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{{About|the budding yeast cyclin}}
{{About|the budding yeast cyclin}}


{{Protein
⚫
The Cln3 protein (gene name ''CLN3'', systematic name [http://www.yeastgenome.org/cgi-bin/locus.fpl?locus=CLN3 YAL040C]) is a yeast [[G1 and G1/S cyclins- 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,<ref>{{cite journal|last=Tyers|first=M|coauthors=Tokiwa, G, Futcher, B|title=Comparison of the Saccharomyces cerevisiae G1 cyclins: Cln3 may be an upstream activator of Cln1, Cln2 and other cyclins.|journal=The EMBO journal|date=1993 May|volume=12|issue=5|pages=1955-68|pmid=8387915}}</ref> and it is thought to be the key regulator linking cell growth to cell cycle progression.<ref>{{cite journal|last=Futcher|first=B|title=Cyclins and the wiring of the yeast cell cycle.|journal=Yeast (Chichester, England)|date=1996 Dec|volume=12|issue=16|pages=1635-46|pmid=9123966}}</ref>
| Name = Cln3
| image =
| width =
| caption =
| Symbol = Cln3
| AltSymbols = YAL040C, Whi1, Daf1, Fun10
| UniProt = P13365
}}



⚫
References:
⚫
The Cln3 protein (gene name ''CLN3'', systematic name [http://www.yeastgenome.org/cgi-bin/locus.fpl?locus=CLN3 YAL040C]) is a [[Saccharomyces cerevisiae|budding yeast]] [[G1 and G1/S cyclins- budding yeast|G1 cyclin]] that controls the timing of [[Start point (yeast)|''Start'']], the point of commitment to a mitotic cell cycle. It is an upstream regulator of the other G1 cyclins,<ref name="tyers 1993" /> and it is thought to be the key regulator linking cell growth to cell cycle progression.<ref name="Futcher 1996" /> <ref name="Jorgensen 2004" /> It is a 65 kD, unstable protein;<ref name="tyers 1992" /> like other [[Cyclin|cyclins]], it functions by binding and activating [[Cyclin-dependent kinase]] (CDK).<ref name="cross unstable" />
<references />

==Cln3 in ''Start'' regulation==
Cln3 regulates [[Start point (yeast)|''Start'']], the point at which [[Saccharomyces cerevisiae|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.

