Cln3

Last updated
G1/S-specific cyclin CLN3
Identifiers
Organism S. cerevisiae (Baker's yeast)
SymbolCLN3
Alt. symbolsYAL040C, WHI1, DAF1, FUN10
Entrez 851191
RefSeq (mRNA) NM_001178185
RefSeq (Prot) NP_009360
UniProt P13365
Other data
Chromosome 1: 0.07 - 0.07 Mb
Search for
Structures Swiss-model
Domains InterPro

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, [1] and it is thought to be the key regulator linking cell growth to cell cycle progression. [2] [3] It is a 65 kD, unstable protein; [4] like other cyclins, it functions by binding and activating cyclin-dependent kinase (CDK). [5]

Contents

Cln3 in Start regulation

Cln3 regulates Start, the point at which budding yeast commit to the G1/S transition and thus a round of mitotic division. It was first identified as a gene controlling this process in the 1980s; research over the past few decades has provided a mechanistic understanding of its function.[ citation needed ]

Identification of CLN3 gene

The CLN3 gene was originally identified as the whi1-1 allele in a screen for small size mutants of Saccharomyces cerevisiae (for Cln3's role in size control, see below). [6] [7] This screen was inspired by a similar study in Schizosaccharomyces pombe, in which the Wee1 gene was identified as an inhibitor of cell cycle progression that maintained normal cell size. [8] Thus, the WHI1 gene was at first thought to perform a size control function analogous to that of Wee1 in pombe. However, it was later found that WHI1 was in fact a positive regulator of Start, as its deletion caused cells to delay in G1 and grow larger than wild-type cells. [9] [10] The original WHI1-1 allele (changed from whi1-1 because it is a dominant allele) in fact contained a nonsense mutation that removed a degradation-promoting PEST sequence from the Whi1 protein and thus accelerated G1 progression. [4] [9] WHI1 was furthermore found to be a cyclin homologue, [9] and it was shown that simultaneous deletion of WHI1—renamed CLN3—and the previously identified G1 cyclins, CLN1 and CLN2, caused permanent G1 arrest. [11] [12] This showed that the three G1 cyclins were responsible for controlling Start entry in budding yeast.[ citation needed ]

G1-S transition

The three G1 cyclins collaborate to drive yeast cells through the G1-S transition, i.e. to enter S-phase and begin DNA replication. The current model of the gene regulatory network controlling the G1-S transition is shown in Figure 1.

Figure 1: Regulation of the G1-S transition in budding yeast Quendiljt start schematic 2011.svg
Figure 1: Regulation of the G1-S transition in budding yeast

The key targets of the G1 cyclins in this transition are the transcription factors SBF and MBF (not shown in the diagram), [13] [14] [15] [16] as well as the B-type cyclin inhibitor Sic1. [17] Cln-CDKs activate SBF by phosphorylating and promoting nuclear export of its inhibitor, Whi5, which associates with promoter-bound SBF. [18] [19] [20] [21] The precise mechanism of MBF activation is unknown. Together, these transcription factors promote the expression of over 200 genes, which encode the proteins necessary for carrying out the biochemical activities of S-phase. [22] [23] These include the S-phase cyclins Clb5 and Clb6, which bind CDK to phosphorylate S-phase targets. However, Clb5,6-CDK complexes are inhibited by Sic1, so S-phase initiation requires phosphorylation and degradation of Sic1 by Cln1,2-CDK to proceed fully. [17]

Cln3 activates a Cln1,2 positive feedback loop

Although all three G1 cyclins are necessary for normal regulation of Start and the G1-S transition, Cln3 activity seems to be the deciding factor in S-phase initiation, with Cln1 and Cln2 serving to actuate the Cln3-based decision to transit Start. It was found early on that Cln3 activity induced expression of Cln1 and Cln2. Furthermore, Cln3 was a stronger activator Start transit than Cln1 and Cln2, even though Cln3-CDK had an inherently weaker kinase activity than the other Clns. This indicated that Cln3 was an upstream regulator of Cln1 and Cln2. [1] Furthermore, it was found, as shown in Figure 1, that Cln1 and Cln2 could activate their own transcription via SBF, completing a positive feedback loop that could contribute to rapid activation and S-phase entry. [24] [25] Thus, Start transit seems to rely on reaching a sufficient level of Cln3-CDK activity to induce the Cln1,2 positive feedback loop, which rapidly increases SBF/MBF and Cln1,2 activity, allowing a switch-like G1-S transition. The role of positive feedback in this process has been challenged, [26] [27] but recent experiments have confirmed its importance for rapid inactivation and nuclear export of Whi5, [28] which is the molecular basis of commitment to S-phase. [29]

