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Cln3
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).
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]
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). 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. 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 that removed a degradation-promoting PEST sequence 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.[citation needed]
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.
The key targets of the G1 cyclins in this transition are the transcription factors SBF and MBF (not shown in the diagram), as well as the B-type cyclin inhibitor Sic1. Cln-CDKs activate SBF by phosphorylating and promoting nuclear export of its inhibitor, Whi5, 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.
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. 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. 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 Whi5, which is the molecular basis of commitment to S-phase.
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]
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. 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.
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Cln3
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).
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]
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). 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. 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 that removed a degradation-promoting PEST sequence 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.[citation needed]
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.
The key targets of the G1 cyclins in this transition are the transcription factors SBF and MBF (not shown in the diagram), as well as the B-type cyclin inhibitor Sic1. Cln-CDKs activate SBF by phosphorylating and promoting nuclear export of its inhibitor, Whi5, 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.
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. 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. 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 Whi5, which is the molecular basis of commitment to S-phase.
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]
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. 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.