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)

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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

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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

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