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The eukaryotic replisome is disassembled in each cell cycle, dependent upon ubiquitylation of the CMG helicase. Studies of Saccharomyces cerevisiae, Caenorhabditis elegans and Xenopus laevis have revealed surprising evolutionary diversity in the ubiquitin ligases that control CMG ubiquitylation, but regulated disassembly of the mammalian replisome has yet to be explored. Here, we describe a model system for studying the ubiquitylation and chromatin extraction of the mammalian CMG replisome, based on mouse embryonic stem cells. We show that the ubiquitin ligase CUL2 LRR1 is required for ubiquitylation of the CMG-MCM7 subunit during S-phase, leading to disassembly by the p97 ATPase. Moreover, a second pathway of CMG disassembly is activated during mitosis, dependent upon the TRAIP ubiquitin ligase that is mutated in primordial dwarfism and mis-regulated in various cancers. These findings indicate that replisome disassembly in diverse metazoa is regulated by a conserved pair of ubiquitin ligases, distinct from those present in other eukaryotes.

Titel:	CUL2 <superscript>LRR1</superscript> , TRAIP and p97 control CMG helicase disassembly in the mammalian cell cycle.
Autor/in / Beteiligte Person:	Villa, F ; Fujisawa, R ; Ainsworth, J ; Nishimura, K ; Lie-A-Ling, M ; Lacaud, G ; Labib, KP
Link:	Full Text Finder (Volltext)
Zeitschrift:	EMBO reports, Jg. 22 (2021-03-03), Heft 3, S. e52164
Veröffentlichung:	2024- : [London] : Nature Publishing Group ; <i>Original Publication</i>: Oxford, UK : Published for EMBO by Oxford University Press, 2000-, 2021
Medientyp:	academicJournal
ISSN:	1469-3178 (electronic)
DOI:	10.15252/embr.202052164
Schlagwort:	Animals Cell Cycle genetics Mice Minichromosome Maintenance Complex Component 7 genetics Minichromosome Maintenance Complex Component 7 metabolism Ubiquitination Xenopus Proteins metabolism Xenopus laevis metabolism DNA Helicases genetics DNA Helicases metabolism DNA Replication
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [EMBO Rep] 2021 Mar 03; Vol. 22 (3), pp. e52164. <i>Date of Electronic Publication: </i>2021 Feb 15. MeSH Terms: DNA Helicases* / genetics ; DNA Helicases* / metabolism ; DNA Replication* ; Animals ; Cell Cycle / genetics ; Mice ; Minichromosome Maintenance Complex Component 7 / genetics ; Minichromosome Maintenance Complex Component 7 / metabolism ; Ubiquitination ; Xenopus Proteins / metabolism ; Xenopus laevis / metabolism References: Dev Cell. 2010 Nov 16;19(5):753-64. (PMID: 21074724) ; Nat Cell Biol. 2017 May;19(5):468-479. (PMID: 28368371) ; Mol Cell. 2020 Jan 2;77(1):17-25.e5. (PMID: 31704183) ; Nature. 2009 Apr 9;458(7239):732-6. (PMID: 19360080) ; Mol Cells. 2001 Dec 31;12(3):304-12. (PMID: 11804328) ; Elife. 2020 Aug 17;9:. (PMID: 32804080) ; J Cell Biol. 2000 Apr 17;149(2):271-80. (PMID: 10769021) ; Nature. 2020 Feb;578(7795):461-466. 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(PMID: 17927961) Grant Information: 24558 United Kingdom CRUK_ Cancer Research UK; MC_UU_12016/13 United Kingdom MRC_ Medical Research Council; BB/I001794/1/BB United Kingdom BB_ Biotechnology and Biological Sciences Research Council; C578/A25669 United Kingdom CRUK_ Cancer Research UK; United Kingdom WT_ Wellcome Trust; C5759/A20971 United Kingdom CRUK_ Cancer Research UK; 102943/Z/13/Z United Kingdom WT_ Wellcome Trust; C578/A24558 United Kingdom CRUK_ Cancer Research UK; MC_UU_00018/4 United Kingdom MRC_ Medical Research Council Contributed Indexing: Keywords: CMG helicase; CUL2LRR1; DNA replication; TRAIP; p97 ATPase Substance Nomenclature: 0 (Xenopus Proteins) ; EC 3.6.4.- (DNA Helicases) ; EC 3.6.4.12 (Mcm7 protein, Xenopus) ; EC 3.6.4.12 (Minichromosome Maintenance Complex Component 7) Entry Date(s): Date Created: 20210216 Date Completed: 20210531 Latest Revision: 20230819 Update Code: 20231215 PubMed Central ID: PMC7926238

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CUL2 <superscript>LRR1</superscript> , TRAIP and p97 control CMG helicase disassembly in the mammalian cell cycle.