A Mathematical Model of Mitotic Exit in Budding Yeast: The Role of Polo Kinase

Cell cycle progression in eukaryotes is regulated by periodic activation and inactivation of a family of cyclin–dependent kinases (Cdk's). Entry into mitosis requires phosphorylation of many proteins targeted by mitotic Cdk, and exit from mitosis requires proteolysis of mitotic cyclins and dephosphorylation of their targeted proteins. Mitotic exit in budding yeast is known to involve the interplay of mitotic kinases (Cdk and Polo kinases) and phosphatases (Cdc55/PP2A and Cdc14), as well as the action of the anaphase promoting complex (APC) in degrading specific proteins in anaphase and telophase. To understand the intricacies of this mechanism, we propose a mathematical model for the molecular events during mitotic exit in budding yeast. The model captures the dynamics of this network in wild-type yeast cells and 110 mutant strains. The model clarifies the roles of Polo-like kinase (Cdc5) in the Cdc14 early anaphase release pathway and in the G-protein regulated mitotic exit network.

[1]  Eduardo Sontag,et al.  Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2 , 2003, Nature Cell Biology.

[2]  F. Cross,et al.  Mitotic exit in the absence of separase activity. , 2009, Molecular biology of the cell.

[3]  Edda Klipp,et al.  Cell Size at S Phase Initiation: An Emergent Property of the G1/S Network , 2007, PLoS Comput. Biol..

[4]  Katherine C. Chen,et al.  Integrative analysis of cell cycle control in budding yeast. , 2004, Molecular biology of the cell.

[5]  John J. Tyson,et al.  Quantitative analysis of a molecular model of mitotic control in fission yeast , 1995 .

[6]  Yanchang Wang,et al.  Phosphatase 2A negatively regulates mitotic exit in Saccharomyces cerevisiae. , 2005, Molecular biology of the cell.

[7]  M. Kirschner,et al.  Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC-dependent degradation of the anaphase inhibitor Pds1p. , 1996, Genes & development.

[8]  D. Fesquet,et al.  The Bub2-dependent mitotic pathway in yeast acts every cell cycle and regulates cytokinesis. , 2001, Journal of cell science.

[9]  Jennifer L. Snead,et al.  A coupled chemical-genetic and bioinformatic approach to Polo-like kinase pathway exploration. , 2007, Chemistry & biology.

[10]  Béla Novák,et al.  Supplementary Fig. 1 , 2021 .

[11]  D. Koshland,et al.  Pds1p of budding yeast has dual roles: inhibition of anaphase initiation and regulation of mitotic exit. , 1999, Genes & development.

[12]  K Nasmyth,et al.  Control of cyclin ubiquitination by CDK-regulated binding of Hct1 to the anaphase promoting complex. , 1998, Science.

[13]  F. M. Yeong,et al.  Exit from mitosis in budding yeast: biphasic inactivation of the Cdc28-Clb2 mitotic kinase and the role of Cdc20. , 2000, Molecular cell.

[14]  J. Tyson,et al.  Modeling the control of DNA replication in fission yeast. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Kim Nasmyth,et al.  The Polo‐like kinase Cdc5p and the WD‐repeat protein Cdc20p/fizzy are regulators and substrates of the anaphase promoting complex in Saccharomyces cerevisiae , 1998, The EMBO journal.

[16]  F. Stegmeier,et al.  The role of the polo kinase Cdc5 in controlling Cdc14 localization. , 2003, Molecular biology of the cell.

[17]  S. Jaspersen,et al.  Cdc14 activates Cdc15 to promote mitotic exit in budding yeast , 2000, Current Biology.

[18]  Angelika Amon,et al.  The regulation of Cdc20 proteolysis reveals a role for the APC components Cdc23 and Cdc27 during S phase and early mitosis , 1998, Current Biology.

[19]  Angelika Amon,et al.  Cfi1 prevents premature exit from mitosis by anchoring Cdc14 phosphatase in the nucleolus , 1999, Nature.

[20]  Yanchang Wang,et al.  The molecular function of the yeast polo-like kinase Cdc5 in Cdc14 release during early anaphase. , 2009, Molecular biology of the cell.

[21]  Grigoriy E. Pinchuk,et al.  Stochastic hybrid modeling of DNA replication across a complete genome , 2009 .

[22]  L. Johnston,et al.  In Vitro Regulation of Budding Yeast Bfa1/Bub2 GAP Activity by Cdc5* , 2003, The Journal of Biological Chemistry.

[23]  M. Tyers,et al.  The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation. , 1998, Molecular cell.

[24]  Anna Shevchenko,et al.  Exit from Mitosis Is Triggered by Tem1-Dependent Release of the Protein Phosphatase Cdc14 from Nucleolar RENT Complex , 1999, Cell.

[25]  Roland S Annan,et al.  Cdc5 influences phosphorylation of Net1 and disassembly of the RENT complex , 2002, BMC Molecular Biology.

[26]  Michael S. Cohen,et al.  APC/C-Cdh1-mediated degradation of the Polo kinase Cdc5 promotes the return of Cdc14 into the nucleolus. , 2008, Genes & Development.

[27]  John J Tyson,et al.  System-level feedbacks make the anaphase switch irreversible , 2011, Proceedings of the National Academy of Sciences.

