Compartmentalization of the SUMO/RNF4 pathway by SLX4 drives DNA repair

SLX4, disabled in the Fanconi anemia group P, is a scaffolding protein that coordinates the action of struc-ture-specific endonucleases and other proteins involved in the replication-coupled repair of DNA interstrand cross-links. Here, we show that SLX4 dimerization and SUMO-SIM interactions drive the assembly of SLX4 membraneless compartments in the nucleus called condensates. Super-resolution microscopy reveals that SLX4 forms chromatin-bound clusters of nanocondensates. We report that SLX4 compartmentalizes the SUMO-RNF4 signaling pathway. SENP6 and RNF4 regulate the assembly and disassembly of SLX4 conden-sates, respectively. SLX4 condensation per se triggers the selective modification of proteins by SUMO and ubiquitin. Specifically, SLX4 condensation induces ubiquitylation and chromatin extraction of topoisomerase 1 DNA-protein cross-links. SLX4 condensation also induces the nucleolytic degradation of newly replicated DNA. We propose that the compartmentalization of proteins by SLX4 through site-specific interactions ensures the spatiotemporal control of protein modifications and nucleolytic reactions during DNA repair.

Automated summary

SLX4 is a scaffolding protein that coordinates the action of structure-specific endonucleases and other proteins involved in the replication-coupled repair of DNA interstrand cross-links. It forms membraneless compartments called condensates in the nucleus through dimerization and SUMO-SIM interactions. These condensates compartmentalize proteins, such as the SUMO-RNF4 signaling pathway, and regulate protein modifications and nucleolytic reactions during DNA repair.