G1 and G1/S cyclins- budding yeast

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Cln1, Cln2, and Cln3 are cyclin proteins expressed in the G1-phase of the cell cycle of budding yeast. Like other cyclins, they function by binding and activating cyclin-dependent kinase. They are responsible for initiating entry into a new mitotic cell cycle at Start. As described below, Cln3 is the primary regulator of this process during normal yeast growth, with the other two G1 cyclins performing their function upon induction by Cln3. However, Cln1 and Cln2 are also directly regulated by pathways sensing extracellular conditions, including the mating pheremone pathway. [1]

Contents

Cln3

Cln3 is thought to be the main regulator linking cell growth to the cell cycle. This is because it is the most upstream regulator of Start and because, unlike other cyclins, concentration of Cln3 does not oscillate much with the cell cycle (see Cln3). Rather, Cln3 activity is thought to increase gradually throughout the cycle in response to cell growth. [2] Furthermore, Cln3 levels differ between mother and daughter cells, a difference that explains the asymmetry in cell cycle behavior between these two cell types. [3] Cln3 regulation also responds to external signals, including stress signals that stop division. [4]

Cln1,2

The G1 cyclins CLN1 and CLN2, upon transcriptional activation by Cln3 in mid-G1, bind Cdk1 (Cdc28) to complete progression through Start. These cyclins oscillate during the cell cycle - rise in late G1 and fall in early S phase. The primary function of G1/S cyclin-Cdk complexes is to trigger progression through Start and initiate the processes leading to DNA replication, principally by shutting down the various braking systems that suppress S-phase Cdk activity in G1. G1/S cyclins also initiate other early cell-cycles events such as duplication of the spindle pole body in yeast. [2] The rise of G1/S cyclins is accompanied by the appearance of the S cyclins (Clb5 and Clb6 in budding yeast), which form S cyclin-Cdk complexes that are directly responsible for stimulating DNA replication. [2]

Cln1 and Cln2 are involved in regulation of the cell cycle. Cln1 is closely related to Cln2 and has overlapping functions with Cln2. [5] For instance, Cln1 and Cln2 repress the mating factor response pathway at Start. [1] Additionally, both Cln1 and Cln2 are expressed in late G1 phase when they associate with Cdc28p to activate its kinase activity. Lastly, late G1-specific expression for both of them depends on transcription factor complexes, MBF and SBF. [5]

Related Research Articles

Cell cycle Series of events and stages that result in cell division

The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm and other components into two daughter cells in a process called cell division.

Cyclin-dependent kinase complex

A cyclin-dependent kinase complex is a protein complex formed by the association of an inactive catalytic subunit of a protein kinase, cyclin-dependent kinase (CDK), with a regulatory subunit, cyclin. Once cyclin-dependent kinases bind to cyclin, the formed complex is in an activated state. Substrate specificity of the activated complex is mainly established by the associated cyclin within the complex. Activity of CDKCs is controlled by phosphorylation of target proteins, as well as binding of inhibitory proteins.

S phase DNA replication phase of the cell cycle, between G1 and G2 phase

S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during S-phase are tightly regulated and widely conserved.

G2 phase, Gap 2 phase, or Growth 2 phase, is the third subphase of interphase in the cell cycle directly preceding mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated. G2 phase ends with the onset of prophase, the first phase of mitosis in which the cell’s chromatin condenses into chromosomes.

Cell cycle checkpoint

Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, with progression through the various phases of the cell cycle occurring only when favorable conditions are met. There are many checkpoints in the cell cycle, but the three major ones are: the G1 checkpoint, also known as the Start or restriction checkpoint or Major Checkpoint; the G2/M checkpoint; and the metaphase-to-anaphase transition, also known as the spindle checkpoint. Progression through these checkpoints is largely determined by the activation of cyclin-dependent kinases by regulatory protein subunits called cyclins, different forms of which are produced at each stage of the cell cycle to control the specific events that occur therein.

Cyclin A is a member of the cyclin family, a group of proteins that function in regulating progression through the cell cycle. The stages that a cell passes through that culminate in its division and replication are collectively known as the cell cycle Since the successful division and replication of a cell is essential for its survival, the cell cycle is tightly regulated by several components to ensure the efficient and error-free progression through the cell cycle. One such regulatory component is cyclin A which plays a role in the regulation of two different cell cycle stages.

CDK-activating kinase

CDK-activating kinase (CAK) activates the cyclin-CDK complex by phosphorylating threonine residue 160 in the CDK activation loop. CAK itself is a member of the Cdk family and functions as a positive regulator of Cdk1, Cdk2, Cdk4, and Cdk6.

Cyclin D

Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition. Cyclin D protein is anywhere from 155 to 477 amino acids in length.

The Cyclin D/Cdk4 complex is a multi-protein structure consisting of the proteins Cyclin D and cyclin-dependent kinase 4, or Cdk4, a serine-threonine kinase. This complex is one of many cyclin/cyclin-dependent kinase complexes that are the "hearts of the cell-cycle control system" and govern the cell cycle and its progression. As its name would suggest, the cyclin-dependent kinase is only active and able to phosphorylate its substrates when it is bound by the corresponding cyclin. The Cyclin D/Cdk4 complex is integral for the progression of the cell from the Growth 1 phase to the Synthesis phase of the cell cycle, for the Start or G1/S checkpoint.

