G1/S transition of the mitotic cell cycle (Start / restriction point)

A taxon-neutral decomposition of the G1/S transition: the commitment step ("Start" in yeasts, the "restriction point" in metazoa) at which a cell irreversibly enters a new division cycle. Four steps are modeled: (1) a G1 cyclin-CDK (cyclin D-CDK4/6 in metazoa, Cln3-Cdc28 in budding yeast, Puc1/Cig-Cdc2 in fission yeast) accumulates with growth and phosphorylates the transcriptional corepressor of the G1/S program; (2) the G1/S transcription factor is released from its corepressor (Rb from E2F-DP in metazoa, Whi5 from SBF/MBF in budding yeast; fission yeast MBF has no Rb/Whi5-type corepressor and is modeled as its own variant); (3) the G1/S cyclins transcribed by that program (cyclin E, Cln1/2 and Clb5/6, Cig2) activate the G1/S CDK; and (4) the G1/S CDK phosphorylates the stoichiometric CDK inhibitor (p27/Kip1, Sic1, Rum1), marking it for SCF-dependent ubiquitination and proteasomal destruction, which releases S-phase CDK activity in a switch-like positive feedback loop. The module ends with active S-phase cyclin-CDK; DNA replication licensing and initiation are downstream and are not part of this module. Representative members are drawn from human, Saccharomyces cerevisiae and Schizosaccharomyces pombe. Grounded in GO:0000082 (G1/S transition of mitotic cell cycle).

MODULE:g1_s_transitionDRAFTCONCRETEBiological Processmodules/g1_s_transition.yaml
G1/S transition of mitotic cell cycleGO:0000082
GO:0000082
G1/S transition of mitotic cell cycle
The module is grounded in the GO biological process term for the G1/S transition.
PMID:9442875
Cyclin-dependent kinases: engines, clocks, and microprocessors
Review establishing the cyclin-CDK framework in which successive cyclin-CDK complexes drive the G1/S and G2/M transitions and are gated by CDK inhibitors and inhibitory phosphorylation.
PMID:23877564
Control of cell cycle transcription during G1 and S phases
Review of the conserved logic of G1/S transcription: an Rb/Whi5-type corepressor bound to E2F/SBF/MBF is inactivated by CDK phosphorylation, releasing a G1/S transcriptional wave in metazoa and yeasts.
PMID:32946743
Integrating Old and New Paradigms of G1/S Control
Review integrating the Rb-E2F and Whi5-SBF paradigms of G1/S commitment with positive feedback by G1/S cyclin-CDKs.
PMID:15210111
CDK activity antagonizes Whi5, an inhibitor of G1/S transcription in yeast
Whi5 is the SBF-bound repressor of G1/S transcription in budding yeast and is antagonized by Cln-Cdc28 activity.
PMID:15210110
Cln3 activates G1-specific transcription via phosphorylation of the SBF bound repressor Whi5
Cln3-Cdc28 phosphorylates Whi5 to release SBF and activate G1-specific transcription, the budding-yeast counterpart of Rb phosphorylation.
PMID:8372350
A role for the transcription factors Mbp1 and Swi4 in progression from G1 to S phase
Mbp1 (MBF) and Swi4 (SBF) are the DNA-binding subunits of the two budding-yeast G1/S transcription factors.
PMID:1832338
The role of SWI4 and SWI6 in the activity of G1 cyclins in yeast
SWI4 and SWI6 are required for G1 cyclin (CLN1/CLN2) transcription and hence for Start.
PMID:9694791
The regulation of E2F by pRB-family proteins
pRB-family pocket proteins bind and repress E2F transcription factors; CDK phosphorylation of pRB releases E2F to activate G1/S genes.
PMID:7954792
The B-type cyclin kinase inhibitor p40SIC1 controls the G1 to S transition in S. cerevisiae
Sic1 is a stoichiometric inhibitor of Clb-Cdc28 kinases whose destruction is required for S-phase entry in budding yeast.
PMID:8121488
Regulation of progression through the G1 phase of the cell cycle by the rum1+ gene
rum1 encodes the fission-yeast G1 CDK inhibitor whose loss abolishes the G1 pre-Start interval and whose overexpression blocks Start.
PMID:8521500
p25rum1 orders S phase and mitosis by acting as an inhibitor of the p34cdc2 mitotic kinase
Rum1 acts as a direct inhibitor of Cdc2 kinase activity.
PMID:10385618
CDK inhibitors: positive and negative regulators of G1-phase progression
Review of the Cip/Kip (p21, p27, p57) and INK4 CDK inhibitor families that gate G1 progression in mammalian cells.
PMID:9346239
A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiquitination of the phosphorylated CDK inhibitor Sic1p
The SCF(Cdc4) complex (Cdc4-Skp1-Cdc53/cullin) ubiquitinates phosphorylated Sic1, the founding SCF substrate.
PMID:10559916
SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27
SKP2 is the F-box substrate adaptor for phosphorylated p27 in mammalian cells.
PMID:9203581
Fission yeast WD-repeat protein pop1 regulates genome ploidy through ubiquitin-proteasome-mediated degradation of the CDK inhibitor Rum1 and the S-phase initiator Cdc18
Pop1 is a Cdc4-like WD-repeat F-box adaptor required for ubiquitin-proteasome degradation of Rum1 in fission yeast.
PMID:8657126
Cig2, a B-type cyclin, promotes the onset of S in Schizosaccharomyces pombe
Cig2-Cdc2 is the principal fission-yeast S-phase-promoting cyclin-CDK.
PMID:8631306
A single fission yeast mitotic cyclin B p34cdc2 kinase promotes both S-phase and mitosis in the absence of G1 cyclins
In fission yeast a single Cdc13-Cdc2 complex can drive both S phase and mitosis, showing that G1 cyclin specificity is dispensable and that CDK activity level orders the cycle.
PMID:1734281
Control of DNA synthesis genes in fission yeast by the cell-cycle gene cdc10+
cdc10 is the core subunit of the fission-yeast MBF transcription factor that activates DNA-synthesis genes at Start.
PMID:21179163
Driving the cell cycle with a minimal CDK control network
A single cyclin-CDK fusion suffices to order S phase and mitosis in fission yeast, supporting the quantitative CDK-activity model of cell cycle progression.
PMID:4587263
Genetic control of the cell division cycle in yeast
Defines Start as the point in G1 at which budding-yeast cells commit to a new division cycle.
PMID:3062366
DAF1, a mutant gene affecting size control, pheromone arrest, and cell cycle kinetics of Saccharomyces cerevisiae
DAF1/WHI1 (CLN3) mutants alter cell size at Start, identifying Cln3 as the upstream size-coupled G1 cyclin.

