Periodic Cyclin-Cdk Activity Entrains an Autonomous Cdc14 Release Oscillator

One oscillation of Cyclin-dependent kinase (Cdk) activity, largely driven by periodic synthesis and destruction of cyclins, is tightly coupled to a single complete eukaryotic cell division cycle. Tight linkage of different steps in diverse cell-cycle processes to Cdk activity has been proposed to explain this coupling. Here, we demonstrate an intrinsically oscillatory module controlling nucleolar release and resequestration of the Cdc14 phosphatase, which is essential for mitotic exit in budding yeast. We find that this Cdc14 release oscillator functions at constant and physiological cyclin-Cdk levels, and is therefore independent of the Cdk oscillator. However, the frequency of the release oscillator is regulated by cyclin-Cdk activity. This observation together with its mechanism 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. This concept may have broad implications for the structure and evolution of eukaryotic cell-cycle control.

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

[2]  Frederick R. Cross,et al.  Multiple levels of cyclin specificity in cell-cycle control , 2007, Nature Reviews Molecular Cell Biology.

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

[4]  Michael Schwab,et al.  Yeast Hct1 Is a Regulator of Clb2 Cyclin Proteolysis , 1997, Cell.

[5]  L. Hartwell.  Saccharomyces cerevisiae cell cycle. , 1974, Bacteriological reviews.

[6]  J. Hopfield,et al.  From molecular to modular cell biology , 1999, Nature.

[7]  J. Broach,et al.  The Molecular biology of the yeast saccharomyces, life cycle and inheritance , 1981 .

[8]  M. Mendenhall,et al.  Regulation of Cdc28 Cyclin-Dependent Protein Kinase Activity during the Cell Cycle of the Yeast Saccharomyces cerevisiae , 1998, Microbiology and Molecular Biology Reviews.

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

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

[11]  Marco Geymonat,et al.  Spatial regulation of the guanine nucleotide exchange factor Lte1 in Saccharomyces cerevisiae , 2002, Journal of Cell Science.

[12]  M. Kirschner,et al.  The KEN box: an APC recognition signal distinct from the D box targeted by Cdh1. , 2000, Genes & development.

[13]  Curt Wittenberg,et al.  Cell cycle-dependent transcription in yeast: promoters, transcription factors, and transcriptomes , 2005, Oncogene.

[14]  K Nasmyth,et al.  Sister chromatid separation and chromosome re‐duplication are regulated by different mechanisms in response to spindle damage , 1999, The EMBO journal.

[15]  David O. Morgan,et al.  The Polo-related kinase Cdc5 activates and is destroyed by the mitotic cyclin destruction machinery in S. cerevisiae , 1998, Current Biology.

[16]  Albert,et al.  Emergence of scaling in random networks , 1999, Science.

[17]  Joshua E. S. Socolar,et al.  Global control of cell-cycle transcription by coupled CDK and network oscillators , 2008, Nature.

[18]  W. Lim,et al.  Domains, motifs, and scaffolds: the role of modular interactions in the evolution and wiring of cell signaling circuits. , 2006, Annual review of biochemistry.

[19]  D. Fesquet,et al.  A Bub2p‐dependent spindle checkpoint pathway regulates the Dbf2p kinase in budding yeast , 1999, The EMBO journal.

[20]  L. Glass.  Synchronization and rhythmic processes in physiology , 2001, Nature.

[21]  A. Toh-E,et al.  Regulation of the localization of Dbf2 and mob1 during cell division of saccharomyces cerevisiae. , 2001, Genes & genetic systems.

[22]  K Nasmyth,et al.  Destruction of the CDC28/CLB mitotic kinase is not required for the metaphase to anaphase transition in budding yeast. , 1993, The EMBO journal.

[23]  K Nasmyth,et al.  Evolution of the cell cycle. , 1995, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[24]  Steven B. Haase,et al.  Evidence that a free-running oscillator drives G1 events in the budding yeast cell cycle , 1999, Nature.

[25]  S. Doplicher,et al.  Mathematical Problems in Theoretical Physics , 1978 .

[26]  P. Nurse,et al.  A quantitative model for the cdc2 control of S phase and mitosis in fission yeast. , 1996, Trends in genetics : TIG.

[27]  Curt Wittenberg,et al.  G1-specific cyclins of S. cerevisiae: Cell cycle periodicity, regulation by mating pheromone, and association with the p34 CDC28 protein kinase , 1990, Cell.

[28]  S. Carr,et al.  Phosphorylation of Sic1p by G1 Cdk required for its degradation and entry into S phase. , 1997, Science.

