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The eukaryotic replisome assembles around the CMG helicase, which stably associates with DNA replication forks throughout elongation. When replication terminates, CMG is ubiquitylated on its Mcm7 subunit and disassembled by the Cdc48/p97 ATPase. Until now, the regulation that restricts CMG ubiquitylation to termination was unknown, as was the mechanism of disassembly. By reconstituting these processes with purified budding yeast proteins, we show that ubiquitylation is tightly repressed throughout elongation by the Y-shaped DNA structure of replication forks. Termination removes the repressive DNA structure, whereupon long K48-linked ubiquitin chains are conjugated to CMG-Mcm7, dependent on multiple replisome components that bind to the ubiquitin ligase SCF Dia2 . This mechanism pushes CMG beyond a '5-ubiquitin threshold' that is inherent to Cdc48, which specifically unfolds ubiquitylated Mcm7 and thereby disassembles CMG. These findings explain the exquisite regulation of CMG disassembly and provide a general model for the disassembly of ubiquitylated protein complexes by Cdc48.

Competing Interests: TD, PM, RF, CP, KL No competing interests declared

Titel:	CMG helicase disassembly is controlled by replication fork DNA, replisome components and a ubiquitin threshold.
Autor/in / Beteiligte Person:	Deegan, TD ; Mukherjee, PP ; Fujisawa, R ; Polo Rivera, C ; Labib, K
Link:	Full Text Finder (Volltext)
Zeitschrift:	ELife, Jg. 9 (2020-08-17)
Veröffentlichung:	Cambridge, UK : eLife Sciences Publications, Ltd., 2012-, 2020
Medientyp:	academicJournal
ISSN:	2050-084X (electronic)
DOI:	10.7554/eLife.60371
Schlagwort:	Escherichia coli Humans Nucleic Acid Conformation Recombinant Proteins chemistry Recombinant Proteins metabolism Valosin Containing Protein chemistry Valosin Containing Protein metabolism DNA chemistry DNA metabolism DNA Helicases chemistry DNA Helicases metabolism DNA Replication Ubiquitin chemistry Ubiquitin metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Elife] 2020 Aug 17; Vol. 9. <i>Date of Electronic Publication: </i>2020 Aug 17. MeSH Terms: DNA* / chemistry ; DNA* / metabolism ; DNA Helicases* / chemistry ; DNA Helicases* / metabolism ; DNA Replication* ; Ubiquitin* / chemistry ; Ubiquitin* / metabolism ; Escherichia coli ; Humans ; Nucleic Acid Conformation ; Recombinant Proteins / chemistry ; Recombinant Proteins / metabolism ; Valosin Containing Protein / chemistry ; Valosin Containing Protein / metabolism References: Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):E697-E706. (PMID: 28096349) ; Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20240-5. (PMID: 19910535) ; Cell. 1997 Oct 3;91(1):59-69. (PMID: 9335335) ; Nature. 2015 Mar 26;519(7544):431-5. (PMID: 25739503) ; Science. 2014 Oct 24;346(6208):477-81. (PMID: 25342805) ; Mol Cell. 2018 Jan 18;69(2):182-194. 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(PMID: 28235849) Grant Information: 24558 United Kingdom CRUK_ Cancer Research UK; MC_UU_12016/13 United Kingdom MRC_ Medical Research Council; C578/A25669 United Kingdom CRUK_ Cancer Research UK; 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; DNA replication; S. cerevisiae; chromosomes; gene expression; termination Substance Nomenclature: 0 (Recombinant Proteins) ; 0 (Ubiquitin) ; 9007-49-2 (DNA) ; EC 3.6.4.- (DNA Helicases) ; EC 3.6.4.6 (Valosin Containing Protein) Entry Date(s): Date Created: 20200818 Date Completed: 20210225 Latest Revision: 20240313 Update Code: 20240313 PubMed Central ID: PMC7462611

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CMG helicase disassembly is controlled by replication fork DNA, replisome components and a ubiquitin threshold.