===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 [[#Cln3 and cell size control|below]]).<ref name="sudbery 1980" /><ref name="carter 1980" /> This screen was inspired by a similar study in [[Schizosaccharomyces pombe]], in which the [[Wee1|''Wee1'']] gene was identified as an inhibitor of cell cycle progression that maintained normal cell size. <ref name="nurse wee" /> 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.<ref name="nash whi1" /><ref name="cross daf1" /> 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.<ref name="nash whi1" /><ref name="tyers 1992" /> ''WHI1'' was furthermore found to be a cyclin homologue,<ref name="nash whi1" /> and it was shown that simultaneous deletion of ''WHI1''—renamed ''CLN3''—and the previously identified G1 cyclins, ''CLN1'' and ''CLN2'', caused permanent G1 arrest.<ref name="richardson cyclins" /><ref name="hadwiger cyclins" /> 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]] and begin [[DNA replication]]. The current model of the gene regulatory network controlling the G1-S transition is shown in Figure 1. [[File:Quendiljt_start_schematic_2011.svg|thumb|500px|Figure 1: Regulation of the G1-S transition in budding yeast.]] The key targets of the G1 cyclins in this transition are the [[Transcription factor|transcription factors]] SBF and MBF (not shown in the diagram),<ref name="wijnen 2002" /><ref name="koch mbfsbf" /><ref name="dirick swi6" /><ref name="Nasmyth swi46" /> as well as the [[Clb 5,6 (Cdk1)|B-type cyclin]] inhibitor [[Sic1]].<ref name="Schwob SIc1" /> Cln-CDKs activate SBF by phosphorylating and promoting nuclear export of its inhibitor, Whi5, which associates with promoter-bound SBF.<ref name="jorgensen screen" /> <ref name="de bruin whi5" /><ref name="costanzo whi5" /><ref name="koch whi5sbf" /><ref name="cosma ordered recruitment" /> 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.<ref name="ferrezuelo network" /><ref name="bean overlap" /> These include the S-phase cyclins [[Clb 5,6 (Cdk1)|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.<ref name="Schwob SIc1" />
===Cln3 activates a Cln1,2 positive feedback loop===
Although all three [[G1 and G1/S cyclins- budding yeast|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.<ref name="tyers 1993" /> 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.<ref name="dirick pro-feedback" /><ref name="cross pro-feedback" /> 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,<ref name="stuart anti-feedback" /><ref name="Dirick anti-feedback" /> but recent experiments have confirmed its importance for rapid inactivation and nuclear export of Whi5,<ref name="skotheim 2008" /> which is the molecular basis of commitment to S-phase.<ref name=doncic />
==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 biology|cell biologists]]. The study of [[cell size control]] in budding yeast began in earnest in the mid 1970's, when the regulation of the budding yeast cell cycle was first being elucidated by [[Leland H. Hartwell|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.<ref name="Johnston 1977" /><ref name="unger 1977" /> 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.<ref name="ditalia 2007" />
===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 (biology)|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.<ref name=Schneiderman_instability /> 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,<ref name="donachie 1968" /> 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 [[#Cln3 as size sensor|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,<ref name=Elliott /> 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''.<ref name="popolo 1982" /><ref name="moore kinetic" /> 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''.<ref name="shilo turnover" />
===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.<ref name="nash whi1" /> Second, it was expressed nearly [[Glossary of gene expression terms#C|constitutively]] throughout the cell cycle and in G1 in particular<ref name="tyers 1993" />—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).<ref name="cross unstable" /><ref name="tyers 1992" />

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.<ref name="edge nuc" /> <ref name="miller nuc" /><ref name="Futcher 1996" /> However, the nucleus has recently been shown to grow during G1, irrespective of genome content, undermining this model.<ref name="jorgensen nuc size" /> Recent experiments have suggested that Cln3 activity could be titrated directly against genomic DNA, through its DNA-bound interaction with SBF-Whi5 complexes.<ref name="wang cln3" /> 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]];<ref name="polymenis uorf" /> 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]].<ref name="aldea ydj1" />

