Concerted SUMO-targeted ubiquitin ligase activities of TOPORS and RNF4 are essential for stress management and cell proliferation

Julio C.Y. Liu, Leena Ackermann, Saskia Hoffmann, Zita Gál, Ivo A. Hendriks, Charu Jain, Louise Morlot, Michael H. Tatham, Gian-Luca McLelland, Ronald T. Hay, Michael Lund Nielsen, Thijn Brummelkamp, Peter Haahr*, Niels Mailand*

*Corresponding author for this work

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2 Citations (Scopus)
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Abstract

Protein SUMOylation provides a principal driving force for cellular stress responses, including DNA–protein crosslink (DPC) repair and arsenic-induced PML body degradation. In this study, using genome-scale screens, we identified the human E3 ligase TOPORS as a key effector of SUMO-dependent DPC resolution. We demonstrate that TOPORS promotes DPC repair by functioning as a SUMO-targeted ubiquitin ligase (STUbL), combining ubiquitin ligase activity through its RING domain with poly-SUMO binding via SUMO-interacting motifs, analogous to the STUbL RNF4. Mechanistically, TOPORS is a SUMO1-selective STUbL that complements RNF4 in generating complex ubiquitin landscapes on SUMOylated targets, including DPCs and PML, stimulating efficient p97/VCP unfoldase recruitment and proteasomal degradation. Combined loss of TOPORS and RNF4 is synthetic lethal even in unstressed cells, involving defective clearance of SUMOylated proteins from chromatin accompanied by cell cycle arrest and apoptosis. Our findings establish TOPORS as a STUbL whose parallel action with RNF4 defines a general mechanistic principle in crucial cellular processes governed by direct SUMO–ubiquitin crosstalk.

Original languageEnglish
JournalNature Structural and Molecular Biology
Volume31
Issue number9
Pages (from-to)1355–1367
Number of pages32
ISSN1545-9993
DOIs
Publication statusPublished - 2024

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