a. Domain/motif architecture of human SPRTN and its yeast ortholog Wss1. ZBD, Zinc binding domain; PIP, PCNA interaction peptide; SHP, p97 or VCP-binding motif; SIM, SUMO interaction motif; SprT, the metalloprotease domain similar to that of the Escherichia coli SprT protein; UBZ, ubiquitin-binding zinc finger; VIM; VCP interaction motif; WLM, Wss1- like metalloprotease domain Schematic of the repair of TOP-DPC by SPRTN/Wss1. b. As a component of the replisome, SPRTN/WSS1 is activated by its binding to ssDNA. It targets TOP-DPC as well as general DPC for proteolysis in association with replication.