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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 publication

DOI

10.1016/j.molcel.2018.02.023

Type

Journal article

Journal

Mol Cell

Publication Date

05/04/2018

Volume

70

Pages

150 - 164.e6

Keywords

DNA damage response, DNA repair, DUB, Lys63 chains, deubiquitinating enzyme, polyubiquitin, ubiquitin signaling, uniquitin binding domain, Binding Sites, Cell Nucleus, Cell Survival, DNA Damage, Deubiquitinating Enzymes, Genomic Instability, HEK293 Cells, HeLa Cells, Humans, Jurkat Cells, Lysine, Polyubiquitin, Protein Binding, Protein Conformation, Protein Interaction Domains and Motifs, Structure-Activity Relationship, Substrate Specificity, Ubiquitination