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

Summary Protein SUMOylation provides a principal driving force for cellular stress responses including DNA-protein crosslink (DPC) repair and arsenic-induced PML body degradation. In 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) for DPCs, combining ubiquitin ligase activity through its RING domain with poly-SUMO chain binding via a cluster of SUMO-interacting motifs, analogous to the STUbL RNF4. Surprisingly, the STUbL activities of TOPORS and RNF4 are both required for SUMO-dependent DPC repair, PML degradation and other stress responses, making overlapping and distinct contributions to ubiquitin chain formation on SUMOylated targets to enable p97/VCP unfoldase recruitment. Combined loss of TOPORS and RNF4 is synthetic lethal even in unstressed cells, leading to defective clearance of SUMOylated proteins from chromatin accompanied by cell cycle arrest and apoptosis. Together, our findings establish TOPORS as a novel STUbL whose concerted action with RNF4 defines a general mechanistic principle in crucial cellular processes governed by direct SUMO-ubiquitin crosstalk. Highlights The RING E3 ligase TOPORS is required for SUMO-dependent DPC repair TOPORS is a novel SUMO-targeted ubiquitin ligase (STUbL) TOPORS promotes multiple STUbL-driven processes in conjunction with RNF4 Combined TOPORS and RNF4 loss is synthetic lethal in human cells