CUL-2LRR-1 and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis

Remi Sonneville, Sara Priego Moreno, Axel Knebel, Clare Johnson, C. James Hastie, Anton Gartner, Agnieszka Gambus (Lead / Corresponding author), Karim Labib (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)
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Abstract

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 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 co-factors 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 co-factor UBXN-3, orthologous to the human tumour suppressor FAF1. Partial inactivation of lrr-1 and ubxn-3 leads to synthetic lethality, suggesting future strategies by which a deeper understanding of CMG disassembly in metazoa could be exploited therapeutically.
Original languageEnglish
Pages (from-to)468-479
Number of pages11
JournalNature Cell Biology
Volume19
DOIs
Publication statusPublished - 3 Apr 2017

Keywords

  • DNA replication termination
  • replisome disassembly
  • CMG 18 helicase
  • Caenorhabditis elegans
  • Xenopus laevis
  • Cullin
  • CUL-2
  • LRR-1
  • UBXN-3
  • FAF1
  • CUL2
  • LRR1
  • CDC-48, UFD-1
  • NPL-4
  • p97
  • VCP
  • ULP-4

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