Mitotic Exit in the Absence of Separase Activity

doi:10.1091/MBC.E08-10-1042

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Mitotic Exit in the Absence of Separase Activity

Journal Article•DOI•

Mitotic Exit in the Absence of Separase Activity

Ying Lu¹, Frederick R. Cross¹•Institutions (1)

Rockefeller University¹

01 Mar 2009-Molecular Biology of the Cell (American Society for Cell Biology)-Vol. 20, Iss: 5, pp 1576-1591

TL;DR: The first quantitative measure for Cdc14 release based on colocalization with the Net1 nucleolar anchor is defined, indicating efficient CDC14 release upon MEN activation; release driven by Esp1 in the absence of microtubules was inefficient and incapable of driving ME.

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Abstract: In budding yeast, three interdigitated pathways regulate mitotic exit (ME): mitotic cyclin–cyclin-dependent kinase (Cdk) inactivation; the Cdc14 early anaphase release (FEAR) network, including a n...

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Journal Article•DOI•

Phosphatases: providing safe passage through mitotic exit

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Claudia Wurzenberger¹, Daniel W. Gerlich¹•Institutions (1)

ETH Zurich¹

01 Aug 2011-Nature Reviews Molecular Cell Biology

TL;DR: This work has shown that the key mitotic exit phosphatase in budding yeast, Cdc14, is now well understood, and in animal cells, it is now emerging that mitoticexit relies on distinct regulatory networks, including the protein phosphatases PP1 and PP2A.

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Abstract: The mitosis-to-interphase transition involves dramatic cellular reorganization from a state that supports chromosome segregation to a state that complies with all functions of an interphase cell. This process, termed mitotic exit, depends on the removal of mitotic phosphorylations from a broad range of substrates. Mitotic exit regulation involves inactivation of mitotic kinases and activation of counteracting protein phosphatases. The key mitotic exit phosphatase in budding yeast, Cdc14, is now well understood. By contrast, in animal cells, it is now emerging that mitotic exit relies on distinct regulatory networks, including the protein phosphatases PP1 and PP2A.

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294 citations

Journal Article•DOI•

Periodic cyclin-Cdk activity entrains an autonomous Cdc14 release oscillator.

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Ying Lu¹, Frederick R. Cross¹•Institutions (1)

Rockefeller University¹

16 Apr 2010-Cell

TL;DR: An intrinsically oscillatory module controlling nucleolar release and resequestration of the Cdc14 phosphatase is demonstrated, which is essential for mitotic exit in budding yeast and suggests that the intrinsically autonomous CDC14 release cycles are locked at once-per-cell-cycle through entrainment by the Cdk oscillator in wild-type cells.

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97 citations

Cites methods from "Mitotic Exit in the Absence of Sepa..."

...Cdc14 release was quantified as the coefficient of variation (CV, standard deviation divided by mean) of Cdc14-YFP pixel intensities (mother and bud treated separately), divided by the Net1-mCherry CV....
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...We determined the response of the Cdc14 release cycle to fixed cyclin-Cdk levels (Drapkin et al., 2009), using a quantitative, single cell measurement for Cdc14 localization based on variation of cellular Cdc14-YFP pixel intensities, standardized to variation of nucleolar Net1-mCherry (Lu and Cross, 2009) (Experimental Procedures; Figure 1A)....
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...…cycle to fixed cyclin-Cdk levels (Drapkin et al., 2009), using a quantitative, single cell measurement for Cdc14 localization based on variation of cellular Cdc14-YFP pixel intensities, standardized to variation of nucleolar Net1-mCherry (Lu and Cross, 2009) (Experimental Procedures; Figure 1A)....
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..., 2009), using a quantitative, single cell measurement for Cdc14 localization based on variation of cellular Cdc14-YFP pixel intensities, standardized to variation of nucleolar Net1-mCherry (Lu and Cross, 2009) (Experimental Procedures; Figure 1A)....
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Journal Article•DOI•

Inhibition of Cdc42 during mitotic exit is required for cytokinesis

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Benjamin D. Atkins¹, Satoshi Yoshida², Satoshi Yoshida¹, Koji Saito³, Chi-Fang Wu³, Daniel J. Lew³, David Pellman¹, David Pellman⁴ - Show less +4 more•Institutions (4)

Harvard University¹, Brandeis University², Duke University³, Howard Hughes Medical Institute⁴

22 Jul 2013-Journal of Cell Biology

TL;DR: A decrease in Cdc42 activation during mitotic exit is necessary to allow localization of key cytokinesis regulators and proper septum formation.

