The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
WHI5 encodes a non-enzymatic, G1-specific transcriptional corepressor that restrains passage through Start, the budding-yeast G1/S decision point. Its primary site of action is the nucleus, where it is recruited to G1/S promoters by the SBF transcription factor (Swi4–Swi6). Whi5 does not catalyze a reaction and is not known to bind DNA sequence-specifically by itself. Rather, it inhibits promoter-bound SBF and helps maintain low expression of genes needed for budding, G1-cyclin positive feedback, and cell-cycle entry. Cyclin–Cdk1-dependent multisite phosphorylation weakens this repression and promotes Whi5 nuclear export, allowing the G1/S transcriptional program to proceed. Foundational biochemical, promoter-occupancy, genetic, and localization experiments strongly support this annotation. (costanzo2004cdkactivityantagonizes pages 1-2, travesa2013repressionofg1s pages 1-2, bruin2004cln3activatesg1specific pages 2-3)
Recent work substantially refines this model. A 2023 study showed that acute glucose starvation can dephosphorylate, re-import, and return Whi5 to chromatin for approximately 15–20 minutes after Start, demonstrating that commitment is initially reversible. A 2024 study resolved distinct early-G1 hypo-phosphorylation and late-G1 hyper-phosphorylation programs, while another showed that Whi5 cooperates with SWI4-LUTI repression to prevent inappropriate mitotic transcription during meiotic entry. A 2024 systems model integrated these interactions into an executable START network. (xiao2024whi5hypoand pages 1-3, su2024controlofmeiotic pages 14-15, irvali2023whenyeastcells pages 10-11, irvali2023whenyeastcells pages 2-3, irvali2023whenyeastcells pages 9-10)
The target is the budding-yeast protein specified by the user:
The organism-specific literature is internally consistent with this identity: it describes S. cerevisiae Whi5 as an SBF-associated Start inhibitor, reports the characteristic small-cell phenotype of whi5Δ, and distinguishes it from its sequence-related paralog Whi7/Srl3 and from the MBF corepressor Nrm1. No literature concerning a different organism’s similarly named protein was used to infer Q12416 function. (costanzo2004cdkactivityantagonizes pages 1-2, gomaralba2017whi7isan pages 10-11, travesa2013repressionofg1s pages 1-2, metwally2015molecularretentionmechanisms pages 87-90, bruin2004cln3activatesg1specific pages 2-3)
A qualification is necessary: the retrieved primary papers generally call the protein “Whi5” rather than printing the UniProt accession Q12416 or Pfam/InterPro identifiers. Thus, accession and domain identifiers are verified against the supplied UniProt identity context, while the biological identity is independently corroborated by organism, pathway, interaction, and mutant-phenotype evidence.
Whi5, Nrm1, and Whi7 belong to a fungal G1/S-corepressor group, but they are not interchangeable. Whi5 principally represses SBF, whereas Nrm1 is the canonical negative-feedback corepressor of MBF. Both Whi5 and Nrm1 contain a G1/S-transcription-factor-binding, or GTB, motif that engages Swi6 and targets the repressors to their cognate transcription-factor complexes. This supports classification as a transcriptional coregulator rather than an enzyme or independent DNA-binding transcription factor. (travesa2013repressionofg1s pages 1-2)
Whi7/Srl3 is a Whi5 paralog with overlapping Start-repressor activity. Whi5 nevertheless has approximately 3–4-fold greater enrichment at the CLN2 promoter and makes the larger contribution to normal Start timing; Whi7 becomes especially important under cell-wall or environmental stress. Whi7 overexpression can compensate for the cell-size defect of a whi5 mutant, demonstrating partial functional equivalence rather than identity. (gomaralba2017whi7isan pages 10-11, mendez2020thebuddingyeast pages 3-3, mendez2020thebuddingyeast pages 11-12)
