# Cln3

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This article is about the budding yeast cyclin. For other uses, see [Cln3 (disambiguation)](/source/Cln3_(disambiguation)).

**G1/S-specific cyclin Cln3** is a [protein](/source/Protein) that is encoded by the *CLN3* [gene](/source/Gene). The Cln3 protein is a [budding yeast](/source/Saccharomyces_cerevisiae) [G1 cyclin](/source/G1_and_G1/S_cyclins-_budding_yeast) that controls the timing of [*Start*](/source/Start_point_(yeast)), the point of commitment to a mitotic [cell cycle](/source/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](/source/Cyclin), it functions by binding and activating [cyclin-dependent kinase](/source/Cyclin-dependent_kinase) (CDK).[5]

## Cln3 in *Start* regulation

Cln3 regulates [*Start*](/source/Start_point_(yeast)), the point at which [budding yeast](/source/Saccharomyces_cerevisiae) commit to the [G1/S transition](/source/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](/source/Allele) in a screen for small size mutants of [Saccharomyces cerevisiae](/source/Saccharomyces_cerevisiae) (for Cln3's role in size control, see [below](#Cln3_and_cell_size_control)).[6][7] This screen was inspired by a similar study in [Schizosaccharomyces pombe](/source/Schizosaccharomyces_pombe), in which the *[Wee1](/source/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](/source/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](/source/Nonsense_mutation) that removed a degradation-promoting [PEST sequence](/source/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](/source/S-phase) and begin [DNA replication](/source/DNA_replication). The current model of the [gene regulatory network](/source/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 factors](/source/Transcription_factor) SBF and MBF (not shown in the diagram),[13][14][15][16] as well as the [B-type cyclin](/source/Clb_5,6_(Cdk1)) inhibitor [Sic1](/source/Sic1).[17] Cln-CDKs activate SBF by phosphorylating and promoting nuclear export of its inhibitor, [Whi5](/source/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](/source/Clb_5,6_(Cdk1)), which bind CDK to phosphorylate S-phase targets. However, Clb5,6-CDK complexes are inhibited by Sic1, so S-phase initiation requires [phosphorylation](/source/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](/source/G1_and_G1/S_cyclins-_budding_yeast) 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](/source/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](/source/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](/source/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](/source/Cell_biology). The study of [cell size control](/source/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](/source/Leland_H._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](/source/Translation_(biology)) rate. Essentially, since cell growth consists, to a great extent, of the synthesis of [ribosomes](/source/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](#Cln3_as_size_sensor)).

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](/source/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](/source/Glossary_of_gene_expression_terms#C) 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](/source/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](/source/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](/source/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](/source/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](/source/Chaperone_(protein)) Ydj1, which otherwise holds Cln3 molecules in the [Endoplasmic reticulum](/source/Endoplasmic_reticulum).[44]

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Adapted from the Wikipedia article [Cln3](https://en.wikipedia.org/wiki/Cln3) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Cln3?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.