Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
EMBO Rep
2021 Mar 03;223:e52164. doi: 10.15252/embr.202052164.
Show Gene links
Show Anatomy links
CUL2LRR1 , TRAIP and p97 control CMG helicase disassembly in the mammalian cell cycle.
Villa F
,
Fujisawa R
,
Ainsworth J
,
Nishimura K
,
Lie-A-Ling M
,
Lacaud G
,
Labib KP
.
???displayArticle.abstract???
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 CUL2LRR1 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.
C578/A25669 Cancer Research UK (CRUK), JP20K21423 MEXT | Japan Society for the Promotion of Science (JSPS), MC_UU_12016/13 UKRI | Medical Research Council (MRC), BB/I001794/1/BB Biotechnology and Biological Sciences Research Council , MC_UU_00018/4 Medical Research Council , JP19K06611 MEXT | Japan Society for the Promotion of Science (JSPS), Wellcome Trust , C5759/A20971 Cancer Research UK (CRUK), Naito Foundation (), C578/A24558 Cancer Research UK (CRUK), 102943/Z/13/Z Wellcome Trust (WT), C578/A25669 Cancer Research UK, MC_UU_12016/13 Medical Research Council , C5759/A20971 Cancer Research UK, C578/A24558 Cancer Research UK, 102943/Z/13/Z Wellcome Trust
Al Mamun,
Inevitability and containment of replication errors for eukaryotic genome lengths spanning megabase to gigabase.
2016, Pubmed
Al Mamun,
Inevitability and containment of replication errors for eukaryotic genome lengths spanning megabase to gigabase.
2016,
Pubmed
Anderson,
Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis.
2015,
Pubmed
Baek,
NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly.
2020,
Pubmed
Bai,
Architecture of the Saccharomyces cerevisiae Replisome.
2017,
Pubmed
Bell,
Chromosome Duplication in Saccharomyces cerevisiae.
2016,
Pubmed
Bhowmick,
RAD52 Facilitates Mitotic DNA Synthesis Following Replication Stress.
2016,
Pubmed
Bravo,
Existence of two populations of cyclin/proliferating cell nuclear antigen during the cell cycle: association with DNA replication sites.
1987,
Pubmed
Burdon,
Signalling, cell cycle and pluripotency in embryonic stem cells.
2002,
Pubmed
Burger,
CRL2(LRR-1) E3-ligase regulates proliferation and progression through meiosis in the Caenorhabditis elegans germline.
2013,
Pubmed
Burgers,
Eukaryotic DNA Replication Fork.
2017,
Pubmed
Chapard,
TRAIP is a regulator of the spindle assembly checkpoint.
2014,
Pubmed
Deegan,
CMG helicase disassembly is controlled by replication fork DNA, replisome components and a ubiquitin threshold.
2020,
Pubmed
Deng,
Mitotic CDK Promotes Replisome Disassembly, Fork Breakage, and Complex DNA Rearrangements.
2019,
Pubmed
,
Xenbase
Dewar,
CRL2Lrr1 promotes unloading of the vertebrate replisome from chromatin during replication termination.
2017,
Pubmed
,
Xenbase
Dewar,
The mechanism of DNA replication termination in vertebrates.
2015,
Pubmed
,
Xenbase
Douglas,
The mechanism of eukaryotic CMG helicase activation.
2018,
Pubmed
Ekkebus,
On terminal alkynes that can react with active-site cysteine nucleophiles in proteases.
2013,
Pubmed
Essers,
Nuclear dynamics of PCNA in DNA replication and repair.
2005,
Pubmed
Evrin,
A double-hexameric MCM2-7 complex is loaded onto origin DNA during licensing of eukaryotic DNA replication.
2009,
Pubmed
,
Xenbase
Fu,
Selective bypass of a lagging strand roadblock by the eukaryotic replicative DNA helicase.
2011,
Pubmed
,
Xenbase
Gambus,
GINS maintains association of Cdc45 with MCM in replisome progression complexes at eukaryotic DNA replication forks.
2006,
Pubmed
Gambus,
MCM2-7 form double hexamers at licensed origins in Xenopus egg extract.
2011,
Pubmed
,
Xenbase
Gambus,
A key role for Ctf4 in coupling the MCM2-7 helicase to DNA polymerase alpha within the eukaryotic replisome.
2009,
Pubmed
Gasser,
Once and Only Once.
2019,
Pubmed
Glover,
Fragile sites in cancer: more than meets the eye.
2017,
Pubmed
Han,
TRAIP regulates Histone H2B monoubiquitination in DNA damage response pathways.
2019,
Pubmed
Harley,
TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.
2016,
Pubmed
Hills,
DNA replication and oncogene-induced replicative stress.
2014,
Pubmed
Hoffmann,
TRAIP is a PCNA-binding ubiquitin ligase that protects genome stability after replication stress.
