The eukaryotic replisome is rapidly disassembled during DNA replication 
termination. In metazoa, the cullin-RING ubiquitin ligase CUL-2LRR-1 drives 
ubiquitylation of the CMG helicase, leading to replisome disassembly by the 
p97/CDC-48 "unfoldase". Here, we combine in vitro reconstitution with in vivo 
studies in Caenorhabditis elegans embryos, to show that the replisome-associated 
TIMELESS-TIPIN complex is required for CUL-2LRR-1 recruitment and efficient CMG 
helicase ubiquitylation. Aided by TIMELESS-TIPIN, CUL-2LRR-1 directs a suite of 
ubiquitylation enzymes to ubiquitylate the MCM-7 subunit of CMG. Subsequently, 
the UBXN-3 adaptor protein directly stimulates the disassembly of ubiquitylated 
CMG by CDC-48_UFD-1_NPL-4. We show that UBXN-3 is important in vivo for 
replisome disassembly in the absence of TIMELESS-TIPIN. Correspondingly, 
co-depletion of UBXN-3 and TIMELESS causes profound synthetic lethality. Since 
the human orthologue of UBXN-3, FAF1, is a candidate tumour suppressor, these 
findings suggest that manipulation of CMG disassembly might be applicable to 
future strategies for treating human cancer.