CLN3

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000082 G1/S transition of mitotic cell cycle	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (PAINT) annotation of the G1/S transition to the G1 cyclin clade (node PTN000019791, which also carries cyclin D, Cln1/Cln2 and fission-yeast Puc1). Cln3 is the founding budding-yeast G1 cyclin: Cln3-Cdc28 initiates the Start transcriptional program whose output (CLN1/CLN2/CLB5/6) commits the cell to S phase, exactly the process that GO:0000082 describes. Reason: The IBD node placement is sound - the G1/S-promoting activity of the G1 cyclin family is ancestral - and Cln3 has abundant direct experimental support for the same term (IGI/IMP rows below, and the classical Start genetics). The target appears in its own WITH/FROM list (SGD:S000000038 is CLN3), which is expected when the target's own experimental annotation contributed to the IBD. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000019791 · PTN000019791 SUPPORTS TRANSFER G1-cyclin ancestral node; Cln3 is inside the clade and carries its own experimental G1/S evidence. Supporting Evidence: PMID:8387915 the G1 cyclins Cln1, Cln2 and Cln3 regulate entry into the cell cycle (Start) by activating the Cdc28 protein kinase PMID:2574633 The data are consistent with the hypothesis that Cln proteins activate the Cdc28 protein kinase, shown to be essential for the G1 to S phase transition in S. cerevisiae
GO:0000082 G1/S transition of mitotic cell cycle	IGI PMID:19823668 Dual regulation by pairs of cyclin-dependent protein kinases...	ACCEPT	Summary: Genetic-interaction annotation from Huang et al. 2009 with PHO85: a cln3 pho85 double mutant has a G1 delay and severely reduced SBF-dependent transcription, showing that the Cln3-Cdc28 and Pcl-Pho85 CDKs act in parallel on Whi5 to trigger the G1/S transition. Reason: The cached full text shows the double-mutant G1 delay and its suppression by whi5 deletion; this is the core Start function of Cln3 and the IGI is appropriately coded. Supporting Evidence: PMID:19823668 We show that a strain deleted for both PHO85 and CLN3 has a slow growth phenotype, a G1 delay, and is severely compromised for SBF-dependent reporter gene expression, yet all of these defects are alleviated by deletion of WHI5 PMID:19823668 Phosphorylation and removal of Whi5 by the cyclin-dependent kinase (CDK) Cln3-Cdc28 alleviates the Whi5-dependent repression on SBF and MBF, initiating entry into a new cell cycle
GO:0000082 G1/S transition of mitotic cell cycle	IGI PMID:19823668 Dual regulation by pairs of cyclin-dependent protein kinases...	ACCEPT	Summary: Genetic-interaction annotation with WHI5 from the same study: deletion of WHI5 alleviates the growth, G1-delay and SBF-reporter defects of cln3 pho85 cells, placing Whi5 as the downstream target through which Cln3-Cdc28 drives G1/S. Reason: Whi5 bypass of the CLN3 requirement is the defining genetic result for Cln3's role at Start (also Costanzo et al. 2004 and de Bruin et al. 2004); the term describes Cln3's core function. Supporting Evidence: PMID:19823668 We show that a strain deleted for both PHO85 and CLN3 has a slow growth phenotype, a G1 delay, and is severely compromised for SBF-dependent reporter gene expression, yet all of these defects are alleviated by deletion of WHI5 PMID:15210110 Whi5 inactivation bypasses the requirement for Cln3 both for transcriptional activation and cell cycle initiation PMID:15210111 Deletion of WHI5 bypasses the requirement for upstream activators of the G1/S transcription factors SBF/MBF and thereby accelerates the G1/S transition
GO:0000082 G1/S transition of mitotic cell cycle	IMP PMID:19823668 Dual regulation by pairs of cyclin-dependent protein kinases...	ACCEPT	Summary: Mutant-phenotype annotation: cln3 deletion impairs SBF-driven reporter transcription (no growth on 30 mM 3-AT with an SCB-HIS3 reporter) and, in combination with pho85, delays G1 exit. Reason: Consistent with all classical cln3 phenotypes (large cells, delayed Start) and with the biochemical role of Cln3-Cdc28 in relieving Whi5 repression; core function. Supporting Evidence: PMID:19823668 both cln3Δ and pho85Δ mutants showed no growth in media containing 30 mM 3-AT indicating that SBF transcription is impaired in these mutants PMID:19823668 Phosphorylation and removal of Whi5 by the cyclin-dependent kinase (CDK) Cln3-Cdc28 alleviates the Whi5-dependent repression on SBF and MBF, initiating entry into a new cell cycle