⚫
==References==
{{reflist|
refs=
<ref name="tyers 1993">{{cite journal|last=Tyers|first=M|coauthors=Tokiwa, G, Futcher, B|title=Comparison of the Saccharomyces cerevisiae G1 cyclins: Cln3 may be an upstream activator of Cln1, Cln2 and other cyclins.|journal=The EMBO journal|date=1993 May|volume=12|issue=5|pages=1955-68|pmid=8387915}}</ref>
<ref name="Futcher 1996">{{cite journal|last=Futcher|first=B|title=Cyclins and the wiring of the yeast cell cycle.|journal=Yeast (Chichester, England)|date=1996 Dec|volume=12|issue=16|pages=1635-46|pmid=9123966}}</ref>
<ref name="Jorgensen 2004">{{cite journal|last=Jorgensen|first=P|coauthors=Tyers, M|title=How cells coordinate growth and division.|journal=Current biology : CB|date=2004 Dec 14|volume=14|issue=23|pages=R1014-27|pmid=15589139}}</ref>
<ref name="tyers 1992">{{cite journal|last=Tyers|first=M|coauthors=Tokiwa, G, Nash, R, Futcher, B|title=The Cln3-Cdc28 kinase complex of S. cerevisiae is regulated by proteolysis and phosphorylation.|journal=The EMBO journal|date=1992 May|volume=11|issue=5|pages=1773-84|pmid=1316273}}</ref>
<ref name="cross unstable">{{cite journal|last=Cross|first=FR|coauthors=Blake, CM|title=The yeast Cln3 protein is an unstable activator of Cdc28.|journal=Molecular and cellular biology|date=1993 Jun|volume=13|issue=6|pages=3266-71|pmid=8497251}}</ref>
<ref name="carter 1980">{{cite journal|last=Carter|first=BL|coauthors=Sudbery, PE|title=Small-sized mutants of Saccharomyces cerevisiae.|journal=Genetics|date=1980 Nov|volume=96|issue=3|pages=561-6|pmid=7021310}}</ref>
<ref name="sudbery 1980">{{cite journal|last=Sudbery|first=PE|coauthors=Goodey, AR, Carter, BL|title=Genes which control cell proliferation in the yeast Saccharomyces cerevisiae.|journal=Nature|date=1980 Nov 27|volume=288|issue=5789|pages=401-4|pmid=7001255}}</ref>
<ref name="unger 1977">{{cite journal|last=Hartwell|first=LH|coauthors=Unger, MW|title=Unequal division in Saccharomyces cerevisiae and its implications for the control of cell division.|journal=The Journal of cell biology|date=1977 Nov|volume=75|issue=2 Pt 1|pages=422-35|pmid=400873}}</ref>
<ref name="Johnston 1977">{{cite journal|last=Johnston|first=GC|coauthors=Pringle, JR, Hartwell, LH|title=Coordination of growth with cell division in the yeast Saccharomyces cerevisiae.|journal=Experimental cell research|date=1977 Mar 1|volume=105|issue=1|pages=79-98|pmid=320023}}</ref>
<ref name="ditalia 2007">{{cite journal|last=Di Talia|first=S|coauthors=Skotheim, JM, Bean, JM, Siggia, ED, Cross, FR|title=The effects of molecular noise and size control on variability in the budding yeast cell cycle.|journal=Nature|date=2007 Aug 23|volume=448|issue=7156|pages=947-51|pmid=17713537}}</ref>
<ref name="nurse wee">{{cite journal|last=Nurse|first=P|title=Genetic control of cell size at cell division in yeast.|journal=Nature|date=1975 Aug 14|volume=256|issue=5518|pages=547-51|pmid=1165770}}</ref>
<ref name="nash whi1">{{cite journal|last=Nurse|first=P|title=Genetic control of cell size at cell division in yeast.|journal=Nature|date=1975 Aug 14|volume=256|issue=5518|pages=547-51|pmid=1165770}}</ref>
<ref name="cross daf1">{{cite journal|last=Cross|first=FR|title=DAF1, a mutant gene affecting size control, pheromone arrest, and cell cycle kinetics of Saccharomyces cerevisiae.|journal=Molecular and cellular biology|date=1988 Nov|volume=8|issue=11|pages=4675-84|pmid=3062366}}</ref>
<ref name="richardson cyclins">{{cite journal|last=Richardson|first=HE|coauthors=Wittenberg, C, Cross, F, Reed, SI|title=An essential G1 function for cyclin-like proteins in yeast.|journal=Cell|date=1989 Dec 22|volume=59|issue=6|pages=1127-33|pmid=2574633}}</ref>
