Replisome disassembly is the final step of DNA replication in eukaryotes, 
involving the ubiquitylation and CDC48-dependent dissolution of the CMG helicase 
(CDC45-MCM-GINS). Using Caenorhabditis elegans early embryos and Xenopus laevis 
egg extracts, we show that the E3 ligase CUL-2LRR-1 associates with the 
replisome and drives ubiquitylation and disassembly of CMG, together with the 
CDC-48 cofactors UFD-1 and NPL-4. Removal of CMG from chromatin in frog egg 
extracts requires CUL2 neddylation, and our data identify chromatin recruitment 
of CUL2LRR1 as a key regulated step during DNA replication termination. 
Interestingly, however, CMG persists on chromatin until prophase in worms that 
lack CUL-2LRR-1, but is then removed by a mitotic pathway that requires the 
CDC-48 cofactor UBXN-3, orthologous to the human tumour suppressor FAF1. Partial 
inactivation of lrr-1 and ubxn-3 leads to synthetic lethality, suggesting future 
approaches by which a deeper understanding of CMG disassembly in metazoa could 
be exploited therapeutically.