GO:0000307 cyclin-dependent protein kinase holoenzyme complex	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic annotation placing Cln3 in a cyclin-dependent protein kinase holoenzyme complex. Cln3 forms an active kinase complex with Cdc28 (Cdk1), the sole essential CDK of budding yeast. Reason: Being the regulatory subunit of a cyclin-CDK holoenzyme is the ancestral property of the whole cyclin family; Cln3-Cdc28 complexes have been immunoprecipitated and assayed directly since 1992. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000019791 · PTN000019791 SUPPORTS TRANSFER Cyclin-CDK holoenzyme membership is a family-wide property; Cln3-Cdc28 is directly demonstrated. Supporting Evidence: PMID:1316273 Cln3 associates with Cdc28 to form an active kinase complex that phosphorylates Cln3 itself and a co-precipitated substrate of 45 kDa PMID:10913169 The levels of Cln2-Cdc28 and Cln3-Cdc28 protein kinase activity are severely reduced in cks1-38 cell extracts
GO:0000307 cyclin-dependent protein kinase holoenzyme complex	IPI PMID:10688190 A comprehensive analysis of protein-protein interactions in ...	ACCEPT	Summary: Complex-membership annotation derived from the Uetz et al. 2000 genome-wide two-hybrid screen (Cln3-Cdc28 pair). The cached record is abstract-only, but the Cln3-Cdc28 complex is independently established biochemically. Reason: The two-hybrid interaction with Cdc28 is a legitimate, if high-throughput, line of evidence for the holoenzyme, and the complex is confirmed by co-immunoprecipitation and kinase assays in other papers. Supporting Evidence: PMID:10688190 Two large-scale yeast two-hybrid screens were undertaken to identify protein-protein interactions between full-length open reading frames predicted from the Saccharomyces cerevisiae genome sequence PMID:1316273 Cln3 associates with Cdc28 to form an active kinase complex that phosphorylates Cln3 itself and a co-precipitated substrate of 45 kDa
GO:0005515 protein binding	IPI PMID:10688190 A comprehensive analysis of protein-protein interactions in ...	MODIFY	Summary: Generic protein-binding annotation for the Cln3-Cdc28 two-hybrid interaction (Uetz et al. 2000). Cdc28 is the CDK catalytic subunit that Cln3 binds and activates; the interaction is real and physiologically central, but the term carries no functional information. Reason: Repository policy is to resolve bare protein-binding IPI rows to an informative molecular function where the partner supports one. The partner is a protein kinase, so protein kinase binding (GO:0019901) is the minimal informative term for a two-hybrid pair; the activator activity itself is captured by the GO:0016538/GO:0061575 rows. Proposed replacements: protein kinase binding Supporting Evidence: PMID:10688190 Two large-scale yeast two-hybrid screens were undertaken to identify protein-protein interactions between full-length open reading frames predicted from the Saccharomyces cerevisiae genome sequence PMID:1316273 Cln3 associates with Cdc28 to form an active kinase complex that phosphorylates Cln3 itself and a co-precipitated substrate of 45 kDa
GO:0005515 protein binding	IPI PMID:10913169 Cks1 is required for G(1) cyclin-cyclin-dependent kinase act...	MODIFY	Summary: Protein-binding annotation with Cdc28 from Reynard et al. 2000, which measured Cln3-Cdc28 kinase activity in cell extracts and showed it depends on Cks1. The evidence is an active Cln3-Cdc28 kinase complex, i.e. Cln3 acting as the CDK activator. Reason: The paper assays Cln3-Cdc28 protein kinase activity, which directly supports cyclin-dependent protein serine/threonine kinase activator activity (GO:0061575) rather than uninformative protein binding. Proposed replacements: cyclin-dependent protein serine/threonine kinase activator activity Supporting Evidence: PMID:10913169 The levels of Cln2-Cdc28 and Cln3-Cdc28 protein kinase activity are severely reduced in cks1-38 cell extracts
GO:0005515 protein binding	IPI PMID:14690591 Assigning function to yeast proteins by integration of techn...	MODIFY	Summary: Protein-binding annotation with Cdc28 from the Hazbun et al. 2003 multi-technology (affinity purification/MS and two-hybrid) survey. The Cln3-Cdc28 interaction is genuine but the term is uninformative. Reason: High-throughput interaction evidence with a protein kinase partner; protein kinase binding (GO:0019901) is the informative MF supported by this kind of evidence. Removal of the generic term does not question the interaction. Proposed replacements: protein kinase binding Supporting Evidence: PMID:14690591 These proteins were subjected to affinity purification and mass spectrometry analysis to identify copurifying proteins, two-hybrid analysis to identify interacting proteins PMID:1316273 Cln3 associates with Cdc28 to form an active kinase complex that phosphorylates Cln3 itself and a co-precipitated substrate of 45 kDa
GO:0005515 protein binding	IPI PMID:19823669 Recruitment of Cln3 cyclin to promoters controls cell cycle ...	MODIFY	Summary: Protein-binding annotation with Swi6 from Wang et al. 2009: Cln3 co-immunoprecipitates with the Swi6 subunit of the SBF transcription factor in a Swi4-dependent manner and is found by ChIP at the CLN2 promoter next to the SBF sites. This is the physical basis for Cln3-Cdc28 acting on promoter-bound Whi5/SBF. Reason: The partner is a transcription factor subunit and the interaction recruits Cln3-Cdc28 to SBF-regulated promoters, so transcription factor binding (GO:0008134) is the informative replacement for the generic term. Proposed replacements: transcription factor binding Supporting Evidence: PMID:19823669 We found that Cln3 co-immunoprecipitates with the Swi6 component of SBF, and that this co-immunoprecipitation depends on Swi4 PMID:19823669 ChIP showed that Cln3 is found on the CLN2 promoter close to the SBF binding sites