In early G1, SBF—composed of the DNA-binding subunit Swi4 and regulatory subunit Swi6—is present at G1/S promoters. Whi5 associates with this promoter-bound complex and suppresses transcription. Affinity purification/MudPIT, in-vitro and in-vivo interaction assays, chromatin recruitment, expression analysis, and genetics established this mechanism. Directly studied promoters include CLN2 and PCL1. Later specificity experiments showed that an intact Swi4–Swi6 complex is required for Whi5 promoter association, reinforcing the conclusion that Whi5 is recruited by SBF rather than recognizing promoter DNA independently. (costanzo2004cdkactivityantagonizes pages 1-2, mendez2020thebuddingyeast pages 3-3, travesa2013repressionofg1s pages 1-2, bruin2004cln3activatesg1specific pages 2-3)
Functionally important SBF outputs include G1 cyclins and genes involved in budding and cell-wall biogenesis. Repression of CLN1 and CLN2 is especially consequential because their products form Cln1/2–Cdk1 complexes that further inactivate Whi5 and other repressors. Whi5 therefore sits at the inhibitory side of a positive-feedback switch: initial Start activation relieves Whi5 repression, newly produced cyclins raise Cdk1 activity, and that activity reinforces SBF activation. (mendez2020thebuddingyeast pages 1-2, su2024controlofmeiotic pages 16-18)
Earlier studies sometimes described Whi5 association with the broader SBF/MBF system. Current functional resolution favors SBF as its principal direct target, with Nrm1 providing the corresponding canonical repression of MBF. That distinction should be preferred in functional annotation. (mendez2020thebuddingyeast pages 3-3, travesa2013repressionofg1s pages 1-2, bruin2004cln3activatesg1specific pages 2-3)
No catalytic reaction, substrate turnover, or transporter activity is known. “Substrate specificity” is therefore not applicable in the enzymatic sense. Its molecular specificity is instead interaction-based: Whi5 recognizes the SBF regulatory machinery—particularly Swi6 within assembled SBF—through its corepressor module and is thereby delivered to SBF-controlled promoters. (travesa2013repressionofg1s pages 1-2, bruin2004cln3activatesg1specific pages 2-3)
Whi5 carries out its primary repressor function inside the nucleus at chromatin-bound SBF promoters. It accumulates in the nucleus from mitotic exit through pre-Start G1. At Start, phosphorylation leads to dissociation or functional disengagement from the SBF-promoter complex and exclusion from the nucleus. After Cdk1 activity declines near mitotic exit, Whi5 returns to the nucleus for the next G1. (costanzo2004cdkactivityantagonizes pages 1-2, mendez2020thebuddingyeast pages 3-3, mendez2020thebuddingyeast pages 11-12)
Transport is actively regulated. Phosphorylation of Whi5 sites associated with its export signal enables recognition by the export karyopherin Msn5. Nuclear re-import uses the classical Kap60–Kap95 import pathway. Whi5 becomes essentially fully nuclear during G1, whereas Whi7 remains more evenly partitioned between nucleus and cytosol, one mechanistic distinction between the paralogs. (mendez2020thebuddingyeast pages 11-12)
Localization should not be interpreted as a simple on/off surrogate for function. Whi5 phosphorylation, chromatin occupancy, SBF/Swi6 regulation, and export are partly redundant layers. For example, non-phosphorylatable WHI5-12A or SWI6-SA4 single mutants can retain nearly wild-type size, whereas the double mutant is approximately 40% larger, indicating that alteration of either regulatory branch can be sufficient for reasonably timely SBF activation. (ravi2024modelingthestart pages 3-5, ravi2024modelingthestart pages 5-6)