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Abstract: The role of Cdc42 and its regulation during cytokinesis is not well understood. Using biochemical and imaging approaches in budding yeast, we demonstrate that Cdc42 activation peaks during the G1/S transition and during anaphase but drops during mitotic exit and cytokinesis. Cdc5/Polo kinase is an important upstream cell cycle regulator that suppresses Cdc42 activity. Failure to down-regulate Cdc42 during mitotic exit impairs the normal localization of key cytokinesis regulators-Iqg1 and Inn1-at the division site, and results in an abnormal septum. The effects of Cdc42 hyperactivation are largely mediated by the Cdc42 effector p21-activated kinase Ste20. Inhibition of Cdc42 and related Rho guanosine triphosphatases may be a general feature of cytokinesis in eukaryotes.

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79 citations

Journal Article•DOI•

Global analysis of Cdc14 phosphatase reveals diverse roles in mitotic processes.

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Joanna Bloom¹, Joanna Bloom², Ileana M. Cristea², Andrea L. Procko², Veronica Lubkov², Brian T. Chait², Michael Snyder¹, Frederick R. Cross² - Show less +4 more•Institutions (2)

Yale University¹, Rockefeller University²

18 Feb 2011-Journal of Biological Chemistry

TL;DR: The findings suggest the dephosphorylation of the formins may be important for their observed localization change during exit from mitosis and indicate that Cdc14 targets proteins involved in wide-ranging mitotic events.

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79 citations

Journal Article•DOI•

From START to FINISH: computational analysis of cell cycle control in budding yeast.

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Pavel Kraikivski¹, Katherine C. Chen¹, Teeraphan Laomettachit², T. M. Murali¹, John J. Tyson¹ - Show less +1 more•Institutions (2)

Virginia Tech¹, King Mongkut's University of Technology Thonburi²

10 Dec 2015

TL;DR: This work crafted a new mathematical model of cell cycle progression in yeast that exploits a natural separation of time scales in the cell cycle control network to construct a system of differential-algebraic equations for protein synthesis and degradation, post-translational modifications, and rapid formation and dissociation of multimeric complexes.

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Abstract: In the cell division cycle of budding yeast, START refers to a set of tightly linked events that prepare a cell for budding and DNA replication, and FINISH denotes the interrelated events by which the cell exits from mitosis and divides into mother and daughter cells. On the basis of recent progress made by molecular biologists in characterizing the genes and proteins that control START and FINISH, we crafted a new mathematical model of cell cycle progression in yeast. Our model exploits a natural separation of time scales in the cell cycle control network to construct a system of differential-algebraic equations for protein synthesis and degradation, post-translational modifications, and rapid formation and dissociation of multimeric complexes. The model provides a unified account of the observed phenotypes of 257 mutant yeast strains (98% of the 263 strains in the data set used to constrain the model). We then use the model to predict the phenotypes of 30 novel combinations of mutant alleles. Our comprehensive model of the molecular events controlling cell cycle progression in budding yeast has both explanatory and predictive power. Future experimental tests of the model's predictions will be useful to refine the underlying molecular mechanism, to constrain the adjustable parameters of the model, and to provide new insights into how the cell division cycle is regulated in budding yeast.

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69 citations

Additional excerpts

...In this case, anaphase proceeds normally, activating the MEN while the FEAR pathway remains blocked.(42) In agreement with Lu and Cross,(42) our simulations (Figure 3) show that MEN activity is absolutely needed for mitotic exit, and FEAR is dispensable....
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Journal Article•DOI•

A Mechanism for Coupling Exit from Mitosis to Partitioning of the Nucleus

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Allison J. Bardin¹, Rosella Visintin¹, Angelika Amon¹•Institutions (1)

Massachusetts Institute of Technology¹

07 Jul 2000-Cell

TL;DR: The results suggest that the spatial segregation of Tem1 and Lte1 ensures that exit from mitosis only occurs after the genetic material is partitioned between mother and daughter cell.

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340 citations

"Mitotic Exit in the Absence of Sepa..." refers background or result in this paper