GO:0005515 protein binding	IPI PMID:20489023 A global protein kinase and phosphatase interaction network ...	MODIFY	Summary: Protein-binding annotation with Cdc28 from the Breitkreutz et al. 2010 kinase/phosphatase interaction network (AP-MS). Cln3 co-purifies with its cognate CDK. Reason: Mass-spectrometric co-purification with a protein kinase supports protein kinase binding (GO:0019901); the generic term adds nothing beyond the holoenzyme and activator annotations. Proposed replacements: protein kinase binding Supporting Evidence: PMID:20489023 We identified a kinase and phosphatase interaction (KPI) network of 1844 interactions in budding yeast by mass spectrometric analysis of protein complexes PMID:1316273 Cln3 associates with Cdc28 to form an active kinase complex that phosphorylates Cln3 itself and a co-precipitated substrate of 45 kDa
GO:0005515 protein binding	IPI PMID:23217712 CDK-dependent Hsp70 Phosphorylation controls G1 cyclin abund...	MODIFY	Summary: Protein-binding annotation with Cdc28 (Cdk1) from Truman et al. 2012, a study of how CDK phosphorylation of the Hsp70 Ssa1 controls Cln3 abundance; Cln3 is phosphorylated by Cdk1 in vitro and Cdk1-Cln3 activity is assayed genetically via Whi5 overexpression. Reason: The partner is the CDK catalytic subunit; protein kinase binding (GO:0019901) is the informative term that this evidence supports. The paper's main finding (Ssa1-dependent Cln3 turnover) concerns regulation of Cln3 rather than a molecular function of Cln3. Proposed replacements: protein kinase binding Supporting Evidence: PMID:23217712 Bacterially expressed Cln3 can still be phosphorylated in vitro by Cdk1 purified from T36A cells PMID:23217712 T36 phosphorylation triggers displacement of Ydj1, allowing Ssa1 to bind the G1 cyclin Cln3 and promote its degradation
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic annotation that Cln3 is active in the nucleus. Cln3 is predominantly nuclear, carries a C-terminal bipartite NLS, and needs nuclear localization for its Start function (activation of SBF/MBF-dependent transcription at promoters). Reason: Family-level inference confirmed by immunofluorescence, fractionation and NLS mutagenesis on Cln3 itself; the nucleus is where Cln3-Cdc28 executes its core function. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000019791 · PTN000019791 SUPPORTS TRANSFER Nuclear site of action of G1 cyclin-CDKs is ancestral and directly shown for Cln3. Supporting Evidence: PMID:10611233 Cln3p localization appears to be primarily nuclear, with the most obvious accumulation of Cln3p to the nuclei of large budded cells PMID:11509671 Thus, wild-type Cln3p requires nuclear localization to carry out its normal roles
GO:0005634 nucleus	IDA PMID:10611233 Distinct subcellular localization patterns contribute to fun...	ACCEPT	Summary: Direct localization by indirect immunofluorescence and cell fractionation (Miller & Cross 2000): Cln3 is primarily nuclear, accumulating in the nuclei of large budded cells, in contrast to cytoplasmic Cln2. Reason: Full text cached; nuclear localization is shown by two independent methods and is functionally relevant (nuclear localization drives the Cln3-like functional profile). Supporting Evidence: PMID:10611233 Cln3p localization appears to be primarily nuclear, with the most obvious accumulation of Cln3p to the nuclei of large budded cells
GO:0005634 nucleus	IDA PMID:11509671 Mechanisms controlling subcellular localization of the G(1) ...	ACCEPT	Summary: Direct localization (Miller & Cross 2001): nuclear Cln3 localization depends on a C-terminal bipartite NLS that is necessary and sufficient to confer RAN-dependent nuclear import on GFP. Reason: Full text cached; defines the NLS and confirms nuclear residence of wild-type Cln3. Supporting Evidence: PMID:11509671 Cln3p localization requires a bipartite nuclear localization signal (NLS) located at the C terminus of the protein
GO:0005634 nucleus	IDA PMID:11792824 Relationship between the function and the location of G1 cyc...	ACCEPT	Summary: Independent localization study (Edgington & Futcher 2001) using fractionation, microscopy and forced-localization cassettes: Cln3 requires nuclear localization and has an autonomous C-terminal NLS. Reason: Abstract-only cache but the abstract states the result explicitly; concordant with the Miller & Cross studies. Supporting Evidence: PMID:11792824 The G1 cyclin Cln3 required nuclear localization. An autonomous, nuclear localization sequence was found near the C-terminus of Cln3
