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

Research output: Contribution to journalArticlepeer-review

Authors

  • Remi Sonnerville
  • Axel Knebel
  • Clare Johnson
  • C. James Hastle
  • Anton Gartner
  • Karim Labib

Colleges, School and Institutes

External organisations

  • University of Dundee

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 approaches by which a deeper understanding of CMG disassembly in metazoa could be exploited therapeutically.

Details

Original languageEnglish
Pages (from-to)468–479
JournalNature Cell Biology
Volume19
Early online date3 Apr 2017
Publication statusPublished - May 2017

Keywords

  • DNA replication termination , replisome disassembly , CMG 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