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•

Cdc14 activates Cdc15 to promote mitotic exit in budding yeast

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Sue L. Jaspersen¹, David O. Morgan¹•Institutions (1)

University of California, San Francisco¹

15 May 2000-Current Biology

TL;DR: It is shown that the ability of Cdc15 to promote mitotic exit is inhibited by phosphorylation, and this scheme raises the possibility that positive feedback promotes Cdc14 activation, but presents evidence that such feedback is not essential for CDC14 activation in vivo.

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170 citations

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

...…was shown to induce Cdc15 phosphorylation and lower Dbf2 kinase activity, and these reactions could have the potential to impair Cdc14 release (Jaspersen and Morgan, 2000; Menssen et al., 2001; Stegmeier et al., 2002); conversely, Clb-Cdk was proposed to phosphorylate Net1, facilitating FEAR…...
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...…Net1, contributing to early release of Cdc14 (Azzam et al., 2004); in addition, the MEN may be inhibited by Clb-Cdk, at least at very high levels (Jaspersen and Morgan, 2000; Stegmeier et al., 2002), and Cdc14 released by the MEN promotes Clb– Cdk inactivation (Stegmeier and Amon, 2004)....
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...Cdc15 may be phosphorylated by cyclin (Clb)-Cdk, potentially leading to inhibition of the MEN (Jaspersen and Morgan, 2000); despite this, high Clb-Cdk does not block Cdc14 release from the nucleolus (Stegmeier et al., 2002)....
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...Cdc15 may be phosphorylated by cyclin (Clb)-Cdk, potentially leading to inhibition of the MEN (Jaspersen and Morgan, 2000); despite this, high Clb-Cdk does not block Cdc14 release from the nucleolus (Stegmeier et al....
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...A high level of Cdk activity was shown to induce Cdc15 phosphorylation and lower Dbf2 kinase activity, and these reactions could have the potential to impair Cdc14 release (Jaspersen and Morgan, 2000; Menssen et al., 2001; Stegmeier et al., 2002); conversely, Clb-Cdk was proposed to phosphorylate Net1, facilitating FEAR network activity (Azzam et al....
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Journal Article•DOI•

Cdc20 is essential for the cyclosome-mediated proteolysis of both Pds1 and Clb2 during M phase in budding yeast.

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Hong Hwa Lim¹, Phuay-Yee Goh¹, Uttam Surana¹•Institutions (1)

Institute of Molecular and Cell Biology¹

12 Feb 1998-Current Biology

TL;DR: Evidence is presented that in the absence of CDC20, cells are unable to degrade either Pds1 at the onset of anaphase or the mitotic cyclin Clb2 during telophase, consistent with observations that Cdc20 is localized in the nucleus and co-immunoprecipitates with an APC component, Cdc23.

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163 citations

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

...This result confirms and extends previous findings that the Cdc20 requirement for sister chromatid separation can be bypassed by PDS1 deletion (Yamamoto et al., 1996; Lim et al., 1998; Shirayama et al., 1999)....
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Journal Article•DOI•

Cdc14-regulated midzone assembly controls anaphase B

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Anton Khmelinskii¹, Clare Louise Lawrence, Johanna Roostalu¹, Elmar Schiebel¹•Institutions (1)

Heidelberg University¹

18 Jun 2007-Journal of Cell Biology

TL;DR: It is shown that Ase1 and the separase–Slk19 complex drive midzone assembly in yeast and that Cdc14 regulates spindle midzoneAssembly and function directly through Ase 1 and indirectly via the separases–SlK19 complex.

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Abstract: Spindle elongation in anaphase of mitosis is a cell cycle–regulated process that requires coordination between polymerization, cross-linking, and sliding of microtubules (MTs). Proteins that assemble at the spindle midzone may be important for this process. In this study, we show that Ase1 and the separase–Slk19 complex drive midzone assembly in yeast. Whereas the conserved MT-bundling protein Ase1 establishes a midzone, separase–Slk19 is required to focus and center midzone components. An important step leading to spindle midzone assembly is the dephosphorylation of Ase1 by the protein phosphatase Cdc14 at the beginning of anaphase. Failure to dephosphorylate Ase1 delocalizes midzone proteins and delays the second, slower phase of anaphase B. In contrast, in cells expressing nonphosphorylated Ase1, anaphase spindle extension is faster, and spindles frequently break. Cdc14 also controls the separase–Slk19 complex indirectly via the Aurora B kinase. Thus, Cdc14 regulates spindle midzone assembly and function directly through Ase1 and indirectly via the separase–Slk19 complex.