GO:0005634 nucleus	IMP PMID:11509671 Mechanisms controlling subcellular localization of the G(1) ...	ACCEPT	Summary: Mutant-based localization evidence: deleting the C-terminal NLS shifts Cln3 to the cytoplasm and reduces its activity in Cln3-specific genetic assays (rescue of cln1 cln2 cln3 and bck2 cln3 strains, cell size), while an appended SV40 NLS restores function. Reason: Loss-of-NLS phenotypes show that the nucleus is the compartment in which Cln3 performs its normal function. Supporting Evidence: PMID:11509671 Mislocalized Cln3p, lacking the NLS, is much less active in genetic assays specific for Cln3p, but more active in assays normally specific for Cln2p PMID:11509671 Thus, wild-type Cln3p requires nuclear localization to carry out its normal roles
GO:0005737 cytoplasm	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Phylogenetic annotation that Cln3 is active in the cytoplasm, propagated from the G1-cyclin node whose members include cytoplasmically active cyclins (Cln1/Cln2, cyclin D). Cln3 is indeed present in the cytoplasm in early G1 - it is retained at the ER, bound to Cdc28, until Ydj1 releases it in late G1 - but that pool is a sequestered, pre-activation pool; Cln3 requires nuclear localization for its Start function and artificially cytoplasmic Cln3 only performs Cln2-like tasks. Reason: Target-specific evidence argues against 'active in cytoplasm' for Cln3: nuclear localization is required for its normal roles (Miller & Cross 2001; Edgington & Futcher 2001), and the ER-associated cytoplasmic pool is a retention state rather than a site of action (Verges et al. 2007). The clade-level inference reflects Cln1/Cln2-type cytoplasmic functions that Cln3 does not normally perform. Not wrong as a location, but over-stated as an activity site. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000019791 · PTN000019791 SUPPORTS SOURCE BUT NOT TARGET Cytoplasmic activity holds for Cln1/Cln2-type members of the node; Cln3 diverged to a nuclear site of action with an ER-retained cytoplasmic pool. Supporting Evidence: PMID:11509671 Thus, wild-type Cln3p requires nuclear localization to carry out its normal roles PMID:11509671 Mislocalized Cln3p, lacking the NLS, is much less active in genetic assays specific for Cln3p, but more active in assays normally specific for Cln2p PMID:17560371 We show here that Cln3 is retained bound to the ER in early G1 cells. ER retention requires binding of Cln3 to the cyclin-dependent kinase Cdc28, a fraction of which also associates to the ER file:yeast/CLN3/CLN3-deep-research-falcon.md The ER is better understood as an early-G1 site of synthesis, sequestration, or maturation rather than the site of its final transcriptional output.
GO:0005783 endoplasmic reticulum	IDA PMID:17560371 Cyclin Cln3 is retained at the ER and released by the J chap...	NEW	Summary: Proposed localization annotation (not in GOA) from Verges et al. 2007: in early G1 Cln3 is retained bound to the endoplasmic reticulum, together with a fraction of Cdc28; retention requires Cln3-Cdc28 binding and is relieved in late G1 by the Hsp40 chaperone Ydj1, which counteracts a chaperone-regulatory Ji domain in Cln3 and is limiting for nuclear accumulation of Cln3 and timely cell cycle entry. Truman et al. 2012 extended the mechanism: Ydj1 and Cln3 bind Ssa1 (Hsp70) reciprocally, and CDK phosphorylation of Ssa1 T36 displaces Ydj1 so that Ssa1 binds Cln3 and promotes its degradation. Reason: The ER pool of Cln3 is well documented (fractionation and microscopy in Verges et al. 2007, whose abstract states the result explicitly; Whi3-dependent ER retention of newly synthesized Cln3 in later work from the same group) and is a bona fide, regulated location of the protein rather than an artefact, so it merits a located_in annotation. It is a sequestered pre-activation pool, not the site of Cln3's kinase-activating function at promoters, so it is recorded as a location only and the nucleus remains the compartment of activity. The cached record is abstract-only; the full text would be needed to cite the specific fractionation and imaging experiments. Supporting Evidence: PMID:17560371 We show here that Cln3 is retained bound to the ER in early G1 cells. ER retention requires binding of Cln3 to the cyclin-dependent kinase Cdc28, a fraction of which also associates to the ER PMID:17560371 Cln3 contains a chaperone-regulatory Ji domain that counteracts Ydj1, a J chaperone essential for ER release and nuclear accumulation of Cln3 in late G1 PMID:23217712 The J-protein Ydj1 and the G1 cyclin Cln3 display reciprocal patterns of binding to Ssa proteins file:yeast/CLN3/CLN3-deep-research-falcon.md It is reported to be associated predominantly with the endoplasmic reticulum during early G1 and to accumulate in the nucleus during late G1, consistent with its role at SBF-regulated promoters.