...The experiments in Figures 4 and 6 allow us to propose a model for efficient induction of ME by ESP1 overexpression in cdc20-blocked cells: the overexpressed Esp1 cleaves cohesin and allows spindle elongation, prompting MEN activation when the daughter spindle pole approaches the bud cortex (Yeh et al., 1995; Bardin et al., 2000; Molk et al., 2004)....
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...…the finding that both Cdc14 release and ME (assessed by spindle disassembly) in the dyn1 mutant coincide with SPB moving into the bud, rather than spindle elongation per se (implying separase activation), which frequently happens within the mother cell body in this mutant (Bardin et al., 2000)....
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...Spindle elongation could promote ME by driving the daughter spindle pole into proximity to the bud cortex, activating the MEN (Yeh et al., 1995; Bardin et al., 2000; Molk et al., 2004; Stegmeier and Amon, 2004)....
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...This oscillatory movement could potentially activate the MEN by allowing one SPB to contact Lte1 near the bud cortex (Bardin et al., 2000)....
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...…a model for efficient induction of ME by ESP1 overexpression in cdc20-blocked cells: the overexpressed Esp1 cleaves cohesin and allows spindle elongation, prompting MEN activation when the daughter spindle pole approaches the bud cortex (Yeh et al., 1995; Bardin et al., 2000; Molk et al., 2004)....
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Journal Article•DOI•

A Late Mitotic Regulatory Network Controlling Cyclin Destruction in Saccharomyces cerevisiae

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Sue L. Jaspersen¹, Julia F. Charles¹, Rachel L. Tinker-Kulberg¹, David O. Morgan¹•Institutions (1)

University of California, San Francisco¹

01 Oct 1998-Molecular Biology of the Cell

TL;DR: It is concluded that Cdc15, CDC5, Cdc5, cdc14, Dbf2, and Tem1 cooperate in the activation of the APC in late mitosis but are not required for maintenance of that activity in G1, which contains normal APC activity.

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Abstract: Exit from mitosis requires the inactivation of mitotic cyclin-dependent kinase‐ cyclin complexes, primarily by ubiquitin-dependent cyclin proteolysis. Cyclin destruction is regulated by a ubiquitin ligase known as the anaphase-promoting complex (APC). In the budding yeast Saccharomyces cerevisiae, members of a large class of late mitotic mutants, including cdc15, cdc5, cdc14, dbf2, and tem1, arrest in anaphase with a phenotype similar to that of cells expressing nondegradable forms of mitotic cyclins. We addressed the possibility that the products of these genes are components of a regulatory network that governs cyclin proteolysis. We identified a complex array of genetic interactions among these mutants and found that the growth defect in most of the mutants is suppressed by overexpression of SPO12, YAK1, and SIC1 and is exacerbated by overproduction of the mitotic cyclin Clb2. When arrested in late mitosis, the mutants exhibit a defect in cyclin-specific APC activity that is accompanied by high Clb2 levels and low levels of the anaphase inhibitor Pds1. Mutant cells arrested in G1 contain normal APC activity. We conclude that Cdc15, Cdc5, Cdc14, Dbf2, and Tem1 cooperate in the activation of the APC in late mitosis but are not required for maintenance of that activity in G1.

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333 citations

"Mitotic Exit in the Absence of Sepa..." refers background in this paper

...Cdh1 is likely activated by MEN-released Cdc14 (Jaspersen et al., 1998; Visintin et al., 1998), and Cdc14 also promotes ME via accumulation of the Sic1 Cdk inhibitor (Visintin et al., 1998)....
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...Cdh1 is likely activated by MEN-released Cdc14 (Jaspersen et al., 1998; Visintin et al., 1998), and Cdc14 also promotes ME via accumulation of the Sic1 Cdk inhibitor (Visintin et al....
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Journal Article•DOI•

Nuclear export of 60s ribosomal subunits depends on Xpo1p and requires a nuclear export sequence-containing factor, Nmd3p, that associates with the large subunit protein Rpl10p.

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Olivier Gadal, Daniela Strauß, Jacques J. Kessl¹, Bernard L. Trumpower¹, David Tollervey², Ed Hurt - Show less +2 more•Institutions (2)

Dartmouth College¹, University of Edinburgh²

15 May 2001-Molecular and Cellular Biology

TL;DR: It is concluded that nuclear export of 60S subunits requires the nuclear export sequence-containing nonribosomal protein Nmd3p, which directly binds to the large subunit protein Rpl10p.

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Abstract: Nuclear export of ribosomes requires a subset of nucleoporins and the Ran system, but specific transport factors have not been identified. Using a large subunit reporter (Rpl25p-eGFP), we have isolated several temperature-sensitive ribosomal export (rix) mutants. One of these corresponds to the ribosomal protein Rpl10p, which interacts directly with Nmd3p, a conserved and essential protein associated with 60S subunits. We find that thermosensitive nmd3 mutants are impaired in large subunit export. Strikingly, Nmd3p shuttles between the nucleus and cytoplasm and is exported by the nuclear export receptor Xpo1p. Moreover, we show that export of 60S subunits is Xpo1p dependent. We conclude that nuclear export of 60S subunits requires the nuclear export sequence-containing nonribosomal protein Nmd3p, which directly binds to the large subunit protein Rpl10p.