[29]  C. Darwin.  On the Origin of Species by Means of Natural Selection: Or, The Preservation of Favoured Races in the Struggle for Life , 2019 .

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

[31]  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.

[32]  P. O’Farrell,et al.  RNAi of Mitotic Cyclins in Drosophila Uncouples the Nuclear and Centrosome Cycle , 2008, Current Biology.

[33]  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.

[34]  David O. Morgan,et al.  The Cell Cycle: Principles of Control , 2014 .

[35]  F. Cross,et al.  Analysis of the mitotic exit control system using locked levels of stable mitotic cyclin , 2009, Molecular systems biology.

[36]  K Nasmyth,et al.  Characterization of four B-type cyclin genes of the budding yeast Saccharomyces cerevisiae. , 1992, Molecular biology of the cell.

[37]  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.

[38]  Javier M. Buldú,et al.  Phase Locking Induces Scale-Free Topologies in Networks of Coupled Oscillators , 2008, PloS one.

[39]  Yoshiki Kuramoto,et al.  Self-entrainment of a population of coupled non-linear oscillators , 1975 .

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

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

[42]  A. Bennett.  The Origin of Species by means of Natural Selection; or the Preservation of Favoured Races in the Struggle for Life , 1872, Nature.

[43]  S. Doxsey,et al.  Centrosome duplication continues in cycloheximide-treated Xenopus blastulae in the absence of a detectable cell cycle , 1990, The Journal of cell biology.

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

[45]  Stephen J. Elledge,et al.  Cell Cycle Checkpoints: Preventing an Identity Crisis , 1996, Science.

[46]  Frederick R. Cross,et al.  APC-dependent proteolysis of the mitotic cyclin Clb2 is essential for mitotic exit , 2002, Nature.

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

[48]  S. Prinz,et al.  CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis. , 1997, Science.

[49]  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.

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

[51]  C. Rieder,et al.  Protein synthesis and the cell cycle: centrosome reproduction in sea urchin eggs is not under translational control , 1990, The Journal of cell biology.

[52]  D. M. Krylov,et al.  Evolution of Eukaryotic Cell Cycle Regulation Stepwise Addition of Regulatory Kinases and Late Advent of the CDKs , 2003, Current Biology.

[53]  A. Winfree.  Biological rhythms and the behavior of populations of coupled oscillators. , 1967, Journal of theoretical biology.

[54]  Markus Brede,et al.  Construction principles for highly synchronizable sparse directed networks , 2008 .

[55]  Gilles Charvin,et al.  A Microfluidic Device for Temporally Controlled Gene Expression and Long-Term Fluorescent Imaging in Unperturbed Dividing Yeast Cells , 2008, PloS one.

[56]  S. Kearsey,et al.  Enigmatic variations: divergent modes of regulating eukaryotic DNA replication. , 2003, Molecular cell.

[57]  S. Avery,et al.  Destabilized green fluorescent protein for monitoring dynamic changes in yeast gene expression with flow cytometry , 2000, Yeast.

[58]  F. Cross,et al.  Coherence and timing of cell cycle start examined at single-cell resolution. , 2006, Molecular cell.

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

[60]  L. Hartwell,et al.  Mitotic checkpoint genes in budding yeast and the dependence of mitosis on DNA replication and repair. , 1994, Genes & development.

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

[62]  C. Darwin.  Charles Darwin The Origin of Species by means of Natural Selection or The Preservation of Favoured Races in the Struggle for Life , 2004 .

[63]  Frank Uhlmann,et al.  Orchestrating anaphase and mitotic exit: separase cleavage and localization of Slk19 , 2001, Nature Cell Biology.

[64]  Yu. V. Vagin,et al.  Charles Robert Darwin (to the 200th Birthday and the 150th Anniversary of the publication of the book «On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life» , 2009 .

[65]  L. Johnston,et al.  The Swi5 transcription factor of Saccharomyces cerevisiae has a role in exit from mitosis through induction of the cdk-inhibitor Sic1 in telophase. , 1997, Genetics.

[66]  S. Reed,et al.  Multi-step control of spindle pole body duplication by cyclin-dependent kinase , 2000, Nature Cell Biology.

[67]  M. Latterich,et al.  Phosphorylation and spindle pole body localization of the Cdc15p mitotic regulatory protein kinase in budding yeast , 2000, Current Biology.

[68]  K. Nasmyth.  At the heart of the budding yeast cell cycle. , 1996, Trends in genetics : TIG.