At mitotic exit and in early G1, low G1-Cdk activity permits nuclear Whi5 to bind promoter-associated SBF and repress transcription. Whi5 thereby delays expression of CLN1, CLN2, and other Start genes until growth and environmental inputs support cell-cycle entry. (costanzo2004cdkactivityantagonizes pages 1-2, mendez2020thebuddingyeast pages 1-2)
Cln3–Cdk1, together with additional Start inputs such as Bck2, promotes initial SBF activation. The classical model assigns an important role to phosphorylation of SBF-bound Whi5. Once CLN1 and CLN2 transcription begins, Cln1/2–Cdk1 rapidly reinforces the transition by further phosphorylating Whi5 and Swi6. The result is a coherent transcriptional wave rather than gradual independent activation of individual genes. (mendez2020thebuddingyeast pages 1-2, ravi2024modelingthestart pages 3-5, ravi2024modelingthestart pages 5-6)
The mechanistic literature now cautions against treating Whi5 as the sole Cln3 target or Whi5 phosphorylation as the unique Start trigger. The near-normal single-mutant phenotypes of WHI5-12A and SWI6-SA4, the strong double-mutant phenotype, and Whi5-independent Bck2 signaling support a distributed network with partially redundant activation routes. (ravi2024modelingthestart pages 3-5, ravi2024modelingthestart pages 5-6)
Xiao et al., published in Current Biology in June 2024, identified 19 appreciably phosphorylated Whi5 sites. Seven sites—three Cdk and four non-Cdk sites—account for early-G1 hypo-phosphorylation. Mutating these seven sites enlarged cells and delayed G1/S entry, even though later Whi5 translocation and post-G1 expression dynamics remained largely intact. (xiao2024whi5hypoand pages 1-3, xiao2024whi5hypoand pages 3-5)
At late G1, Cln1/2–Cdk1 produces rapid Whi5 hyper-phosphorylation. Phosphorylated threonine sites recruit the Cks1 adaptor, enabling semi-processive multisite phosphorylation. Converting relevant threonines to serines allowed phosphorylation but disrupted efficient Cks1-dependent progression and increased cell size. Mutating the Cdk sites or all 19 sites caused persistent nuclear retention. The results assign different biological jobs to the two states: early hypo-phosphorylation helps set timely Start, whereas late hyper-phosphorylation ensures full inactivation, nuclear exclusion, robust CLN2 expression, and timely S/G2/M progression. The study combined synchronized Phos-tag time courses, purified Cln2–Cdk1/Cks1 assays, live-cell Whi5 localization, CLN2 reporters, and budding measurements; one glucose-deprivation analysis contained 162 wild-type and 104 Δcks1 cells. Publication: Xiao et al., 2024-06, DOI/URL: https://doi.org/10.1016/j.cub.2024.04.052. (xiao2024whi5hypoand pages 1-3, xiao2024whi5hypoand pages 3-5, xiao2024whi5hypoand pages 19-23)
The defining genetic phenotype is premature Start. whi5Δ cells are approximately 30% smaller than wild type yet grow at a normal rate, demonstrating that Whi5 normally imposes a growth-dependent delay before division. Deletion can bypass requirements for some upstream SBF/MBF activators and confers resistance to mating-pheromone arrest. A systematic screen reported an approximately 88 ± 2 min doubling time, 18 ± 0 fL daughter size, and 32 ± 1 fL median size for whi5Δ under the assayed conditions. Conversely, elevated Whi5 extends pre-Start G1 and increases cell size. (costanzo2004cdkactivityantagonizes pages 1-2, nishikawa2008asystematiccellb pages 87-93, nishikawa2008asystematiccell pages 87-93)
