The Wellcome Lecture, 1992. Cell cycle control

1993 ◽  
Vol 341 (1298) ◽  
pp. 449-454 ◽  
Keyword(s):  
Cell Cycle ◽  
Fission Yeast ◽  
Gene Network ◽  
Cell Cycle Control ◽  
Regulatory Gene ◽  
Eukaryotic Cell ◽  
S Phase ◽  
M Phase ◽  
A Cell ◽  
Future Work

Genetic analysis using the fission yeast has provided a powerful methodology to investigate the eukaryotic cell cycle and its control. The onset of M -phase in fission yeast is controlled by a regulatory gene network which activates the p34 cdc2 protein kinase encoded by the cdc 2 + gene. The coupling of M -phase to the completion of S-phase also works through p34 cdc2 . A similar network is operative in vertebrate cells. Future work will focus on the controls regulating onset of S-phase and on the mechanisms by which a cell duplicates itself in space during division.

scholarly journals Fission yeast cell cycle mutants and the logic of eukaryotic cell cycle control

2020 ◽  
Vol 31 (26) ◽  
pp. 2871-2873
Author(s):  
Paul Nurse
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Fission Yeast ◽  
Cell Cycle Control ◽  
Eukaryotic Cell ◽  
S Phase ◽  
Cyclin Dependent Kinases ◽  
Starting Point ◽  
Rate Limiting ◽  
Working Out

Cell cycle mutants in the budding and fission yeasts have played critical roles in working out how the eukaryotic cell cycle operates and is controlled. The starting point was Lee Hartwell’s 1970s landmark papers describing the first cell division cycle (CDC) mutants in budding yeast. These mutants were blocked at different cell cycle stages and so were unable to complete the cell cycle, thus defining genes necessary for successful cell division. Inspired by Hartwell’s work, I isolated CDC mutants in the very distantly related fission yeast. This started a program of searches for mutants in fission yeast that revealed a range of phenotypes informative about eukaryotic cell cycle control. These included mutants defining genes that were rate-limiting for the onset of mitosis and of the S-phase, that were responsible for there being only one S-phase in each cell cycle, and that ensured that mitosis only took place when S-phase was properly completed. This is a brief account of the discovery of these mutants and how they led to the identification of cyclin-dependent kinases as core to these cell cycle controls.

Cyclin Dependent Kinases and Regulation of the Fission Yeast Cell Cycle

1999 ◽  
Vol 380 (7-8) ◽  
pp. 729-733 ◽  
Author(s):  
P. Nurse
Keyword(s):  
Cell Cycle ◽  
Yeast Cell ◽  
Fission Yeast ◽  
S Phase ◽  
Yeast Cell Cycle ◽  
Cyclin Dependent Kinases ◽  
Fission Yeast Cell ◽  
Nutritional Deprivation ◽  
Orderly Fashion ◽  
A Cell

AbstractThe cyclin dependent kinases (CDKs), formed by complexes between Cdc2p and the B-cyclins Cig2p and Cdc13p, have a central role in regulating the fission yeast cell cycle and maintaining genomic stability. The CDK Cig2p/Cdc2p controls the onset of S-phase and the CDK Cdc13p/Cdc2p controls the onset of mitosis and ensures that there is only one S-phase in each cell. Cdc13p/Cdc2p can replace Cig2p/Cdc2p for the onset of S-phase, suggesting that the increasing activity of a single CDK during the cell cycle is sufficient to drive a cell in an orderly fashion into S-phase and into mitosis. If S-phase is incomplete, then inhibition of Cdc13p/Cdc2p prevents cells with unreplicated DNA from undergoing a catastrophic entry into mitosis. Control of CDK activity is also important to allow cells to exit the cell cycle and accumulate in G1 in response to nutritional deprivation and the presence of pheromone.

scholarly journals Two distinct ubiquitin-proteolysis pathways in the fission yeast cell cycle

1999 ◽  
Vol 354 (1389) ◽  
pp. 1551-1557 ◽  
Author(s):  
Takashi Toda ◽  
Itziar Ochotorena ◽  
Kin-ichiro Kominami
Keyword(s):  
Cell Cycle ◽  
Fission Yeast ◽  
Cell Cycle Control ◽  
Eukaryotic Cell ◽  
Cdk Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Anaphase Promoting Complex ◽  
Repeat Proteins ◽  
Cycle Dependent ◽  
Universal Mechanism