Cln3 and cell size control

As discussed above, Cln3 was originally identified as a regulator of budding yeast cell size. The elucidation of the mechanisms by which it regulates Start has revealed a means for it to link cell size to cell cycle progression, but questions remain as to how it actually senses cell size.[ citation needed ]

Start requires a threshold cell size

The simple observation that cells of a given type are similar in size, and the question of how this similarity is maintained, has long fascinated cell biologists. The study of cell size control in budding yeast began in earnest in the mid 1970s, when the regulation of the budding yeast cell cycle was first being elucidated by Lee Hartwell and colleagues. Seminal work in 1977 found that yeast cells maintain a constant size by delaying their entry into the cell cycle (as assayed by budding) until they have grown to a threshold size. [30] [31] Later worked refined this result to show that Start specifically, rather than some other aspect of the G1-S transition, is controlled by the size threshold. [32]

Translational size sensing

That Start transit requires the attainment of a threshold cell size directly implies that yeast cells measure their own size, so that they can use that information to regulate Start. A favored model for how yeast cells, as well as cells of other species, measure their size relies on the detection of overall translation rate. Essentially, since cell growth consists, to a great extent, of the synthesis of ribosomes to produce more proteins, the overall rate of protein production should reflect cell size. Thus, a single protein that is produced at a constant rate relative to total protein production capacity will be produced in higher quantities as the cell grows. If this protein promotes cell cycle progression (Start in the case of yeast), then it will link cell cycle progression to translation rate and, therefore, cell size. Importantly, this protein must be unstable, so that its levels depend on its current translation rate, rather than the rate of translation over time. [33] Furthermore, since the cell grows in volume as well as mass, the concentration of this size sensor will remain constant with growth, so its activity must be compared against something that does not change with cell growth. Genomic DNA was suggested as such a standard early on, [34] because it is (by definition) present in a constant quantity until the start of DNA replication. How this occurs remains a major question in current studies of size control (see below).

Before the identification of Cln3 and its function, accrued evidence indicated that such translational size sensing operated in yeast. First, it was confirmed that the total rate of protein synthesis per cell increases with growth, [35] a fundamental prerequisite for this model. It was later shown that treatment with the protein synthesis inhibitor cycloheximide delayed Start in yeast, indicating that translation rate controlled Start. [36] [37] Finally, it was also shown that this delay occurred even with short pulses of cycloheximide, confirming that an unstable activating protein was required for Start. [38]

Cln3 as size sensor

The model of budding yeast size control, in which a threshold size for Start entry is detected by a translational size sensor, required a "sizer" protein; the properties of Cln3 made it the prime candidate for that role from the time of its discovery. First, it was a critical Start activator, as G1 length varied inversely with Cln3 expression and activity levels. [9] Second, it was expressed nearly constitutively throughout the cell cycle and in G1 in particular [1] —unusual for cyclins, which (as their name suggests) oscillate in expression with the cell cycle. These two properties meant that Cln3 could serve as a Start activator that depended on total translation rate. Finally, Cln3 was also shown to be highly unstable, the third necessary property of a translational sizer (as discussed above). [4] [5]

Thus, Cln3 seems to be the size sensor in budding yeast, as it exhibits the necessary properties of a translational sizer and is the most upstream regulator of Start. A critical question remains, however, as to how its activity is rendered size dependent. As noted above, any translational size sensor should be at constant concentration, and thus constant activity, in the cytoplasm as cells grow. In order to detect its size, the cell must compare the absolute number of sizer molecules to some non-growing standard, with the genome the obvious choice for such a standard. It was originally thought that yeast accomplished this with Cln3 by localizing it (and its target, Whi5) to the nucleus: nuclear volume was assumed to scale with genome content, so that an increasing concentration of Cln3 in the nucleus could indicate increasing Cln3 molecules relative to the genome. [2] [39] [40] However, the nucleus has recently been shown to grow during G1, irrespective of genome content, undermining this model. [41] Recent experiments have suggested that Cln3 activity could be titrated directly against genomic DNA, through its DNA-bound interaction with SBF-Whi5 complexes. [42] Finally, other models exist that do not rely on comparison of Cln3 levels to DNA. One posits a non-linear relationship between total translation rate and Cln3 translation rate caused by an Upstream open reading frame; [43] another suggests that the increase in Cln3 activity at the end of G1 relies on competition for the chaperone protein Ydj1, which otherwise holds Cln3 molecules in the Endoplasmic reticulum. [44]

Related Research Articles

<span class="mw-page-title-main">Cell cycle</span> Series of events and stages that result in cell division

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

<span class="mw-page-title-main">Anaphase-promoting complex</span> Cell-cycle regulatory complex

Anaphase-promoting complex is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin (Apc2) and RING (Apc11) subunit much like SCF. Other parts of the APC/C have unknown functions but are highly conserved.

