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J Cell Biol
2021 Aug 02;2208:. doi: 10.1083/jcb.202009147.
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LRR1-mediated replisome disassembly promotes DNA replication by recycling replisome components.
Fan Y
,
Köberlin MS
,
Ratnayeke N
,
Liu C
,
Deshpande M
,
Gerhardt J
,
Meyer T
.
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After two converging DNA replication forks meet, active replisomes are disassembled and unloaded from chromatin. A key process in replisome disassembly is the unloading of CMG helicases (CDC45-MCM-GINS), which is initiated in Caenorhabditis elegans and Xenopus laevis by the E3 ubiquitin ligase CRL2LRR1. Here, we show that human cells lacking LRR1 fail to unload CMG helicases and accumulate increasing amounts of chromatin-bound replisome components as cells progress through S phase. Markedly, we demonstrate that the failure to disassemble replisomes reduces the rate of DNA replication increasingly throughout S phase by sequestering rate-limiting replisome components on chromatin and blocking their recycling. Continued binding of CMG helicases to chromatin during G2 phase blocks mitosis by activating an ATR-mediated G2/M checkpoint. Finally, we provide evidence that LRR1 is an essential gene for human cell division, suggesting that CRL2LRR1 enzyme activity is required for the proliferation of cancer cells and is thus a potential target for cancer therapy.
Anderson,
Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis.
2015, Pubmed
Anderson,
Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis.
2015,
Pubmed
Beck,
Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption.
2012,
Pubmed
Behan,
Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens.
2019,
Pubmed
Bell,
Chromosome Duplication in Saccharomyces cerevisiae.
2016,
Pubmed
Bellelli,
Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis.
2018,
Pubmed
Bergoglio,
DNA synthesis by Pol η promotes fragile site stability by preventing under-replicated DNA in mitosis.
2013,
Pubmed
Bertolin,
Under-Replicated DNA: The Byproduct of Large Genomes?
2020,
Pubmed
Bester,
Nucleotide deficiency promotes genomic instability in early stages of cancer development.
2011,
Pubmed
Bianco,
Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner.
2019,
Pubmed
Bracken,
E2F target genes: unraveling the biology.
2004,
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
Cappell,
Irreversible APC(Cdh1) Inactivation Underlies the Point of No Return for Cell-Cycle Entry.
2016,
Pubmed
Chen,
Emerging roles of E2Fs in cancer: an exit from cell cycle control.
2009,
Pubmed
Chou,
Tipin and Timeless form a mutually protective complex required for genotoxic stress resistance and checkpoint function.
2006,
Pubmed
Chung,
Transient Hysteresis in CDK4/6 Activity Underlies Passage of the Restriction Point in G1.
2019,
Pubmed
Chèneby,
ReMap 2020: a database of regulatory regions from an integrative analysis of Human and Arabidopsis DNA-binding sequencing experiments.
2020,
Pubmed
Costa,
Mechanisms for initiating cellular DNA replication.
2013,
Pubmed
Davis,
The Encyclopedia of DNA elements (ENCODE): data portal update.
2018,
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,
Mechanisms of DNA replication termination.
2017,
Pubmed
,
Xenbase
Dewar,
The mechanism of DNA replication termination in vertebrates.
2015,
Pubmed
,
Xenbase
Dewar,
CRL2Lrr1 promotes unloading of the vertebrate replisome from chromatin during replication termination.
2017,
Pubmed
,
Xenbase
Di Micco,
Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication.
2006,
Pubmed
Dimova,
The E2F transcriptional network: old acquaintances with new faces.
2005,
Pubmed
ENCODE Project Consortium,
An integrated encyclopedia of DNA elements in the human genome.
2012,
Pubmed
Fischer,
Cell cycle transcription control: DREAM/MuvB and RB-E2F complexes.
2017,
Pubmed
Forment,
A flow cytometry-based method to simplify the analysis and quantification of protein association to chromatin in mammalian cells.
2015,
Pubmed
Fragkos,
DNA replication origin activation in space and time.
2015,
Pubmed
Franz,
CDC-48/p97 coordinates CDT-1 degradation with GINS chromatin dissociation to ensure faithful DNA replication.
2011,
Pubmed
,
Xenbase
Fujita,
In vivo interaction of human MCM heterohexameric complexes with chromatin. Possible involvement of ATP.
1997,
Pubmed
Fullbright,
p97 Promotes a Conserved Mechanism of Helicase Unloading during DNA Cross-Link Repair.
