title: CUL-2LRR-1and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis.
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-1associates 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 CUL2LRR1as 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.
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Remi
authors.initials: R
authors.lastname: Sonneville
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Sara Priego
authors.initials: SP
authors.lastname: Moreno
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Axel
authors.initials: A
authors.lastname: Knebel
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Johnson
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: C James
authors.initials: CJ
authors.lastname: Hastie
authors.affiliation: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Anton
authors.initials: A
authors.lastname: Gartner
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Agnieszka
authors.identifier: http://orcid.org/0000-0002-4648-0332
authors.initials: A
authors.lastname: Gambus
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Karim
authors.identifier: http://orcid.org/0000-0001-8861-379X
authors.initials: K
authors.lastname: Labib
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000201:enzymology* / Q000235:genetics; D042002:Chromatin Assembly and Disassembly; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis* / Q000235:genetics; D005838:Genotype; D008938:Mitosis; D046912:Multiprotein Complexes; D009865:Oocytes; D010641:Phenotype; D034622:RNA Interference; D016196:S Phase; D013997:Time Factors; D054875:Ubiquitination; D000074405:Valosin Containing Protein; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin; D044842:Cullin Proteins; D046912:Multiprotein Complexes; C000608562:UBXN-3 protein, C elegans; D029867:Xenopus Proteins; C491027:cul-2 proteins, C elegans; D004247:DNA; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein