G1/S-specific cyclin Cln3 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that is encoded by the ''CLN3''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. The Cln3 protein is a

budding yeast ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been ...

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 Cyclin-dependent kinases (CDKs) are the families of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. They a ...

(CDK).

Cln3 in ''Start'' regulation

Cln3 regulates ''Start'', the point at which

commit to the

G1/S transition 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 sub ...

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.

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 ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...

(for Cln3's role in size control, see

below Below may refer to: *Earth *Ground (disambiguation) *Soil *Floor *Bottom (disambiguation) Bottom may refer to: Anatomy and sex * Bottom (BDSM), the partner in a BDSM who takes the passive, receiving, or obedient role, to that of the top or ...

). This screen was inspired by a similar study in

Schizosaccharomyces pombe ''Schizosaccharomyces pombe'', also called "fission yeast", is a species of yeast used in traditional brewing and as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically meas ...

, in which the ''

Wee1 Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast ''Schizosaccharomyces pombe'' (''S. pombe'')Wee1has a molecular mass of 96 kDa and is a key regulator of cell cycle progression. It influences ...

'' gene was identified as an inhibitor of cell cycle progression that maintained normal cell size. 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. The original ''WHI1-1'' allele (changed from ''whi1-1'' because it is a dominant allele) in fact contained a

nonsense mutation In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and in leading to a truncated, incomplete, and usually nonfunctional protein produc ...

that removed a degradation-promoting

PEST sequence A PEST sequence is a peptide sequence that is rich in proline (P), glutamic acid (E), serine (S), and threonine (T). This sequence is associated with proteins that have a short intracellular half-life; therefore, it is hypothesized that the PES ...

from the Whi1 protein and thus accelerated G1 progression. ''WHI1'' was furthermore found to be a cyclin homologue, and it was shown that simultaneous deletion of ''WHI1''—renamed ''CLN3''—and the previously identified G1 cyclins, ''CLN1'' and ''CLN2'', caused permanent G1 arrest. This showed that the three G1 cyclins were responsible for controlling ''Start'' entry in budding yeast.

G1-S transition

The three G1 cyclins collaborate to drive yeast cells through the G1-S transition, i.e. to enter

S-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 ...

and begin

DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...

. The current model of the gene regulatory network controlling the G1-S transition is shown in Figure 1. The key targets of the G1 cyclins in this transition are the

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

s SBF and MBF (not shown in the diagram), as well as the

B-type cyclin G2/mitotic-specific cyclin-B2 is a protein that in humans is encoded by the ''CCNB2'' gene. Function Cyclin B2 is a member of the cyclin family, specifically the B-type cyclins. The B-type cyclins, B1 and B2, associate with p34cdc2 and are esse ...

inhibitor

Sic1 Sic1, a protein, is a stoichiometric inhibitor of Cdk1-Clb ( B-type cyclins) 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 ...

. Cln-CDKs activate SBF by phosphorylating and promoting nuclear export of its inhibitor,

Whi5 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 disass ...

, which associates with promoter-bound SBF. 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. 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.

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 In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

activity than the other Clns. This indicated that Cln3 was an upstream regulator of Cln1 and Cln2. Furthermore, it was found, as shown in Figure 1, that Cln1 and Cln2 could activate their own transcription via SBF, completing a

positive feedback Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop which exacerbates the effects of a small disturbance. That is, the effects of a perturbation on a system include an increase in the ...

loop that could contribute to rapid activation and S-phase entry. 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, but recent experiments have confirmed its importance for rapid inactivation and nuclear export of

, which is the molecular basis of commitment to S-phase.

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.

''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 Cell biology (also cellular biology or cytology) is a branch of biology that studies the structure, function, and behavior of cells. All living organisms are made of cells. A cell is the basic unit of life that is responsible for the living and ...

. The study of

cell size control Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...

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 Leland Harrison (Lee) Hartwell (born October 30, 1939 in Los Angeles, California) is former president and director of the Fred Hutchinson Cancer Research Center in Seattle, Washington (state), Washington. He shared the 2001 Nobel Prize in Physio ...

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. 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.

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 Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...

rate. Essentially, since cell growth consists, to a great extent, of the synthesis of

ribosomes Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to f ...

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. 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, 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

). 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, 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''. 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''.

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. Second, it was expressed nearly constitutively throughout the cell cycle and in G1 in particular—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). 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 In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

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,

) 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. However, the nucleus has recently been shown to grow during G1, irrespective of genome content, undermining this model. Recent experiments have suggested that Cln3 activity could be titrated directly against genomic DNA, through its DNA-bound interaction with SBF-

complexes. 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; 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 The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

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