<span class="mw-page-title-main">Cyclin-dependent kinase</span> Class of enzymes

Cyclin-dependent kinases (CDKs) are a predominant group of serine/threonine protein kinases involved in the regulation of the cell cycle and its progression, ensuring the integrity and functionality of cellular machinery. These regulatory enzymes play a crucial role in the regulation of eukaryotic cell cycle and transcription, as well as DNA repair, metabolism, and epigenetic regulation, in response to several extracellular and intracellular signals. They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved. The catalytic activities of CDKs are regulated by interactions with CDK inhibitors (CKIs) and regulatory subunits known as cyclins. Cyclins have no enzymatic activity themselves, but they become active once they bind to CDKs. Without cyclin, CDK is less active than in the cyclin-CDK heterodimer complex. CDKs phosphorylate proteins on serine (S) or threonine (T) residues. The specificity of CDKs for their substrates is defined by the S/T-P-X-K/R sequence, where S/T is the phosphorylation site, P is proline, X is any amino acid, and the sequence ends with lysine (K) or arginine (R). This motif ensures CDKs accurately target and modify proteins, crucial for regulating cell cycle and other functions. Deregulation of the CDK activity is linked to various pathologies, including cancer, neurodegenerative diseases, and stroke.

<span class="mw-page-title-main">Cyclin-dependent kinase complex</span>

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.

<span class="mw-page-title-main">S phase</span> 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.

<span class="mw-page-title-main">G1/S transition</span> Stage in cell cycle

The G1/S transition is a stage in the cell cycle at the boundary between the G1 phase, in which the cell grows, and the S phase, during which DNA is replicated. It is governed by cell cycle checkpoints to ensure cell cycle integrity and the subsequent S phase can pause in response to improperly or partially replicated DNA. During this transition the cell makes decisions to become quiescent, differentiate, make DNA repairs, or proliferate based on environmental cues and molecular signaling inputs. The G1/S transition occurs late in G1 and the absence or improper application of this highly regulated checkpoint can lead to cellular transformation and disease states such as cancer.

<span class="mw-page-title-main">Cyclin D</span> Member of the cyclin protein family

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.

<span class="mw-page-title-main">Cyclin-dependent kinase 1</span> 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 protein 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. With its cyclin partners, Cdk1 forms complexes that phosphorylate a variety of target substrates ; phosphorylation of these proteins leads to cell cycle progression.

<span class="mw-page-title-main">Cell division cycle 7-related protein kinase</span> Protein found in humans

Cell division cycle 7-related protein kinase is an enzyme that in humans is encoded by the CDC7 gene. The Cdc7 kinase is involved in regulation of the cell cycle at the point of chromosomal DNA replication. The gene CDC7 appears to be conserved throughout eukaryotic evolution; this means that most eukaryotic cells have the Cdc7 kinase protein.

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.

<span class="mw-page-title-main">Meiotic recombination checkpoint</span>

The meiotic recombination checkpoint monitors meiotic recombination during meiosis, and blocks the entry into metaphase I if recombination is not efficiently processed.

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 point is a major cell cycle checkpoint in yeast, known as the restriction point in multicellular organisms. The Start checkpoint ensures 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.

<span class="mw-page-title-main">Cell division control protein 4</span>

Cdc4 is a substrate recognition component of the SCF ubiquitin ligase complex, which acts as a mediator of ubiquitin transfer to target proteins, leading to their subsequent degradation via the ubiquitin-proteasome pathway. Cdc4 targets primarily cell cycle regulators for proteolysis. It serves the function of an adaptor that brings target molecules to the core SCF complex. Cdc4 was originally identified in the model organism Saccharomyces cerevisiae. CDC4 gene function is required at G1/S and G2/M transitions during mitosis and at various stages during meiosis.

<span class="mw-page-title-main">APC/C activator protein CDH1</span> Fungal protein found in Saccharomyces cerevisiae S288c

Cdh1 is one of the substrate adaptor proteins of the anaphase-promoting complex (APC) in the budding yeast Saccharomyces cerevisiae. Functioning as an activator of the APC/C, Cdh1 regulates the activity and substrate specificity of this ubiquitin E3-ligase. The human homolog is encoded by the FZR1 gene, which is not to be confused with the CDH1 gene.

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.

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 translation. This, in turn, inhibits the G1/S transition.

Whi5 is a transcriptional regulator in the budding yeast, notably in the G1 phase. It plays an important role in cell size control in G1 phase, similarly with Retinoblastoma (Rb) protein in human, although the two have no similarity in sequence Whi5 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

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