[28]  Denis Thieffry,et al.  Dynamical modeling of syncytial mitotic cycles in Drosophila embryos , 2007, Molecular systems biology.

[29]  H. Bourne.  GTPases: a family of molecular switches and clocks. , 1995, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[30]  A. Toh-E,et al.  The yeast TEM1 gene, which encodes a GTP-binding protein, is involved in termination of M phase , 1994, Molecular and cellular biology.

[31]  A. Ciliberto,et al.  Oscillations in Cdc14 release and sequestration reveal a circuit underlying mitotic exit , 2010, The Journal of cell biology.

[32]  D O Morgan,et al.  A late mitotic regulatory network controlling cyclin destruction in Saccharomyces cerevisiae. , 1998, Molecular biology of the cell.

[33]  S. Elledge,et al.  Regulation of the Bub2/Bfa1 GAP Complex by Cdc5 and Cell Cycle Checkpoints , 2001, Cell.

[34]  Kyung S. Lee,et al.  A Novel Function of Saccharomyces cerevisiae CDC5 in Cytokinesis , 2001, The Journal of cell biology.

[35]  Frederick R. Cross,et al.  Periodic Cyclin-Cdk Activity Entrains an Autonomous Cdc14 Release Oscillator , 2010, Cell.

[36]  F. Cross,et al.  Testing a mathematical model of the yeast cell cycle. , 2002, Molecular biology of the cell.

[37]  J. Grindlay,et al.  The Bub2p spindle checkpoint links nuclear migration with mitotic exit. , 2000, Molecular cell.

[38]  R. Steuer.  Effects of stochasticity in models of the cell cycle: from quantized cycle times to noise-induced oscillations. , 2004, Journal of theoretical biology.

[39]  John J. Tyson,et al.  Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[40]  A. Amon,et al.  A Mechanism for Coupling Exit from Mitosis to Partitioning of the Nucleus , 2000, Cell.

[41]  S. Yoshida,et al.  Mitotic Exit Network Controls the Localization of Cdc14 to the Spindle Pole Body in Saccharomyces cerevisiae , 2002, Current Biology.

[42]  J. Tyson,et al.  Numerical analysis of a comprehensive model of M-phase control in Xenopus oocyte extracts and intact embryos. , 1993, Journal of cell science.

[43]  K. Nasmyth,et al.  Whose end is destruction: cell division and the anaphase-promoting complex. , 1999, Genes & development.

[44]  A. Toh-E,et al.  Budding yeast Cdc5 phosphorylates Net1 and assists Cdc14 release from the nucleolus. , 2002, Biochemical and biophysical research communications.

[45]  M. Shirayama,et al.  Dominant mutant alleles of yeast protein kinase gene , 1996 .

[46]  J. Grindlay,et al.  Regulation of the Bfa 1 p – Bub 2 p complex at spindle pole bodies by the cell cycle phosphatase Cdc 14 p , 2002 .

[47]  Bela Novak,et al.  Downregulation of PP2ACdc55 Phosphatase by Separase Initiates Mitotic Exit in Budding Yeast , 2006, Cell.

[48]  David O. Morgan,et al.  Inhibitory phosphorylation of the APC regulator Hct1 is controlled by the kinase Cdc28 and the phosphatase Cdc14 , 1999, Current Biology.

[49]  P. Nurse.  Universal control mechanism regulating onset of M-phase , 1990, Nature.

[50]  John J. Tyson,et al.  Mathematical model of the morphogenesis checkpoint in budding yeast , 2003, The Journal of cell biology.

[51]  F. Uhlmann,et al.  A non-proteolytic function of separase links the onset of anaphase to mitotic exit , 2003, Nature Cell Biology.

[52]  J. Tyson,et al.  Modeling the fission yeast cell cycle: quantized cycle times in wee1- cdc25Delta mutant cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[53]  Angelika Amon,et al.  Separase, Polo Kinase, the Kinetochore Protein Slk19, and Spo12 Function in a Network that Controls Cdc14 Localization during Early Anaphase , 2002, Cell.

[54]  J. Tyson,et al.  Mathematical model for early development of the sea urchin embryo , 2000, Bulletin of mathematical biology.

[55]  Martin A. Nowak,et al.  The role of chromosomal instability in tumor initiation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[56]  Steven A. Carr,et al.  Phosphorylation by Cyclin B-Cdk Underlies Release of Mitotic Exit Activator Cdc14 from the Nucleolus , 2004, Science.

[57]  D Gonze,et al.  A model for a network of phosphorylation-dephosphorylation cycles displaying the dynamics of dominoes and clocks. , 2001, Journal of theoretical biology.

[58]  D. Burke,et al.  The role of Cdc55 in the spindle checkpoint is through regulation of mitotic exit in Saccharomyces cerevisiae. , 2005, Molecular biology of the cell.

[59]  J. Tyson,et al.  Modeling the septation initiation network (SIN) in fission yeast cells , 2007, Current Genetics.

[60]  Andrea Ciliberto,et al.  Computational modelling of mitotic exit in budding yeast: the role of separase and Cdc14 endocycles , 2011, Journal of The Royal Society Interface.

[61]  Angelika Amon,et al.  Closing mitosis: the functions of the Cdc14 phosphatase and its regulation. , 2004, Annual review of genetics.

[62]  D. Morgan,et al.  Finishing mitosis, one step at a time , 2007, Nature Reviews Molecular Cell Biology.