RRC ID 51356
Author Sonneville R, Moreno SP, Knebel A, Johnson C, Hastie CJ, Gartner A, Gambus A, Labib K.
Title CUL-2LRR-1 and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis.
Journal Nat Cell Biol
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 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.
Volume 19(5)
Pages 468-479
Published 2017-5-1
DOI 10.1038/ncb3500
PII ncb3500
PMID 28368371
PMC PMC5410169
MeSH Adenosine Triphosphatases / genetics Adenosine Triphosphatases / metabolism Animals Animals, Genetically Modified Caenorhabditis elegans / enzymology* Caenorhabditis elegans / genetics Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Carrier Proteins / genetics Carrier Proteins / metabolism* Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism Chromatin / enzymology* Chromatin / genetics Chromatin Assembly and Disassembly Cullin Proteins / genetics Cullin Proteins / metabolism* DNA / biosynthesis* DNA / genetics Genotype Mitosis* Multiprotein Complexes Oocytes Phenotype RNA Interference S Phase* Time Factors Ubiquitination Valosin Containing Protein Xenopus Proteins / genetics Xenopus Proteins / metabolism Xenopus laevis / genetics Xenopus laevis / metabolism
IF 20.042
Times Cited 23
C.elegans tm3543