Whi5 is consequently a major cell-size-control effector, but whether dilution of Whi5 concentration is the primary size sensor remains unsettled. Current models include Whi5 dilution, increasing Cln3 activity, titration against genomic SBF sites, and combinations of these mechanisms. The strongest conservative annotation is that Whi5 dosage and phosphorylation influence the size threshold for Start; it is not established that Whi5 alone measures size. The 2024 START-BYCC analysis likewise treats size control as an integrated property involving Whi5 and other regulators. (ravi2024modelingthestart pages 9-10, ravi2024modelingthestart pages 6-9, ravi2024modelingthestart pages 5-6)
Irvali et al., published in The EMBO Journal in 2023, challenged the traditional view that Whi5 export marks an immediately irreversible commitment. Cells were grown in glucose minimal medium, switched in microfluidics to non-metabolizable 1% sorbitol medium for about 10 h, and returned to glucose for at least 4 h. If starvation began within approximately 15–20 min after Start, many cells re-imported Whi5, dephosphorylated its Cdk1 sites, restored chromatin association, interrupted G1/S positive feedback, and reactivated Start only after nutrients returned. (irvali2023whenyeastcells pages 10-11, irvali2023whenyeastcells pages 2-3, irvali2023whenyeastcells pages 1-2, irvali2023whenyeastcells pages 9-10)
The inference of genuine reversal did not rest on localization alone. More than 500 post-Start cells were analyzed; all 102 cells in one reporter analysis had generated a post-Whi5-exit Cln2-promoter signal at least 50% as large as in the preceding unperturbed cycle, confirming prior Start passage. Reverted cells regained mating-pheromone sensitivity and generated a second Cln2-expression/CDK-activation episode after glucose restoration. Phos-tag immunoblotting and Whi5 ChIP supported dephosphorylation and renewed chromatin binding. Commitment was nevertheless not reset perfectly: pheromone-induced shmooing was about 30% lower than in ordinary G1 cells, indicating residual cell-cycle memory. Publication: Irvali et al., online 2023, DOI/URL: https://doi.org/10.15252/embj.2021110321. (irvali2023whenyeastcells pages 10-11, irvali2023whenyeastcells pages 2-3, irvali2023whenyeastcells pages 4-5, irvali2023whenyeastcells pages 9-10)
These results refine the concept of Start: Whi5 export marks entry into a multistep commitment process, but environmental signals can still reverse the early stage.
Su et al. showed in 2024 that Whi5 also prevents inappropriate activation of the mitotic SBF program during entry into meiosis. Two mechanisms act in parallel: a long undecoded transcript isoform, SWI4-LUTI, lowers production of the SBF-specific Swi4 subunit, while nuclear Whi5 inhibits residual SBF activity. Either perturbation alone had little effect, but deleting LUTI regulation while depleting nuclear Whi5 by anchor-away activated SBF targets and delayed meiosis. (su2024controlofmeiotic pages 15-16, su2024controlofmeiotic pages 14-15, su2024controlofmeiotic pages 13-14)
The double perturbation produced SBF-regulon enrichment of NES = 1.95, p < 0.001, early-meiotic-gene depletion of NES = −3.39, p < 0.001, and a significant meiotic-entry delay (p = 0.0112, Mann–Whitney). Misregulated SBF increased CLN1, CLN2, and PCL1. Deleting CLN1 or CLN2 partially rescued the delay, while tethering Ime1 to Ume6 rescued the cyclin-induced sporulation defect, supporting a pathway in which excess G1 cyclin/CDK activity disrupts the Ime1–Ume6 transcriptional complex. Publication: Su et al., 2024, eLife reviewed version, DOI/URL: https://doi.org/10.7554/eLife.90425.2. (su2024controlofmeiotic pages 15-16, su2024controlofmeiotic pages 14-15, su2024controlofmeiotic pages 10-11, su2024controlofmeiotic pages 16-18)
This is a context-specific extension, not a replacement for the primary annotation: Whi5 remains fundamentally an SBF corepressor, with that same biochemical activity repurposed to separate mitotic and meiotic transcriptional states.