The SCF complex (Skp1-Cullin-1-F-box) and the APC/cyclosome (anaphase-promoting complex) are two ubiquitin ligases that play a crucial role in eukaryotic cell cycle control. In fission yeast F-box/WD-repeat proteins Pop1 and Pop2, components of SCF are required for cell-cycle-dependent degradation of the cyclin-dependent kinase (CDK) inhibitor Rum1 and the S-phase regulator Cdc18. Accumulation of these proteins in pop1 and pop2 mutants leads to re-replication and defects in sexual differentiation. Despite structural and functional similarities, Pop1 and Pop2 are not redundant homologues. Instead, these two proteins form heterodimers as well as homodimers, such that three distinct complexes, namely SCF Pop1/Pop1 , SCF Pop1/Pop2 and SCF Pop2/Pop2 , appear to exist in the cell. The APC/cyclosome is responsible for inactivation of CDK/cyclins through the degradation of B-type cyclins. We have identified two novel components or regulators of this complex, called Apc10 and Ste9, which are evolutionarily highly conserved. Apc10 (and Ste9), together with Rum1, are required for the establishment of and progression through the G1 phase in fission yeast. We propose that dual downregulation of CDK, one via the APC/cyclosome and the other via the CDK inhibitor, is a universal mechanism that is used to arrest the cell cycle at G1.

The Effect of Cell Mass on the Cell Cycle Timing and Duration of S-Phase in Fission Yeast

1979 ◽  
Vol 39 (1) ◽  
pp. 215-233
Author(s):  
KIM NASMYTH ◽  
PAUL NURSE ◽  
R. S. S. FRASER
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Fission Yeast ◽  
Critical Level ◽  
Single Cells ◽  
Cell Mass ◽  
S Phase ◽  
Pulse Labelling ◽  
Random Transition ◽  
A Cell

Request for reprints to Paul Nurse. Two isotopic methods for measuring DNA replication in the fission yeast Schizosaccharomyces pombe are described. The first is a method for measuring the total quantity of [3H]uracil incorporated into DNA after pulse labelling. The second is a means of detecting DNA replication in single cells by autoradiography. Both of these techniques have been used to investigate the timing and duration of S-phase in a series of mutant strains whose cell mass at division varies over a 3-fold range. The results support the hypothesis that in S. pombe there are 2 different controls over the timing of S-phase: an attainment of a critical cell mass and a dependency upon the completion of the previous mitosis coupled with a short minimum time in G1. Strains whose cell mass at birth is above this critical level initiate DNA replication almost immediately after septation, that is, very soon after the previous mitosis. Strains whose cell mass at birth is below the critical level do not initiate replication until the critical cell mass is attained. The duration of S-phase has been estimated from the proportion of cells whose nuclei are labelled after a pulse of given duration. S-phase is short in S. pombe, lasting only about 0.1 of a cell cycle in wild type. Cell mass at S-phase does not have any consistent effect on this length. We have also investigated the degree of synchrony of S-phase initiation in daughter cells, and have found that, in a cell cycle 240 min long, their S-phases are initiated within 1–2 min of each other. This result indicates that between sisters variability in the duration of the G1 phase is small compared with variability in the total cell cycle time, and argues against the hypothesis that the rate of cell cycle traverse is determined by a random transition in G1.

scholarly journals Control of cell cycle progression by phosphorylation of cyclin-dependent kinase (CDK) substrates

2010 ◽  
Vol 30 (4) ◽  
pp. 243-255 ◽  
Author(s):  
Randy Suryadinata ◽  
Martin Sadowski ◽  
Boris Sarcevic
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Cycle Progression ◽  
Genetic Material ◽  
Eukaryotic Cell ◽  
S Phase ◽  
Cycle Progression ◽  
M Phase ◽  
Unicellular Organisms ◽  
Multicellular Organisms