<ref name="hadwiger cyclins">{{cite journal|last=Hadwiger|first=JA|coauthors=Wittenberg, C, Richardson, HE, de Barros Lopes, M, Reed, SI|title=A family of cyclin homologs that control the G1 phase in yeast.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=1989 Aug|volume=86|issue=16|pages=6255-9|pmid=2569741}}</ref>
<ref name="dirick pro-feedback">{{cite journal|last=Dirick|first=L|coauthors=Nasmyth, K|title=Positive feedback in the activation of G1 cyclins in yeast.|journal=Nature|date=1991 Jun 27|volume=351|issue=6329|pages=754-7|pmid=1829507}}</ref>
<ref name="cross pro-feedback">{{cite journal|last=Cross|first=FR|coauthors=Tinkelenberg, AH|title=A potential positive feedback loop controlling CLN1 and CLN2 gene expression at the start of the yeast cell cycle.|journal=Cell|date=1991 May 31|volume=65|issue=5|pages=875-83|pmid=2040016}}</ref>
<ref name="stuart anti-feedback">{{cite journal|last=Stuart|first=D|coauthors=Wittenberg, C|title=CLN3, not positive feedback, determines the timing of CLN2 transcription in cycling cells.|journal=Genes & development|date=1995 Nov 15|volume=9|issue=22|pages=2780-94|pmid=7590253}}</ref>
<ref name="Dirick anti-feedback">{{cite journal|last=Dirick|first=L|coauthors=Böhm, T, Nasmyth, K|title=Roles and regulation of Cln-Cdc28 kinases at the start of the cell cycle of Saccharomyces cerevisiae.|journal=The EMBO journal|date=1995 Oct 2|volume=14|issue=19|pages=4803-13|pmid=7588610}}</ref>
<ref name="skotheim 2008">{{cite journal|last=Skotheim|first=JM|coauthors=Di Talia, S, Siggia, ED, Cross, FR|title=Positive feedback of G1 cyclins ensures coherent cell cycle entry.|journal=Nature|date=2008 Jul 17|volume=454|issue=7202|pages=291-6|pmid=18633409}}</ref>
<ref name="doncic">{{cite journal|last=Doncic|first=A|coauthors=Falleur-Fettig, M, Skotheim, JM|title=Distinct interactions select and maintain a specific cell fate.|journal=Molecular cell|date=2011 Aug 19|volume=43|issue=4|pages=528-39|pmid=21855793}}</ref>
<ref name="Nasmyth swi46">{{cite journal|last=Nasmyth|first=K|coauthors=Dirick, L|title=The role of SWI4 and SWI6 in the activity of G1 cyclins in yeast.|journal=Cell|date=1991 Sep 6|volume=66|issue=5|pages=995-1013|pmid=1832338}}</ref>
<ref name="dirick swi6">{{cite journal|last=Dirick|first=L|coauthors=Moll, T, Auer, H, Nasmyth, K|title=A central role for SWI6 in modulating cell cycle Start-specific transcription in yeast.|journal=Nature|date=1992 Jun 11|volume=357|issue=6378|pages=508-13|pmid=1608451}}</ref>
<ref name="koch mbfsbf">{{cite journal|last=Koch|first=C|coauthors=Moll, T, Neuberg, M, Ahorn, H, Nasmyth, K|title=A role for the transcription factors Mbp1 and Swi4 in progression from G1 to S phase.|journal=Science (New York, N.Y.)|date=1993 Sep 17|volume=261|issue=5128|pages=1551-7|pmid=8372350}}</ref>
<ref name="wijnen 2002">{{cite journal|last=Wijnen|first=H|coauthors=Landman, A, Futcher, B|title=The G(1) cyclin Cln3 promotes cell cycle entry via the transcription factor Swi6.|journal=Molecular and cellular biology|date=2002 Jun|volume=22|issue=12|pages=4402-18|pmid=12024050}}</ref>
<ref name="bean overlap">{{cite journal|last=Bean|first=JM|coauthors=Siggia, ED, Cross, FR|title=High functional overlap between MluI cell-cycle box binding factor and Swi4/6 cell-cycle box binding factor in the G1/S transcriptional program in Saccharomyces cerevisiae.|journal=Genetics|date=2005 Sep|volume=171|issue=1|pages=49-61|pmid=15965243}}</ref>
<ref name="ferrezuelo network">{{cite journal|last=Ferrezuelo|first=F|coauthors=Colomina, N, Futcher, B, Aldea, M|title=The transcriptional network activated by Cln3 cyclin at the G1-to-S transition of the yeast cell cycle.|journal=Genome biology|date=2010|volume=11|issue=6|pages=R67|pmid=20573214}}</ref>