2016,
Pubmed
,
Xenbase
Gotter,
Mammalian TIMELESS and Tipin are evolutionarily conserved replication fork-associated factors.
2007,
Pubmed
Halliwell,
DNA Fiber Assay for the Analysis of DNA Replication Progression in Human Pluripotent Stem Cells.
2020,
Pubmed
Harrigan,
Replication stress induces 53BP1-containing OPT domains in G1 cells.
2011,
Pubmed
Hart,
High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities.
2015,
Pubmed
Heinz,
Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities.
2010,
Pubmed
Jagannathan,
A role for USP7 in DNA replication.
2014,
Pubmed
Jao,
Exploring RNA transcription and turnover in vivo by using click chemistry.
2008,
Pubmed
Johansson,
Replicative DNA polymerases.
2013,
Pubmed
Jones,
Increased replication initiation and conflicts with transcription underlie Cyclin E-induced replication stress.
2013,
Pubmed
Kim,
TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions.
2013,
Pubmed
Köhler,
Cdc45 is limiting for replication initiation in humans.
2016,
Pubmed
Laoukili,
FoxM1 is required for execution of the mitotic programme and chromosome stability.
2005,
Pubmed
Leman,
Local and global functions of Timeless and Tipin in replication fork protection.
2012,
Pubmed
Leman,
Human Timeless and Tipin stabilize replication forks and facilitate sister-chromatid cohesion.
2010,
Pubmed
Liao,
featureCounts: an efficient general purpose program for assigning sequence reads to genomic features.
2014,
Pubmed
Limas,
Preparation for DNA replication: the key to a successful S phase.
2019,
Pubmed
Lin,
Highly multiplexed imaging of single cells using a high-throughput cyclic immunofluorescence method.
2015,
Pubmed
Liu,
Altered G1 signaling order and commitment point in cells proliferating without CDK4/6 activity.
2020,
Pubmed
Love,
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.
2014,
Pubmed
Low,
The DNA replication fork suppresses CMG unloading from chromatin before termination.
2020,
Pubmed
,
Xenbase
Lukas,
53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress.
2011,
Pubmed
Macheret,
DNA replication stress as a hallmark of cancer.
2015,
Pubmed
Malumbres,
To cycle or not to cycle: a critical decision in cancer.
2001,
Pubmed
Maric,
Cdc48 and a ubiquitin ligase drive disassembly of the CMG helicase at the end of DNA replication.
2014,
Pubmed
Merlet,
The CRL2LRR-1 ubiquitin ligase regulates cell cycle progression during C. elegans development.
2010,
Pubmed
Meyers,
Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells.
2017,
Pubmed
Minocherhomji,
Replication stress activates DNA repair synthesis in mitosis.
2015,
Pubmed
Moreno,
Polyubiquitylation drives replisome disassembly at the termination of DNA replication.
2014,
Pubmed
,
Xenbase
Nishiyama,
MCM-BP regulates unloading of the MCM2-7 helicase in late S phase.
2011,
Pubmed
,
Xenbase
Pachlopnik Schmid,
Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome").
2012,
Pubmed
Priego Moreno,
Mitotic replisome disassembly depends on TRAIP ubiquitin ligase activity.
2019,
Pubmed
,
Xenbase
Sadasivam,
The MuvB complex sequentially recruits B-Myb and FoxM1 to promote mitotic gene expression.
2012,
Pubmed
Saldivar,
The essential kinase ATR: ensuring faithful duplication of a challenging genome.
2017,
Pubmed
Somyajit,
Redox-sensitive alteration of replisome architecture safeguards genome integrity.
2017,
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
Spencer,
The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit.
2013,
Pubmed
Spies,
53BP1 nuclear bodies enforce replication timing at under-replicated DNA to limit heritable DNA damage.
2019,
Pubmed
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
Toledo,
ATR prohibits replication catastrophe by preventing global exhaustion of RPA.
2013,
Pubmed
Villa,
CUL2LRR1 , 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
Wang,
PTPN14 is required for the density-dependent control of YAP1.
2012,
Pubmed
Wang,
Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase.
2005,
Pubmed
Wong,
Cdc45 limits replicon usage from a low density of preRCs in mammalian cells.
2011,
Pubmed
Zhou,
Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083).
2015,
Pubmed
van den Boom,
VCP/p97-Mediated Unfolding as a Principle in Protein Homeostasis and Signaling.
2018,
Pubmed