Cyclin-dependent kinase 1 Mammalian protein found in Homo sapiens

Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved protein that functions as a serine/threonine kinase, and is a key player in cell cycle regulation. It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S. pombe, where it is encoded by genes cdc28 and cdc2, respectively. In humans, Cdk1 is encoded by the CDC2 gene. With its cyclin partners, Cdk1 forms complexes that phosphorylate a variety of target substrates ; phosphorylation of these proteins leads to cell cycle progression.

G1/S-specific cyclin Cln3 is a protein that is encoded by the CLN3 gene. The Cln3 protein is a budding yeast G1 cyclin that controls the timing of Start, the point of commitment to a mitotic cell cycle. It is an upstream regulator of the other G1 cyclins, and it is thought to be the key regulator linking cell growth to cell cycle progression. It is a 65 kD, unstable protein; like other cyclins, it functions by binding and activating cyclin-dependent kinase (CDK).

Sic1, a protein, is a stoichiometric inhibitor of Cdk1-Clb complexes in the budding yeast Saccharomyces cerevisiae. Because B-type cyclin-Cdk1 complexes are the drivers of S-phase initiation, Sic1 prevents premature S-phase entry. Multisite phosphorylation of Sic1 is thought to time Sic1 ubiquitination and destruction, and by extension, the timing of S-phase entry.

A series of biochemical switches control transitions between and within the various phases of the cell cycle. The cell cycle is a series of complex, ordered, sequential events that control how a single cell divides into two cells, and involves several different phases. The phases include the G1 and G2 phases, DNA replication or S phase, and the actual process of cell division, mitosis or M phase. During the M phase, the chromosomes separate and cytokinesis occurs.

The Start checkpoint is a major cell cycle checkpoint in yeast. The Start checkpoint ensures irreversible cell-cycle entry even if conditions later become unfavorable. The physiological factors that control passage through the Start checkpoint include external nutrient concentrations, presence of mating factor/ pheromone, forms of stress, and size control.

Control of chromosome duplication

In cell biology, eukaryotes possess a regulatory system that ensures that DNA replication occurs only once per cell cycle.

Clb5 and Clb6 are B-type, S-phase cyclins in yeast that assist in cell cycle regulation. Clb5 and Clb6 bind and activate Cdk1, and high levels of these cyclins are required for entering S-phase. S-phase cyclin binding to Cdk1 directly stimulates DNA replication as well as progression to the next phase of the cell cycle.

Mitotic Exit is an important transition point that signifies the end of mitosis and the onset of new G1 phase for a cell, and the cell needs to rely on specific control mechanisms to ensure that once it exits mitosis, it never returns to mitosis until it has gone through G1, S, and G2 phases and passed all the necessary checkpoints. Many factors including cyclins, cyclin-dependent kinases (CDKs), ubiquitin ligases, inhibitors of cyclin-dependent kinases, and reversible phosphorylations regulate mitotic exit to ensure that cell cycle events occur in correct order with fewest errors. The end of mitosis is characterized by spindle breakdown, shortened kinetochore microtubules, and pronounced outgrowth of astral (non-kinetochore) microtubules. For a normal eukaryotic cell, mitotic exit is irreversible.

WHI3 is a developmental regulator in budding yeast. It influences cell size and the cell cycle by binding CLN3 mRNA and inhibiting its transcription. This, in turn, inhibits the G1/S transition.

Whi5 is a transcriptional regulator in the budding yeast cell cycle, notably in the G1 phase. It is an inhibitor of SBF, which is involved in the transcription of G1-specific genes. Cln3 promotes the disassociation of Whi5 from SBF, and its disassociation results in the transcription of genes needed to enter S phase.

BCK2, also named CTR7, is an early cell cycle regulator expressed by the yeast Saccharomyces cerevisiae. It was first discovered in a screen for genes whose overexpression would suppress the phenotypes of PKC1 pathway mutations. Though its mechanism is currently unknown, it is believed to interact with Swi4 and Mcm1, both important transcriptional regulators of early cell cycle.

References

  1. 1 2 Oehlen, Lambertus; Cross, Frederick R. (1994). "G1 Cyclins CLN1 and CLN2 Repress the Mating Factor Response Pathway at Start in the Yeast Cell Cycle". Genes & Development. 8: 1058–070. doi: 10.1101/gad.8.9.1058 . PMID   7926787.
  2. 1 2 3 Morgan, David. The Cell Cycle: Principles of Cell Control. New Science Press Ltd., London, 2007; pp 32.
  3. ↑ Di Talia et al. Daughter-Specific Transcription Factors Regulate Cell Size Control in Budding Yeast, PLoS Biology 2009
  4. ↑ Gari, Eloi, Tom Volpe, and Hongyin Wang. "Whi3 Binds the MRNA of the G1 Cyclin CLN3 to Modulate the Cell Fate in Budding Yeast." Genes and Dev (2001): 2803-808.
  5. 1 2 "CLN1/YMR199W Summary." Yeast Genome. 12 Dec. 1999. Web. <https://www.yeastgenome.org/locus/cln1>.
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