Whi5 and Whi7 collaborate in G1 arrest and recovery from quiescence, but their stress specialization differs. Under normal cycling conditions Whi5 is the principal Start repressor; during cell-wall stress, Whi7 can become dominant because its expression and promoter recruitment are selectively enhanced. Therefore, stress-associated G1 arrest should not automatically be attributed mainly to Whi5. (mendez2020thebuddingyeast pages 3-3, mendez2020thebuddingyeast pages 11-12, spiridonbodi2025dualregulationof pages 2-4)
Whi5 is widely used as a live-cell Start marker: nuclear exit reports Start, while re-entry reports reversal or later shutdown of Cdk activity. Fluorescent Whi5 reporters, often combined with CLN2 transcription reporters, budding markers, or microfluidics, enable single-cell measurements of cell-cycle commitment, nutrient responses, and lineage heterogeneity. The 2023 starvation study and 2024 phosphorylation study illustrate this use with time-resolved localization, transcription, and phospho-state measurements. (xiao2024whi5hypoand pages 19-23, irvali2023whenyeastcells pages 2-3, irvali2023whenyeastcells pages 4-5)
The 2024 START-BYCC nonlinear ODE model provides a computational implementation for hypothesis testing. It expands the original Start subsystem from 1 species and 8 parameters to 51 species and 56 parameters, incorporates SBF, MBF, Whi5, Nrm1, phosphorylation states, localization, Bck2, cyclins, and cell-size control, and was used to simulate more than 200 mutants with reported fitting of approximately 95% of mutant phenotypes. Simulations and supporting data are available through the paper and the cited SBML simulator. Publication: Ravi, Samart & Zwolak, 2024-08-02, PLOS Computational Biology, DOI/URL: https://doi.org/10.1371/journal.pcbi.1012048. This is a valuable research implementation, but model agreement is not independent biochemical proof. (ravi2024modelingthestart pages 9-10, ravi2024modelingthestart pages 6-9)
Because Whi5 is a functional—not close sequence—analogue of mammalian retinoblastoma-pathway repressors, the yeast system is also used to investigate general principles of G1/S commitment, positive feedback, multisite phosphorylation, and reversible cell-state transitions. Direct translation to mammalian Rb biology should remain cautious because the molecular components and promoter architecture differ. (costanzo2004cdkactivityantagonizes pages 1-2, su2024controlofmeiotic pages 1-2, bruin2004cln3activatesg1specific pages 2-3)
The following table summarizes the annotation and distinguishes direct evidence from interpretation.
| Aspect | Current functional annotation | Strongest evidence/method | Key quantitative result | Confidence/caveat |
|---|---|---|---|---|
| Identity and family | WHI5/YOR083W encodes the G1-specific transcriptional repressor Whi5 in Saccharomyces cerevisiae S288c; supplied database annotations place Q12416 in the WHI5/NRM1 family with Srl3/Whi5 and Whi5 domains. | Organism-specific genetic and biochemical literature consistently identifies Whi5 as the budding-yeast Start inhibitor; sequence work identifies a G1/S-transcription-factor-binding motif shared with Nrm1. | Whi5 showed 3–4-fold greater CLN2-promoter enrichment than its paralog Whi7. | High confidence in gene and functional identity. Q12416, PF08528, and InterPro identifiers were supplied by UniProt context but were not printed independently in the retrieved papers. |
| Primary molecular function | Non-enzymatic transcriptional corepressor that binds promoter-associated SBF, principally through Swi4–Swi6, and suppresses the G1/S transcriptional program before Start. It does not itself supply sequence-specific DNA binding. | Affinity purification/MudPIT, in-vivo and in-vitro interaction assays, promoter occupancy assays, transcription measurements, and genetic bypass experiments. | SBF and MBF collectively regulate more than 300 G1/S transcripts; direct foundational studies established Whi5 recruitment to promoters such as CLN2 and PCL1. | High confidence for SBF repression. Early reports of broader MBF association should be interpreted alongside later evidence that Whi5 is principally SBF-specific, whereas Nrm1 is the canonical MBF corepressor. |
| Localization | Predominantly nuclear from mitotic exit through G1, where it represses promoter-bound SBF; excluded from the nucleus after Start and returned to the nucleus when CDK activity falls. | Fluorescent protein imaging across synchronized and single-cell cycles; promoter-binding assays. | Whi5 becomes completely nuclear during G1 in comparative imaging, whereas related Whi7 remains partitioned between nucleus and cytosol. | High confidence. Localization is dynamic rather than constitutively nuclear or cytoplasmic. |