The eukaryotic cell cycle is a fundamental evolutionarily conserved process that regulates cell division from simple unicellular organisms, such as yeast, through to higher multicellular organisms, such as humans. The cell cycle comprises several phases, including the S-phase (DNA synthesis phase) and M-phase (mitotic phase). During S-phase, the genetic material is replicated, and is then segregated into two identical daughter cells following mitotic M-phase and cytokinesis. The S- and M-phases are separated by two gap phases (G1 and G2) that govern the readiness of cells to enter S- or M-phase. Genetic and biochemical studies demonstrate that cell division in eukaryotes is mediated by CDKs (cyclin-dependent kinases). Active CDKs comprise a protein kinase subunit whose catalytic activity is dependent on association with a regulatory cyclin subunit. Cell-cycle-stage-dependent accumulation and proteolytic degradation of different cyclin subunits regulates their association with CDKs to control different stages of cell division. CDKs promote cell cycle progression by phosphorylating critical downstream substrates to alter their activity. Here, we will review some of the well-characterized CDK substrates to provide mechanistic insights into how these kinases control different stages of cell division.

scholarly journals Evidence for a new kind of regulatory gene controlling expression of genes for morphogenesis during the cell cycle in Ustilago violacea

1975 ◽  
Vol 25 (3) ◽  
pp. 253-266 ◽  
Author(s):  
A. W. Day ◽  
J. E. Cummins
Keyword(s):  
Cell Cycle ◽  
Mating Type ◽  
Cell Cycle Control ◽  
Regulatory Gene ◽  
Type Locus ◽  
Ustilago Violacea ◽  
Temporal Properties ◽  
Expression Of Genes ◽  
Separate Control ◽  
A Cell

SUMMARYThe first part of the paper provides strong supportive evidence for the previous findings (Cummins & Day, 1973; Day & Cummins, 1973) that the two alleles of the mating-type locus of the basidiomycete Ustilago violacea have different periods of inducibility during a cell cycle, and that the cell cycle characteristics of each allele are maintained in freshly isolated diploids. This difference in temporal properties of the alleles appears to be the basis of the dominance of allele a2 as it is inducible during a phase of the cell cycle when allele a1 is non-inducible. During G1 both alleles appear to be inducible and apparently ‘neutralize’ each other so that the cell cannot mate.The second part of the paper provides evidence for a unique genetic control mechanism. The evidence suggests that the period of cell cycle inducibility of a locus governing a morphogenetic pathway may be regulated by a separate control gene the cc locus, with two known alleles ccstr(a stringent or restricted period of inducibility) and ccrel (a relaxed or non-restricted period of inducibility). This hypothesis stems from analysis of a diploid that was a1· ccstr/a2· ccrel and showed dominance of allele a2 during the S and G2 phases when freshly isolated, but which became incapable of mating after a period of subculturing. Analysis of haploids derived from this diploid strain showed that both mating-type alleles were functional but that it was now homozygous for ccstr, i.e. of genotype a1· ccstr/a2·ccstr· Thus the temporal and functional aspects of the mating type alleles are determined by different loci. It is postulated that cell cycle control loci may be widespread and serve to regulate the action of genes concerned with morphogenesis in relation to other cell cycle events.

scholarly journals Cyclin C influences the timing of mitosis in fission yeast

2017 ◽  
Vol 28 (13) ◽  
pp. 1738-1744 ◽  
Author(s):  
Gabor Banyai ◽  
Zsolt Szilagyi ◽  
Vera Baraznenok ◽  
Olga Khorosjutina ◽  
Claes M. Gustafsson
Keyword(s):  
Cell Cycle ◽  
Fission Yeast ◽  
Rna Polymerase Ii ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Mediator Complex ◽  
Cycle Progression ◽  
Cyclin C ◽  
M Phase

The multiprotein Mediator complex is required for the regulated transcription of nearly all RNA polymerase II–dependent genes. Mediator contains the Cdk8 regulatory subcomplex, which directs periodic transcription and influences cell cycle progression in fission yeast. Here we investigate the role of CycC, the cognate cyclin partner of Cdk8, in cell cycle control. Previous reports suggested that CycC interacts with other cellular Cdks, but a fusion of CycC to Cdk8 reported here did not cause any obvious cell cycle phenotypes. We find that Cdk8 and CycC interactions are stabilized within the Mediator complex and the activity of Cdk8-CycC is regulated by other Mediator components. Analysis of a mutant yeast strain reveals that CycC, together with Cdk8, primarily affects M-phase progression but mutations that release Cdk8 from CycC control also affect timing of entry into S phase.

scholarly journals SCAPER, a novel cyclin A–interacting protein that regulates cell cycle progression