GO:0006357 regulation of transcription by RNA polymerase II	IGI PMID:19823668 Dual regulation by pairs of cyclin-dependent protein kinases...	MODIFY	Summary: Genetic-interaction annotation (with PHO85) that Cln3 regulates RNA polymerase II transcription: SBF-dependent reporter expression is severely compromised in cln3 pho85 cells and restored by whi5 deletion. The essence is correct, but the regulation is specifically positive activation of the G1/S transcriptional program. Reason: The direction of the effect is unambiguously positive: Cln3-Cdc28 phosphorylation relieves Whi5/HDAC-mediated repression of SBF/MBF and Cln3 is recruited to SBF-bound promoters to activate CLN1/CLN2 and the rest of the Start program (Costanzo et al. 2004; Wang et al. 2009). Positive regulation of transcription by RNA polymerase II (GO:0045944) is the more precise term. The obsolete term 'regulation of transcription involved in G1/S transition' cannot be used; the G1/S context is carried by the GO:0000082 rows. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:19823668 We show that a strain deleted for both PHO85 and CLN3 has a slow growth phenotype, a G1 delay, and is severely compromised for SBF-dependent reporter gene expression, yet all of these defects are alleviated by deletion of WHI5 PMID:19823668 phosphorylation by the early G1 CDKs Cln3-Cdc28 and Pcl9-Pho85 inhibits association of Whi5 with the HDACs PMID:15210110 G1-specific transcriptional activation by Cln3/CDK initiates the budding yeast cell cycle
GO:0006357 regulation of transcription by RNA polymerase II	IGI PMID:19823668 Dual regulation by pairs of cyclin-dependent protein kinases...	MODIFY	Summary: Genetic-interaction annotation (with WHI5): the transcriptional defect of cln3 pho85 cells is alleviated by deleting WHI5, identifying Whi5 as the repressor that Cln3-Cdc28 antagonizes to activate SBF/MBF-dependent transcription. Reason: The direction of the effect is unambiguously positive: Cln3-Cdc28 phosphorylation relieves Whi5/HDAC-mediated repression of SBF/MBF and Cln3 is recruited to SBF-bound promoters to activate CLN1/CLN2 and the rest of the Start program (Costanzo et al. 2004; Wang et al. 2009). Positive regulation of transcription by RNA polymerase II (GO:0045944) is the more precise term. The obsolete term 'regulation of transcription involved in G1/S transition' cannot be used; the G1/S context is carried by the GO:0000082 rows. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:19823668 We show that a strain deleted for both PHO85 and CLN3 has a slow growth phenotype, a G1 delay, and is severely compromised for SBF-dependent reporter gene expression, yet all of these defects are alleviated by deletion of WHI5 PMID:15210110 Whi5 inactivation bypasses the requirement for Cln3 both for transcriptional activation and cell cycle initiation
GO:0006357 regulation of transcription by RNA polymerase II	IMP PMID:19823668 Dual regulation by pairs of cyclin-dependent protein kinases...	MODIFY	Summary: Mutant-phenotype annotation: cln3 deletion abolishes growth of an SCB-HIS3 reporter strain on 30 mM 3-AT, i.e. SBF-dependent transcription is impaired without Cln3; Cln3-Cdc28 phosphorylation of Whi5 dissociates the Rpd3 and Hos3 HDACs from Whi5. Reason: The direction of the effect is unambiguously positive: Cln3-Cdc28 phosphorylation relieves Whi5/HDAC-mediated repression of SBF/MBF and Cln3 is recruited to SBF-bound promoters to activate CLN1/CLN2 and the rest of the Start program (Costanzo et al. 2004; Wang et al. 2009). Positive regulation of transcription by RNA polymerase II (GO:0045944) is the more precise term. The obsolete term 'regulation of transcription involved in G1/S transition' cannot be used; the G1/S context is carried by the GO:0000082 rows. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:19823668 both cln3Δ and pho85Δ mutants showed no growth in media containing 30 mM 3-AT indicating that SBF transcription is impaired in these mutants PMID:19823668 phosphorylation by the early G1 CDKs Cln3-Cdc28 and Pcl9-Pho85 inhibits association of Whi5 with the HDACs
GO:0007033 vacuole organization	IMP PMID:14573462 The G1 cyclin Cln3p controls vacuolar biogenesis in Saccharo...	KEEP AS NON CORE	Summary: Mutant-phenotype annotation from Han et al. 2003: cln3 (but not cln1 or cln2) cells have fragmented vacuoles, perturbed vacuolar segregation and cytosol with reduced homotypic fusion activity. A reproducible but secondary consequence of losing the Cln3-Cdc28 kinase. Reason: The phenotype is specific to CLN3 and the curator read the full paper, so the annotation is retained; but vacuole biogenesis is a pleiotropic downstream effect of a G1 cyclin whose core function is activation of Cdc28 at Start, not a core function of Cln3. The mechanism (which Cdc28 substrate in the vacuole fusion/inheritance machinery is affected) is unknown. Supporting Evidence: PMID:14573462 loss of Cln3p, but not Cln1p or Cln2p, resulted in vacuolar fragmentation PMID:14573462 vacuolar segregation was perturbed in cln3delta cells
