016/j.molcel.2018.02.023

DO - 10.1016/j.molcel.2018.02.023

M3 - Article

C2 - 29576527

SN - 1097-2765

VL - 70

SP - 150-164.e6

JO - Molecular Cell

JF - Molecular Cell

IS - 1

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

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Projects

Activity Based Proteomics of E3 Ligases

Regulation of Lymphocyte Biology by Ubiquitin and Ubiquitin like Modifiers RELYUBL (Starting Grant)

Student theses

Discovery and characterization of a novel Deubiquitinase ZUP1

Quantitative Deubiquitinase (DUB) Interactomics to Dissect the Biology of Cancer Associated DUBs

Profiles

Kulathu, Yogesh

Cite this