ZUFSP Deubiquitylates K63-Linked Polyubiquitin Chains to Promote Genome Stability

TY - JOUR

T1 - ZUFSP Deubiquitylates K63-Linked Polyubiquitin Chains to Promote Genome Stability

AU - Haahr, Peter

AU - Borgermann, Nikoline

AU - Guo, Xiaohu

AU - Typas, Dimitris

AU - Achuthankutty, Divya

AU - Hoffmann, Saskia

AU - Shearer, Robert

AU - Sixma, Titia K

AU - Mailand, Niels

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018/4/5

Y1 - 2018/4/5

N2 - Deubiquitylating enzymes (DUBs) enhance the dynamics of the versatile ubiquitin (Ub) code by reversing and regulating cellular ubiquitylation processes at multiple levels. Here we discovered that the uncharacterized human protein ZUFSP (zinc finger with UFM1-specific peptidase domain protein/C6orf113/ZUP1), which has been annotated as a potentially inactive UFM1 protease, and its fission yeast homolog Mug105 define a previously unrecognized class of evolutionarily conserved cysteine protease DUBs. Human ZUFSP selectively interacts with and cleaves long K63-linked poly-Ub chains by means of tandem Ub-binding domains, whereas it displays poor activity toward mono- or di-Ub substrates. In cells, ZUFSP is recruited to and regulates K63-Ub conjugates at genotoxic stress sites, promoting chromosome stability upon replication stress in a manner dependent on its catalytic activity. Our findings establish ZUFSP as a new type of linkage-selective cysteine peptidase DUB with a role in genome maintenance pathways. Haahr et al. show that human ZUFSP is a deubiquitylating enzyme (DUB) that selectively interacts with and cleaves long K63-linked polyubiquitin chains. ZUFSP regulates K63-linked ubiquitylation at genotoxic stress sites and promotes chromosome stability in a manner dependent on its catalytic activity.

AB - Deubiquitylating enzymes (DUBs) enhance the dynamics of the versatile ubiquitin (Ub) code by reversing and regulating cellular ubiquitylation processes at multiple levels. Here we discovered that the uncharacterized human protein ZUFSP (zinc finger with UFM1-specific peptidase domain protein/C6orf113/ZUP1), which has been annotated as a potentially inactive UFM1 protease, and its fission yeast homolog Mug105 define a previously unrecognized class of evolutionarily conserved cysteine protease DUBs. Human ZUFSP selectively interacts with and cleaves long K63-linked poly-Ub chains by means of tandem Ub-binding domains, whereas it displays poor activity toward mono- or di-Ub substrates. In cells, ZUFSP is recruited to and regulates K63-Ub conjugates at genotoxic stress sites, promoting chromosome stability upon replication stress in a manner dependent on its catalytic activity. Our findings establish ZUFSP as a new type of linkage-selective cysteine peptidase DUB with a role in genome maintenance pathways. Haahr et al. show that human ZUFSP is a deubiquitylating enzyme (DUB) that selectively interacts with and cleaves long K63-linked polyubiquitin chains. ZUFSP regulates K63-linked ubiquitylation at genotoxic stress sites and promotes chromosome stability in a manner dependent on its catalytic activity.

U2 - 10.1016/j.molcel.2018.02.024

DO - 10.1016/j.molcel.2018.02.024

M3 - Journal article

C2 - 29576528

SN - 1097-2765

VL - 70

SP - 165

EP - 174

JO - Molecular Cell

JF - Molecular Cell

IS - 1

ER -