GO:0007089 traversing start control point of mitotic cell cycle	IGI PMID:2147225 Cell cycle arrest caused by CLN gene deficiency in Saccharom...	ACCEPT	Summary: Genetic-interaction annotation (with CLN1 and CLN2) from Cross 1990: cln1 cln2 cln3 triple mutants arrest as unbudded G1 cells at START, independently of the pheromone pathway, and shutting off GAL-CLN3 in that background causes arrest in the next G1. Start passage is precisely the process defined by GO:0007089 (commitment via positive feedback between transcription and G1 CDK activity). Reason: Foundational genetic evidence that the CLN genes are required for START transit; Cln3 is the upstream member that ignites the transcriptional positive feedback loop. Supporting Evidence: PMID:2147225 Null mutations in three genes encoding cyclin-like proteins (CLN1, CLN2, and CLN3) in Saccharomyces cerevisiae cause cell cycle arrest in G1 (cln arrest) PMID:2147225 These results are consistent with a specific CLN requirement for START transit PMID:2147225 cln arrest is distinct from constitutive activation of the mating-factor signalling pathway
GO:0007089 traversing start control point of mitotic cell cycle	IGI PMID:2574633 An essential G1 function for cyclin-like proteins in yeast.	ACCEPT	Summary: Genetic-interaction annotation (with CLN1 and CLN2) from Richardson et al. 1989, the paper that renamed DAF1/WHI1 as CLN3: elimination of all three Cln proteins arrests cells in G1, any one suffices for proliferation, and the essential Cln function is confined to G1 and decays rapidly when Cln synthesis stops. Reason: Establishes the essential, redundant G1 function of the Cln family and its interpretation as activation of Cdc28 for G1/S; core function of Cln3. Supporting Evidence: PMID:2574633 Mutational elimination of the CLN1, CLN2, and DAF1/WHI1 products leads to cell cycle arrest independent of cell type, while expression of any one of the genes allows cell proliferation PMID:2574633 The data are consistent with the hypothesis that Cln proteins activate the Cdc28 protein kinase, shown to be essential for the G1 to S phase transition in S. cerevisiae
GO:0007089 traversing start control point of mitotic cell cycle	IMP PMID:2907481 The WHI1+ gene of Saccharomyces cerevisiae tethers cell divi...	ACCEPT	Summary: Mutant-phenotype annotation from Nash et al. 1988 (WHI1): the dominant WHI1-1 truncation lets cells commit to division at abnormally small size, the wild-type gene activates commitment in a dose-dependent manner, and the protein is a cyclin homolog with C-terminal PEST sequences. Reason: Classic demonstration that CLN3/WHI1 dosage and stability set the timing of commitment to division (Start); core function. Supporting Evidence: PMID:2907481 WHI1-1 is a dominant mutation that reduces cell volume by allowing cells to commit to division at abnormally small sizes, shortening the G1 phase of the cell cycle PMID:2907481 dosage studies indicated that the normal gene activated commitment to division in a dose-dependent manner PMID:2907481 The WHI1 protein had sequence similarity to clam cyclin A, to sea urchin cyclin and to Schizosaccharomyces pombe cdc13, a cyclin homolog
GO:0007089 traversing start control point of mitotic cell cycle	IMP PMID:3062366 DAF1, a mutant gene affecting size control, pheromone arrest...	ACCEPT	Summary: Mutant-phenotype annotation from Cross 1988 (DAF1): the DAF1-1 allele confers small size and pheromone resistance, a DAF1 deletion increases cell volume about 1.5-fold, and extra DAF1-1 copies shorten G1 - the original identification of CLN3 as a G1 size-control gene acting at Start. Reason: Deletion and hyperactive-allele phenotypes both map Cln3 to G1 size control at Start; core function. Supporting Evidence: PMID:3062366 A chromosomal deletion of DAF1 produced by gene transplacement increased cell volume about 1.5-fold; thus, DAF1-1 may be a hyperactive or deregulated allele of a nonessential gene involved in G1 size control PMID:3062366 Multiple copies of DAF1-1 also greatly reduced the duration of the G1 phase of the cell cycle