<ref name="jorgensen screen">{{cite journal|last=Jorgensen|first=P|coauthors=Nishikawa, JL, Breitkreutz, BJ, Tyers, M|title=Systematic identification of pathways that couple cell growth and division in yeast.|journal=Science (New York, N.Y.)|date=2002 Jul 19|volume=297|issue=5580|pages=395-400|pmid=12089449}}</ref>
<ref name="de bruin whi5">{{cite journal|last=de Bruin|first=RA|coauthors=McDonald, WH, Kalashnikova, TI, Yates J, 3rd, Wittenberg, C|title=Cln3 activates G1-specific transcription via phosphorylation of the SBF bound repressor Whi5.|journal=Cell|date=2004 Jun 25|volume=117|issue=7|pages=887-98|pmid=15210110}}</ref>
<ref name="costanzo whi5">{{cite journal|last=Costanzo|first=M|coauthors=Nishikawa, JL, Tang, X, Millman, JS, Schub, O, Breitkreuz, K, Dewar, D, Rupes, I, Andrews, B, Tyers, M|title=CDK activity antagonizes Whi5, an inhibitor of G1/S transcription in yeast.|journal=Cell|date=2004 Jun 25|volume=117|issue=7|pages=899-913|pmid=15210111}}</ref>
<ref name="koch whi5sbf">{{cite journal|last=Koch|first=C|coauthors=Schleiffer, A, Ammerer, G, Nasmyth, K|title=Switching transcription on and off during the yeast cell cycle: Cln/Cdc28 kinases activate bound transcription factor SBF (Swi4/Swi6) at start, whereas Clb/Cdc28 kinases displace it from the promoter in G2.|journal=Genes & development|date=1996 Jan 15|volume=10|issue=2|pages=129-41|pmid=8566747}}</ref>
<ref name="cosma ordered recruitment">{{cite journal|last=Cosma|first=MP|coauthors=Tanaka, T, Nasmyth, K|title=Ordered recruitment of transcription and chromatin remodeling factors to a cell cycle- and developmentally regulated promoter.|journal=Cell|date=1999 Apr 30|volume=97|issue=3|pages=299-311|pmid=10319811}}</ref>
<ref name="Schwob SIc1">{{cite journal|last=Schwob|first=E|coauthors=Böhm, T, Mendenhall, MD, Nasmyth, K|title=The B-type cyclin kinase inhibitor p40SIC1 controls the G1 to S transition in S. cerevisiae.|journal=Cell|date=1994 Oct 21|volume=79|issue=2|pages=233-44|pmid=7954792}}</ref>
<ref name="Schneiderman_instability">{{cite journal|last=Schneiderman|first=MH|coauthors=Dewey, WC, Highfield, DP|title=Inhibition of DNA synthesis in synchronized Chinese hamster cells treated in G1 with cycloheximide.|journal=Experimental cell research|date=1971 Jul|volume=67|issue=1|pages=147-55|pmid=5106077}}</ref>
<ref name="donachie 1968">{{cite journal|last=Donachie|first=WD|title=Relationship between cell size and time of initiation of DNA replication.|journal=Nature|date=1968 Sep 7|volume=219|issue=5158|pages=1077-9|pmid=4876941}}</ref>
<ref name="Elliott">{{cite journal|last=Elliott|first=SG|coauthors=McLaughlin, CS|title=Rate of macromolecular synthesis through the cell cycle of the yeast Saccharomyces cerevisiae.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=1978 Sep|volume=75|issue=9|pages=4384-8|pmid=360219}}</ref>
<ref name="popolo 1982">{{cite journal|last=Popolo|first=L|coauthors=Vanoni, M, Alberghina, L|title=Control of the yeast cell cycle by protein synthesis.|journal=Experimental cell research|date=1982 Nov|volume=142|issue=1|pages=69-78|pmid=6754401}}</ref>
<ref name="moore kinetic">{{cite journal|last=Moore|first=SA|title=Kinetic evidence for a critical rate of protein synthesis in the Saccharomyces cerevisiae yeast cell cycle.|journal=The Journal of biological chemistry|date=1988 Jul 15|volume=263|issue=20|pages=9674-81|pmid=3290211}}</ref>
<ref name="shilo turnover">{{cite journal|last=Shilo|first=B|coauthors=Riddle, VG, Pardee, AB|title=Protein turnover and cell-cycle initiation in yeast.|journal=Experimental cell research|date=1979 Oct 15|volume=123|issue=2|pages=221-7|pmid=387426}}</ref>
<ref name="miller nuc">{{cite journal|last=Miller|first=ME|coauthors=Cross, FR|title=Distinct subcellular localization patterns contribute to functional specificity of the Cln2 and Cln3 cyclins of Saccharomyces cerevisiae.|journal=Molecular and cellular biology|date=2000 Jan|volume=20|issue=2|pages=542-55|pmid=10611233}}</ref>