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316 citations

"Mitotic Exit in the Absence of Sepa..." refers background in this paper

...To examine the possibility that this result is due to residual binding of Cdc14 to other nucleolar components, we examined colocalization of Cdc14-YFP with DNA, with the nucleolar marker Nop1-dsRed (Gadal et al., 2001), and with a general marker of nuclear volume, dsRed-NLS (Rodrigues et al., 2001)....
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...To examine the possibility that this result is due to residual binding of Cdc14 to other nucleolar components, we examined colocalization of Cdc14-YFP with DNA, with the nucleolar marker Nop1-dsRed (Gadal et al., 2001), and with a general marker of nuclear volume, dsRed-NLS (Rodrigues et al....
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Journal Article•DOI•

Characterization of four B-type cyclin genes of the budding yeast Saccharomyces cerevisiae.

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I. Fitch¹, Christian Dahmann¹, Uttam Surana¹, Angelika Amon¹, Kim Nasmyth¹, L Goetsch¹, B Byers¹, Bruce Futcher¹ - Show less +4 more•Institutions (1)

Cold Spring Harbor Laboratory¹

01 Jul 1992-Molecular Biology of the Cell

TL;DR: The sequences of another related pair of B-type cyclin genes, which are term CLB3 and CLB4, are presented and it is suggested that the two groups of Clbs may have distinct roles in spindle formation and elongation.

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Abstract: The previously described CLB1 and CLB2 genes encode a closely related pair of B-type cyclins. Here we present the sequences of another related pair of B-type cyclin genes, which we term CLB3 and CLB4. Although CLB1 and CLB2 mRNAs rise in abundance at the time of nuclear division, CLB3 and CLB4 are turned on earlier, rising early in S phase and declining near the end of nuclear division. When all possible single and multiple deletion mutants were constructed, some multiple mutations were lethal, whereas all single mutants were viable. All lethal combinations included the clb2 deletion, whereas the clb1 clb3 clb4 triple mutant was viable, suggesting a key role for CLB2. The inviable multiple clb mutants appeared to have a defect in mitosis. Conditional clb mutants arrested as large budded cells with a G2 DNA content but without any mitotic spindle. Electron microscopy showed that the spindle pole bodies had duplicated but not separated, and no spindle had formed. This suggests that the Clb/Cdc28 kinase may have a relatively direct role in spindle formation. The two groups of Clbs may have distinct roles in spindle formation and elongation.

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310 citations

"Mitotic Exit in the Absence of Sepa..." refers background in this paper

...Initiation of mitosis requires a combination of B-type cyclindependent kinase (Cdk) activity promoting various mitotic events, including spindle morphogenesis and function (Fitch et al., 1992; Rahal and Amon, 2008)....
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Journal Article•DOI•

Cdc14 and condensin control the dissolution of cohesin-independent chromosome linkages at repeated DNA.

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Damien D’Amours¹, Frank Stegmeier¹, Angelika Amon¹•Institutions (1)

Massachusetts Institute of Technology¹

14 May 2004-Cell

TL;DR: It is proposed that Cdc14 released by the FEAR network mediates the partitioning of rDNA by facilitating the localization of condensin thereto and ensures that exit from mitosis is coupled to the completion of chromosome segregation.

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294 citations

"Mitotic Exit in the Absence of Sepa..." refers background in this paper

...Despite our conclusion that nonproteolytic functions of Esp1 do not make a major contribution to ME kinetics, it is clear that Esp1 does have nonproteolytic biological activity (D’Amours et al., 2004; Ross and Cohen-Fix, 2004)....
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...Esp1-induced Cdc14 Release May Function Primarily in Mitotic Progression Esp1 in combination with the FEAR pathway has the ability to promote Cdc14 release independent of cohesin cleavage (Stegmeier et al., 2002; Sullivan and Uhlmann, 2003; D’Amours et al., 2004; Ross and Cohen-Fix, 2004)....
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...Esp1 in combination with the FEAR pathway has the ability to promote Cdc14 release independent of cohesin cleavage (Stegmeier et al., 2002; Sullivan and Uhlmann, 2003; D’Amours et al., 2004; Ross and Cohen-Fix, 2004)....
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...FEAR-released Cdc14 modulates nuclear movement, rDNA segregation and spindle stability; these functions may facilitate mitotic progression before ME (Azzam et al., 2004; D’Amours et al., 2004; Ross and CohenFix, 2004; Sullivan et al., 2004; Higuchi and Uhlmann, 2005)....
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