GO:0016538 cyclin-dependent protein serine/threonine kinase regulator activity	IBA GO_REF:0000033	MODIFY	Summary: Phylogenetic annotation of cyclin-dependent protein serine/threonine kinase regulator activity to Cln3, the defining molecular function of the cyclin family. Cln3 binds Cdc28 and confers kinase activity on it. Reason: The IBD node placement is sound: CDK-regulatory activity is the ancestral function of the whole cyclin family and Cln3 is inside the clade, with its own direct evidence (immunoprecipitated active Cln3-Cdc28 kinase). But every member of node PTN000019791 is an activating cyclin - the family contains no CDK inhibitors - so the biology is the child term cyclin-dependent protein serine/threonine kinase activator activity (GO:0061575), and for Cln3 specifically association with Cdc28 confers kinase activity (Tyers et al. 1992, 1993). The parent 'regulator' term is not wrong, only less informative; it is refined to the activator child here, consistent with the IDA/IMP rows below. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN000019791 · PTN000019791 SUPPORTS TRANSFER Cyclin regulator activity is the ancestral family function and the transfer is valid; Cln3 has its own IDA/IMP support. The term is simply broader than the activator activity the node's members share. Proposed replacements: cyclin-dependent protein serine/threonine kinase activator activity Supporting Evidence: PMID:1316273 Cln3 associates with Cdc28 to form an active kinase complex that phosphorylates Cln3 itself and a co-precipitated substrate of 45 kDa PMID:8387915 the G1 cyclins Cln1, Cln2 and Cln3 regulate entry into the cell cycle (Start) by activating the Cdc28 protein kinase
GO:0016538 cyclin-dependent protein serine/threonine kinase regulator activity	IDA PMID:1316273 The Cln3-Cdc28 kinase complex of S. cerevisiae is regulated ...	MODIFY	Summary: Direct-assay annotation from Tyers et al. 1992: Cln3 immunoprecipitates with Cdc28 as an active kinase complex that phosphorylates Cln3 itself and a 45 kDa co-precipitated substrate, and the complex is inactivated by phosphatase treatment. Cln3 activates, not merely modulates, Cdc28. Reason: The evidence shows that association with Cln3 confers kinase activity on Cdc28, which is the more specific child term cyclin-dependent protein serine/threonine kinase activator activity (GO:0061575); the parent 'regulator' term is correct but less informative. Proposed replacements: cyclin-dependent protein serine/threonine kinase activator activity Supporting Evidence: PMID:1316273 Cln3 associates with Cdc28 to form an active kinase complex that phosphorylates Cln3 itself and a co-precipitated substrate of 45 kDa
GO:0016538 cyclin-dependent protein serine/threonine kinase regulator activity	IEA GO_REF:0000117	MODIFY	Summary: ARBA machine-learning annotation of CDK regulator activity derived from the cyclin family signature. Correct at family level and redundant with the IBA and experimental rows. Reason: The automated inference is correct but stops at the generic parent; the experimental evidence (active Cln3-Cdc28 kinase complexes, CLN3-driven activation of Start) shows Cln3 is an activator of Cdc28, so the same activator child term (GO:0061575) proposed on the IBA, IDA and IMP rows is the consistent replacement. Proposed replacements: cyclin-dependent protein serine/threonine kinase activator activity Supporting Evidence: PMID:8387915 the G1 cyclins Cln1, Cln2 and Cln3 regulate entry into the cell cycle (Start) by activating the Cdc28 protein kinase
GO:0016538 cyclin-dependent protein serine/threonine kinase regulator activity	IMP PMID:1316273 The Cln3-Cdc28 kinase complex of S. cerevisiae is regulated ...	MODIFY	Summary: Mutant-based annotation from the same paper: the stable, hyperactive Cln3-1 truncation and the cdc34-2 background (which dramatically increases Cln3-associated kinase activity) show that Cln3 levels and post-translational controls set the activity of the Cln3-Cdc28 kinase. Reason: Mutant evidence that Cln3 confers and limits Cdc28 kinase activity; the activator child term (GO:0061575) is the more precise description of what a cyclin does to its CDK. Proposed replacements: cyclin-dependent protein serine/threonine kinase activator activity Supporting Evidence: PMID:1316273 Cln3 associates with Cdc28 to form an active kinase complex that phosphorylates Cln3 itself and a co-precipitated substrate of 45 kDa PMID:1316273 the truncated Cln3-1 protein is stable, suggesting that the PEST-rich C-terminal third of Cln3 is necessary for rapid turnover
GO:0016538 cyclin-dependent protein serine/threonine kinase regulator activity	IMP PMID:8387915 Comparison of the Saccharomyces cerevisiae G1 cyclins: Cln3 ...	MODIFY	Summary: Mutant/overexpression annotation from Tyers et al. 1993: an early-G1 burst of CLN3 accelerates Start and induces CLN1, CLN2, HCS26, ORFD, CLB5 and SWI4, and CLN3 is essential for expression of some of these in a cln1 cln2 strain, despite its low abundance and weak histone H1 kinase activity - the origin of the 'upstream activator' model. Reason: The paper frames Cln3 as activating Cdc28 to trigger Start; activator activity (GO:0061575) is the precise molecular function. Proposed replacements: cyclin-dependent protein serine/threonine kinase activator activity Supporting Evidence: PMID:8387915 the G1 cyclins Cln1, Cln2 and Cln3 regulate entry into the cell cycle (Start) by activating the Cdc28 protein kinase PMID:8387915 An artificial burst of CLN3 expression early in G1 phase accelerates Start and rapidly induces at least five other cyclin genes (CLN1, CLN2, HCS26, ORFD and CLB5) and the cell cycle-specific transcription factor SWI4 PMID:8387915 we propose that Cln3 may be an upstream activator of the G1 cyclins which directly catalyze Start
