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)

Research output: Contribution to journalArticle

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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 languageEnglish
Pages (from-to)150-164.e6
Number of pages15
JournalMolecular Cell
Volume70
Issue number1
Early online date22 Mar 2018
DOIs
Publication statusPublished - 5 Apr 2018

Fingerprint

Genomic Instability
Ubiquitin
Polyubiquitin
DNA Damage
Catalysis
Catalytic Domain
Deubiquitinating Enzymes
DNA

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

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.",
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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 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).",
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Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability. / Kwasna, Dominika; Rehman, Syed Arif Abdul; Natarajan, Jayaprakash; Matthews, Stephen; Madden, Ross; De Cesare, Virginia; Weidlich, Simone; Virdee, Satpal; Ahel, Ivan; Gibbs-Seymour, Ian (Lead / Corresponding author); Kulathu, Yogesh (Lead / Corresponding author).

In: Molecular Cell, Vol. 70, No. 1, 05.04.2018, p. 150-164.e6.

Research output: Contribution to journalArticle

TY - JOUR

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.

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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

VL - 70

SP - 150-164.e6

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 1

ER -