2016,
Pubmed
Jang,
A novel leucine-rich repeat protein (LRR-1): potential involvement in 4-1BB-mediated signal transduction.
2001,
Pubmed
Kamura,
VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases.
2004,
Pubmed
Kurat,
Chromatin Controls DNA Replication Origin Selection, Lagging-Strand Synthesis, and Replication Fork Rates.
2017,
Pubmed
Leonhardt,
Dynamics of DNA replication factories in living cells.
2000,
Pubmed
Lewis,
Tunability of DNA Polymerase Stability during Eukaryotic DNA Replication.
2020,
Pubmed
Li,
Cooperation of the NEIL3 and Fanconi anemia/BRCA pathways in interstrand crosslink repair.
2020,
Pubmed
,
Xenbase
Maric,
Cdc48 and a ubiquitin ligase drive disassembly of the CMG helicase at the end of DNA replication.
2014,
Pubmed
Maric,
Ufd1-Npl4 Recruit Cdc48 for Disassembly of Ubiquitylated CMG Helicase at the End of Chromosome Replication.
2017,
Pubmed
Matson,
Rapid DNA replication origin licensing protects stem cell pluripotency.
2017,
Pubmed
Merlet,
The CRL2LRR-1 ubiquitin ligase regulates cell cycle progression during C. elegans development.
2010,
Pubmed
Moreno,
Unreplicated DNA remaining from unperturbed S phases passes through mitosis for resolution in daughter cells.
2016,
Pubmed
Moreno,
Polyubiquitylation drives replisome disassembly at the termination of DNA replication.
2014,
Pubmed
,
Xenbase
Moyer,
Isolation of the Cdc45/Mcm2-7/GINS (CMG) complex, a candidate for the eukaryotic DNA replication fork helicase.
2006,
Pubmed
Mukherjee,
In Vitro Reconstitution Defines the Minimal Requirements for Cdc48-Dependent Disassembly of the CMG Helicase in Budding Yeast.
2019,
Pubmed
Park,
Early embryonic lethality caused by targeted disruption of the TRAF-interacting protein (TRIP) gene.
2007,
Pubmed
Pellegrini,
New Insights into the Mechanism of DNA Duplication by the Eukaryotic Replisome.
2016,
Pubmed
Priego Moreno,
Mitotic replisome disassembly depends on TRAIP ubiquitin ligase activity.
2019,
Pubmed
,
Xenbase
Pyzocha,
RNA-guided genome editing of mammalian cells.
2014,
Pubmed
Remus,
Concerted loading of Mcm2-7 double hexamers around DNA during DNA replication origin licensing.
2009,
Pubmed
Saksouk,
Constitutive heterochromatin formation and transcription in mammals.
2015,
Pubmed
Sarkar,
Designing active RNF4 monomers by introducing a tryptophan: avidity towards E2∼Ub conjugates dictates the activity of ubiquitin RING E3 ligases.
2019,
Pubmed
Sengupta,
Dpb2 integrates the leading-strand DNA polymerase into the eukaryotic replisome.
2013,
Pubmed
Shibahara,
Replication-dependent marking of DNA by PCNA facilitates CAF-1-coupled inheritance of chromatin.
1999,
Pubmed
Sonneville,
CUL-2LRR-1 and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis.
2017,
Pubmed
,
Xenbase
Sonneville,
TRAIP drives replisome disassembly and mitotic DNA repair synthesis at sites of incomplete DNA replication.
2019,
Pubmed
Soo Lee,
TRAIP/RNF206 is required for recruitment of RAP80 to sites of DNA damage.
2016,
Pubmed
Soucy,
An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer.
2009,
Pubmed
Sparks,
The CMG Helicase Bypasses DNA-Protein Cross-Links to Facilitate Their Repair.
2019,
Pubmed
,
Xenbase
Starostina,
CRL2(LRR-1) targets a CDK inhibitor for cell cycle control in C. elegans and actin-based motility regulation in human cells.
2010,
Pubmed
Ter Huurne,
Distinct Cell-Cycle Control in Two Different States of Mouse Pluripotency.
2017,
Pubmed
Villa,
CUL2<sup>LRR1</sup> , TRAIP and p97 control CMG helicase disassembly in the mammalian cell cycle.
2021,
Pubmed
,
Xenbase
Vrtis,
Single-strand DNA breaks cause replisome disassembly.
2021,
Pubmed
,
Xenbase
Wallace,
TRIP/NOPO E3 ubiquitin ligase promotes ubiquitylation of DNA polymerase η.
2014,
Pubmed
Wu,
TRAIP is a master regulator of DNA interstrand crosslink repair.
2019,
Pubmed
,
Xenbase
Zegerman,
Evolutionary conservation of the CDK targets in eukaryotic DNA replication initiation.
2015,
Pubmed