| Phosphorylation and trafficking | G1 cyclin–Cdk1 activity antagonizes Whi5. Phosphorylation weakens repression and promotes nuclear export through Msn5; re-import uses Kap60–Kap95. Cln1/2–Cdk1 positive feedback reinforces Whi5 inactivation. | Phosphosite mutants, Phos-tag immunoblots, localization microscopy, kinase assays, and nuclear-transport genetics. | A WHI5-12A single mutant and a non-phosphorylatable SWI6-SA4 single mutant had near-wild-type size, but the double mutant was 40% larger. | High confidence that phosphorylation regulates Whi5, but Whi5 phosphorylation alone is not strictly necessary for timely SBF activation because Swi6 phosphorylation and Bck2 provide partially redundant routes. |
| Deletion phenotype and cell size | WHI5 deletion advances Start, shortens the effective G1 growth requirement, and produces small cells without markedly impairing proliferation; overabundance delays Start. | Deletion genetics, cell-size screening, growth measurements, pheromone assays, and epistasis with Start regulators. | whi5Δ cells were approximately 30% smaller than wild type while growing at a normal rate; one screen measured an approximately 88 ± 2 min doubling time, 18 ± 0 fL daughter size, and 32 ± 1 fL median size. | High confidence that Whi5 is a dosage-dependent Start inhibitor. Whether dilution of Whi5 concentration is the primary cell-size sensor remains disputed. |
| Starvation reversibility, 2023 | Acute glucose withdrawal shortly after Start can dephosphorylate and re-import Whi5, restore its chromatin association, interrupt G1/S positive feedback, and return cells to a pre-Start-like state. | Single-cell microfluidics, Whi5 fluorescence, Cln2-promoter reporters, Phos-tag immunoblotting, Whi5 ChIP, starvation/recovery, and mating-pheromone tests. | Start was reversible for approximately 15–20 min; more than 500 post-Start cells were analyzed, all 102 reporter-validated cells had activated the Cln2 promoter, and fewer than 2% completed the cycle despite starvation in one dataset. | Strong evidence that commitment is multistep and conditionally reversible. Reverted cells retained some memory: pheromone-induced shmooing was about 30% lower than in ordinary G1 cells. |
| Phosphorylation dynamics, 2024 | Whi5 undergoes functionally distinct early-G1 hypophosphorylation and late-G1 hyperphosphorylation. Early modification promotes timely Start; Cks1-assisted Cln1/2–Cdk1 hyperphosphorylation drives full inactivation, nuclear exclusion, and timely later-cycle progression. | Phos-tag time courses, synchronized cultures, phosphosite mutants, purified kinase/Cks1 assays, live-cell localization, CLN2 reporters, and budding measurements. | Nineteen appreciably phosphorylated sites were identified; seven early-G1 sites comprised three Cdk and four non-Cdk sites. Imaging used 6-min intervals; one analysis included 162 wild-type and 104 Δcks1 cells. | High confidence for two-stage phosphoregulation. Exact contributions of individual sites and the kinase responsible for every non-Cdk site remain less completely resolved. |
| Meiosis, 2024 | Nuclear Whi5 acts in parallel with SWI4-LUTI-mediated reduction of Swi4 to suppress mitotic SBF output during meiotic entry. Joint failure activates G1 cyclins, weakens early-meiotic transcription, and delays meiosis. | Whi5 anchor-away, SWI4-LUTI mutants, RNA-seq, gene-set enrichment, smFISH, protein measurements, and Rec8-GFP/Htb1-mCherry live imaging. | Combined disruption produced SBF-regulon enrichment of NES = 1.95 and early-meiotic-gene disenrichment of NES = −3.39, both p < 0.001; the meiotic-entry delay had p = 0.0112. | Strong evidence for a context-specific backup role. Whi5 depletion or LUTI disruption alone caused little effect, showing redundancy rather than sole control by Whi5. |
| START-BYCC modeling, 2024 | Mechanistic ODE model integrates Whi5/SBF, MBF, phosphorylation, localization, Bck2, Nrm1, cyclins, and size-control mechanisms across the yeast cell cycle. | Model fitting against wild-type dynamics and extensive mutant phenotypes, followed by executable simulations. | The START subsystem expanded from 1 species and 8 parameters to 51 species and 56 parameters; more than 200 mutants were simulated, with 95% of mutant phenotypes successfully fitted. | Useful research implementation and hypothesis-testing platform, not independent biochemical proof. Conclusions depend on encoded interactions and parameterization. |
Table: Concise audit table summarizing the identity, molecular role, localization, regulation, phenotypes, and major 2023–2024 findings for budding-yeast Whi5 (Q12416/YOR083W).