<ref name="edge nuc">{{cite journal|last=Edgington|first=NP|coauthors=Futcher, B|title=Relationship between the function and the location of G1 cyclins in S. cerevisiae.|journal=Journal of cell science|date=2001 Dec|volume=114|issue=Pt 24|pages=4599-611|pmid=11792824}}</ref>
<ref name="jorgensen nuc size">{{cite journal|last=Jorgensen|first=P|coauthors=Edgington, NP, Schneider, BL, Rupes, I, Tyers, M, Futcher, B|title=The size of the nucleus increases as yeast cells grow.|journal=Molecular biology of the cell|date=2007 Sep|volume=18|issue=9|pages=3523-32|pmid=17596521}}</ref>
<ref name="aldea ydj1">{{cite journal|last=Vergés|first=E|coauthors=Colomina, N, Garí, E, Gallego, C, Aldea, M|title=Cyclin Cln3 is retained at the ER and released by the J chaperone Ydj1 in late G1 to trigger cell cycle entry.|journal=Molecular cell|date=2007 Jun 8|volume=26|issue=5|pages=649-62|pmid=17560371}}</ref>
<ref name="polymenis uorf">{{cite journal|last=Polymenis|first=M|coauthors=Schmidt, EV|title=Coupling of cell division to cell growth by translational control of the G1 cyclin CLN3 in yeast.|journal=Genes & development|date=1997 Oct 1|volume=11|issue=19|pages=2522-31|pmid=9334317}}</ref>
<ref name="wang cln3">{{cite journal|last=Wang|first=H|coauthors=Carey, LB, Cai, Y, Wijnen, H, Futcher, B|title=Recruitment of Cln3 cyclin to promoters controls cell cycle entry via histone deacetylase and other targets.|journal=PLoS biology|date=2009 Sep|volume=7|issue=9|pages=e1000189|pmid=19823669}}</ref>
}}

Revision as of 22:59, 16 December 2011

This article is about the budding yeast cyclin. For other uses, see Cln3 (disambiguation).
Cln3
Identifiers
SymbolCln3
Alt. symbolsYAL040C, Whi1, Daf1, Fun10
UniProtP13365
Search for
StructuresSwiss-model
DomainsInterPro


The Cln3 protein (gene name CLN3, systematic name YAL040C) 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]

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.

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.[9][4] 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.

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.

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][22] 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.[23][24] 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.[25][26] 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,[27][28] but recent experiments have confirmed its importance for rapid inactivation and nuclear export of Whi5,[29] which is the molecular basis of commitment to S-phase.[30]

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. The study of cell size control in budding yeast began in earnest in the mid 1970's, 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.[31][32] 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.[33]

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.[34] 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,[35] 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,[36] 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.[37][38] 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.[39]

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).[5][4]

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.[40] [41][2] However, the nucleus has recently been shown to grow during G1, irrespective of genome content, undermining this model.[42] Recent experiments have suggested that Cln3 activity could be titrated directly against genomic DNA, through its DNA-bound interaction with SBF-Whi5 complexes.[43] 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;[44] 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.[45]

References

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