2007 ◽  
Vol 178 (4) ◽  
pp. 621-633 ◽  
Author(s):  
William Y. Tsang ◽  
Leyu Wang ◽  
Zhihong Chen ◽  
Irma Sánchez ◽  
Brian David Dynlacht
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Regulatory Protein ◽  
Ectopic Expression ◽  
Cyclin A ◽  
Eukaryotic Cell ◽  
S Phase ◽  
Interacting Protein ◽  
M Phase

Cyclin A/Cdk2 plays an important role during S and G2/M phases of the eukaryotic cell cycle, but the mechanisms by which it regulates cell cycle events are not fully understood. We have biochemically purified and identified SCAPER, a novel protein that specifically interacts with cyclin A/Cdk2 in vivo. Its expression is cell cycle independent, and it associates with cyclin A/Cdk2 at multiple phases of the cell cycle. SCAPER localizes primarily to the endoplasmic reticulum. Ectopic expression of SCAPER sequesters cyclin A from the nucleus and results specifically in an accumulation of cells in M phase of the cell cycle. RNAi-mediated depletion of SCAPER decreases the cytoplasmic pool of cyclin A and delays the G1/S phase transition upon cell cycle re-entry from quiescence. We propose that SCAPER represents a novel cyclin A/Cdk2 regulatory protein that transiently maintains this kinase in the cytoplasm. SCAPER could play a role in distinguishing S phase– from M phase–specific functions of cyclin A/Cdk2.

Fission yeast Nda1 and Nda4, MCM homologs required for DNA replication, are constitutive nuclear proteins

1996 ◽  
Vol 109 (2) ◽  
pp. 319-326 ◽  
Author(s):  
N. Okishio ◽  
Y. Adachi ◽  
M. Yanagida
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Fission Yeast ◽  
Budding Yeast ◽  
Affinity Column ◽  
Wild Type ◽  
M Phase ◽  
A Cell ◽  
Mcm Proteins ◽  
Cycle Dependent

The nda1+ and nda4+ genes of the fission yeast Schizosaccharomyces pombe encode proteins similar to budding yeast MCM2 and MCM5/CDC46, respectively, which are required for the early stages of DNA replication. The budding yeast Mcm proteins display cell-cycle dependent localization. They are present in the nucleus specifically from late M phase until the beginning of S phase, so that they were suggested to be components of a replication licensing factor, a positive factor for the onset of replication, which is thought to be inactivated after use, thus restricting replication to only once in a cell cycle. In the present study, we raised antibodies against Nda1 or Nda4 and identified 115 kDa and 80 kDa proteins, respectively. Their immunolocalization was examined in wild-type cells and in various cell-cycle mutants. Both Nda1 and Nda4 proteins remained primarily in the nucleus throughout the cell cycle. In mutants arrested in G1, S, and G2 phases, these proteins were also enriched in the nucleus. These results indicate that the dramatic change in subcellular localization as seen in budding yeast is not essential in fission yeast for the functions of Nda1 and Nda4 proteins to be executed. The histidine-tagged nda1+ gene was constructed and integrated into the chromosome to replace the wild-type nda1+ gene. The resulting His-tagged Nda1 protein was adsorbed to the Ni-affinity column, and co-eluted with the untagged Nda4 protein, suggesting that they formed a complex.

scholarly journals Identification of an activator required for elevation of maturation-promoting factor (MPF) activity by gamma-S-ATP.

1990 ◽  
Vol 110 (5) ◽  
pp. 1583-1588 ◽  
Author(s):  
S Yamashita ◽  
J L Maller
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cell Cycle Control ◽  
Control Element ◽  
Kinase Activation ◽  
Cell Extracts ◽  
M Phase ◽  
A Cell ◽  
Gamma S ◽  
Maturation Promoting Factor

Maturation-promoting factor (MPF) is a cell cycle control element able to cause cells to enter M-phase upon microinjection and will induce metaphase in nuclei incubated in cell extracts. Previous work has shown that MPF is composed of a complex between p34cdc 2 protein kinase and a B-type cyclin. In the present work gamma-S-ATP was found to cause activation of MPF activity in partially purified preparations, but this activation was lost upon chromatography on Matrex Green gel A. Readdition of other Matrex Green fractions to purified MPF restored the ability of gamma-S-ATP to activate MPF for nuclear breakdown as well as phosphorylation of histone H1. Use of the system described here will facilitate study of p34cdc 2 kinase activation and identification of elements involved in MPF regulation.

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