GO:0042144 vacuole fusion, non-autophagic	IDA PMID:14573462 The G1 cyclin Cln3p controls vacuolar biogenesis in Saccharo...	MODIFY	Summary: Direct-assay annotation from Han et al. 2003 based on cell-free vacuole fusion assays: cytosol from cln3 cells has reduced homotypic vacuole fusion activity. The assay demonstrates a requirement for Cln3 in cytosolic fusion competence, not participation of Cln3 in the fusion event itself. Reason: Cln3 is a cyclin and cannot itself execute membrane fusion; the result is that Cln3-Cdc28 is required upstream for the fusion competence of cytosol, which GO expresses as regulation of the process (GO:0032889). This is a secondary, pleiotropic role and is not a core function of Cln3. The cached record is abstract-only, so the specific downstream target is unknown to this review. Proposed replacements: regulation of vacuole fusion, non-autophagic Supporting Evidence: PMID:14573462 cytosol prepared from cells lacking Cln3p had reduced vacuolar homotypic fusion activity in cell-free assays
GO:0042144 vacuole fusion, non-autophagic	IMP PMID:14573462 The G1 cyclin Cln3p controls vacuolar biogenesis in Saccharo...	MODIFY	Summary: Mutant-phenotype annotation from the same study: cln3 cells have fragmented vacuoles, consistent with defective homotypic fusion in vivo. Reason: Cln3 is a cyclin and cannot itself execute membrane fusion; the result is that Cln3-Cdc28 is required upstream for the fusion competence of cytosol, which GO expresses as regulation of the process (GO:0032889). This is a secondary, pleiotropic role and is not a core function of Cln3. The cached record is abstract-only, so the specific downstream target is unknown to this review. Proposed replacements: regulation of vacuole fusion, non-autophagic Supporting Evidence: PMID:14573462 loss of Cln3p, but not Cln1p or Cln2p, resulted in vacuolar fragmentation PMID:14573462 cytosol prepared from cells lacking Cln3p had reduced vacuolar homotypic fusion activity in cell-free assays
GO:0044772 mitotic cell cycle phase transition	IEA GO_REF:0000117	MODIFY	Summary: ARBA electronic annotation to the generic 'mitotic cell cycle phase transition'. Correct but uninformative: Cln3 acts specifically at the G1/S transition (Start). Reason: The specific transition is well established experimentally and already annotated (GO:0000082); the generic parent should be replaced by it. Proposed replacements: G1/S transition of mitotic cell cycle Supporting Evidence: PMID:8387915 the G1 cyclins Cln1, Cln2 and Cln3 regulate entry into the cell cycle (Start) by activating the Cdc28 protein kinase PMID:2574633 The data are consistent with the hypothesis that Cln proteins activate the Cdc28 protein kinase, shown to be essential for the G1 to S phase transition in S. cerevisiae
GO:1902806 regulation of cell cycle G1/S phase transition	NAS PMID:2569741 A family of cyclin homologs that control the G1 phase in yea...	MODIFY	Summary: Author-statement annotation citing Hadwiger et al. 1989, the paper that cloned CLN1 and CLN2 as cyclin homologs and dosage suppressors of cdc28-ts; CLN3 (then WHI1/DAF1) is discussed as the third family member. Cln3 does modulate the G1/S CDK switch, and it does so positively. Reason: The term definition (a signaling pathway that modulates a cell-cycle CDK to control the G1/S switch) fits Cln3, but the sign is unambiguously positive - Cln3 activates Cdc28 and relieves Whi5 repression - so positive regulation of G1/S transition of mitotic cell cycle (GO:1900087) is the precise term. The supporting reference is a NAS on a paper focused on CLN1/CLN2; the far stronger direct evidence lives in the GO:0000082 and GO:0007089 rows. Proposed replacements: positive regulation of G1/S transition of mitotic cell cycle Supporting Evidence: PMID:2569741 CLN1 and CLN2 encode closely related proteins that also share homology with cyclins PMID:8387915 the G1 cyclins Cln1, Cln2 and Cln3 regulate entry into the cell cycle (Start) by activating the Cdc28 protein kinase PMID:15210110 G1-specific transcriptional activation by Cln3/CDK initiates the budding yeast cell cycle

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