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157 citations

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

...FEARreleased Cdc14 modulates nuclear movement, rDNA segregation and spindle stability to facilitate mitotic progression before ME (Jensen et al., 2001; Azzam et al., 2004; Sullivan et al., 2004; Higuchi and Uhlmann, 2005; Khmelinskii et al., 2007)....
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Journal Article•DOI•

Separase: a universal trigger for sister chromatid disjunction but not chromosome cycle progression

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Karin G. Wirth¹, Karin G. Wirth², Gordana Wutz¹, Nobuaki Kudo¹, Chantal Desdouets, Anders Zetterberg³, Shahryar Taghybeeglu¹, Janina Seznec², Germain M. Ducos, Romeo Ricci¹, Nicole Firnberg¹, Jan-Michael Peters¹, Kim Nasmyth¹ - Show less +9 more•Institutions (3)

Research Institute of Molecular Pathology¹, University of Jena², Karolinska Institutet³

13 Mar 2006-Journal of Cell Biology

TL;DR: Conditional knockout alleles of the mouse Separase and Securin genes are created and Destruction of sister chromatid cohesion by Separases may be a universal feature of mitosis in eukaryotic cells.

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Abstract: Separase is a protease whose liberation from its inhibitory chaperone Securin triggers sister chromatid disjunction at anaphase onset in yeast by cleaving cohesin's kleisin subunit. We have created conditional knockout alleles of the mouse Separase and Securin genes. Deletion of both copies of Separase but not Securin causes embryonic lethality. Loss of Securin reduces Separase activity because deletion of just one copy of the Separase gene is lethal to embryos lacking Securin. In embryonic fibroblasts, Separase depletion blocks sister chromatid separation but does not prevent other aspects of mitosis, cytokinesis, or chromosome replication. Thus, fibroblasts lacking Separase become highly polyploid. Hepatocytes stimulated to proliferate in vivo by hepatectomy also become unusually large and polyploid in the absence of Separase but are able to regenerate functional livers. Separase depletion in bone marrow causes aplasia and the presumed death of hematopoietic cells other than erythrocytes. Destruction of sister chromatid cohesion by Separase may be a universal feature of mitosis in eukaryotic cells.

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153 citations

Journal Article•DOI•

A Novel Role of the Budding Yeast Separin Esp1 in Anaphase Spindle Elongation: Evidence That Proper Spindle Association of Esp1 Is Regulated by Pds1

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Sanne Jensen¹, Marisa Segal¹, Duncan J. Clarke¹, Steven I. Reed¹•Institutions (1)

Scripps Research Institute¹

08 Jan 2001-Journal of Cell Biology

TL;DR: It is shown that Esp1 has a novel role in promoting anaphase spindle elongation and mutational analysis reveals that the conserved COOH-terminal region of Esp1 is important for spindle interaction.

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Abstract: In Saccharomyces cerevisiae, the metaphase–anaphase transition is initiated by the anaphase-promoting complex–dependent degradation of Pds1, whereby Esp1 is activated to promote sister chromatid separation. Although this is a fundamental step in the cell cycle, little is known about the regulation of Esp1 and how loss of cohesion is coordinated with movement of the anaphase spindle. Here, we show that Esp1 has a novel role in promoting anaphase spindle elongation. The localization of Esp1 to the spindle apparatus, analyzed by live cell imaging, is regulated in a manner consistent with a function during anaphase B. The protein accumulates in the nucleus in G2 and is mobilized onto the spindle pole bodies and spindle midzone at anaphase onset, where it persists into midanaphase. Association with Pds1 occurs during S phase and is required for efficient nuclear targeting of Esp1. Spindle association is not fully restored in pds1 mutants expressing an Esp1-nuclear localization sequence fusion protein, suggesting that Pds1 is also required to promote Esp1 spindle binding. In agreement, Pds1 interacts with the spindle at the metaphase–anaphase transition and a fraction remains at the spindle pole bodies and the spindle midzone in anaphase cells. Finally, mutational analysis reveals that the conserved COOH-terminal region of Esp1 is important for spindle interaction.

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148 citations

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

...According to this speculation, spindle stabilization by the FEAR pathway including Esp1 (Jensen et al., 2001; Higuchi and Uhlmann, 2005) may largely account for the functional difference in promoting ME after anaphase induction by GAL1-ESP1 compared with GAL1TEV, in the absence of CDC20 (Sullivan and Uhlmann, 2003)....
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...FEARreleased Cdc14 modulates nuclear movement, rDNA segregation and spindle stability to facilitate mitotic progression before ME (Jensen et al., 2001; Azzam et al., 2004; Sullivan et al., 2004; Higuchi and Uhlmann, 2005; Khmelinskii et al., 2007)....
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...Esp1 binds to the spindle (Jensen et al., 2001), and Esp1 might require an intact spindle to drive ME for reasons unrelated to ultimate spindle elongation....
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...According to this speculation, spindle stabilization by the FEAR pathway including Esp1 (Jensen et al., 2001; Higuchi and Uhlmann, 2005) may largely account for the functional difference in promoting ME after anaphase induction by GAL1-ESP1 compared with GAL1TEV, in the absence of CDC20 (Sullivan…...
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