High-confidence conclusions are that Whi5 is a nuclear, non-enzymatic SBF corepressor; that its deletion advances Start and reduces cell size; that cyclin–Cdk1-dependent multisite phosphorylation and regulated transport antagonize its function; and that Whi5 can return to chromatin when early post-Start commitment is reversed by starvation. These conclusions are supported by convergent biochemistry, genetics, ChIP, live-cell imaging, phosphosite manipulation, and transcriptional assays. (costanzo2004cdkactivityantagonizes pages 1-2, xiao2024whi5hypoand pages 1-3, xiao2024whi5hypoand pages 3-5, irvali2023whenyeastcells pages 10-11, irvali2023whenyeastcells pages 9-10, bruin2004cln3activatesg1specific pages 2-3)
Qualified conclusions concern causality within the larger Start switch. Whi5 phosphorylation is important but not uniquely required, because Swi6 phosphorylation and Bck2-dependent activation provide redundancy. Similarly, Whi5 abundance clearly affects Start timing, yet competing experimental and modeling frameworks disagree over whether inhibitor dilution, Cln3 accumulation, promoter-site titration, or a composite mechanism supplies the dominant cell-size measurement. (ravi2024modelingthestart pages 3-5, ravi2024modelingthestart pages 6-9, ravi2024modelingthestart pages 5-6)
Remaining questions include the kinase or kinases responsible for all early-G1 non-Cdk phosphosites, the quantitative division of labor among phosphorylation, promoter dissociation, and nuclear export, and how nutrient withdrawal so rapidly suppresses effective cyclin–Cdk activity without relying on the obvious candidate inhibitors tested to date. The starvation work found no decisive requirement for a newly activated phosphatase, Sic1, Cip1, or Swe1 at early G1/S, leaving the immediate nutrient-responsive target unresolved. (xiao2024whi5hypoand pages 3-5, irvali2023whenyeastcells pages 10-11)
WHI5 (Q12416/YOR083W) encodes a nuclear G1/Start transcriptional corepressor in S. cerevisiae. Whi5 is recruited through the Swi4–Swi6 SBF complex to G1/S promoters, where it suppresses expression of G1 cyclins and other Start genes. Growth- and signal-responsive cyclin–Cdk1 activity produces staged multisite phosphorylation, reducing repression and promoting Msn5-dependent nuclear export; Kap60–Kap95-mediated re-import restores repression after Cdk activity declines. Whi5 thereby delays Start, contributes to cell-size homeostasis, supports environmentally responsive G1 arrest, and prevents inappropriate SBF activity during meiotic entry. It has no established catalytic or independent sequence-specific DNA-binding activity. (costanzo2004cdkactivityantagonizes pages 1-2, mendez2020thebuddingyeast pages 11-12, xiao2024whi5hypoand pages 1-3, su2024controlofmeiotic pages 14-15, travesa2013repressionofg1s pages 1-2, bruin2004cln3activatesg1specific pages 2-3)
References
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