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Nat Cell Biol May 1, 2017; 19 (5): 468-479.
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CUL-2LRR-1 and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis.

Sonneville R , Moreno SP , Knebel A , Johnson C , Hastie CJ , Gartner A , Gambus A , Labib K .

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.

PubMed ID: 28368371
PMC ID: PMC5410169
Article link: Nat Cell Biol
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: cul2 eif4g2 faf1 gins1 gmnn h2bc21 lrr1 mcm10 mcm7 mmut npl rbx1 sfpq znrd2

Article Images: [+] show captions
References [+] :
Avci, Clipping or Extracting: Two Ways to Membrane Protein Degradation. 2015, Pubmed