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

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.

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 -