Boundary decisions. The module starts with growth-coupled accumulation of the G1 cyclin-CDK and ends with active S-phase cyclin-CDK after CKI destruction; origin licensing (MCM loading) and replication initiation (CDC7/DBF4, Cdc45/GINS) are separate modules. The DNA-damage G1 checkpoint (p53/p21, Rad53/Mec1) and mitogen signalling into cyclin D are regulatory context, not parts. Only the corepressor-release step is split by taxon: fission yeast has no Rb/Whi5-type corepressor, so its MBF (Cdc10-Res1-Res2-Rep2) is modeled as a third variant whose CDK-dependent trigger is a knowledge gap (Nrm1-mediated negative feedback and Cdc2-Cig2 regulation are documented but not modeled here as parts). The G1/S cyclin annoton deliberately spans two PANTHER families (PTHR10177 cyclins and PTHR21615 Cln1/Cln2) because the budding-yeast Start cyclins Cln1/2 are not classified with cyclin E, Clb5/6 or Cig2. The CKI annoton carries no PANTHER family term: p27/Kip1 belongs to PTHR10265 whereas Sic1 and Rum1 are unclassified and structurally unrelated to Cip/Kip proteins, so the family descriptor grounds only through representative members and an ANY_WITH_FUNCTION-like description. The F-box adaptor unit of SCF is likewise split across families (Skp2, Cdc4, Pop1, Pop2) and declared with family_terms using the local PANTHER 19.0 classification, which disagrees with the UniProt PANTHER cross-references for these four proteins. Deep research: no module deep-research report accompanies this file (no provider credentials were available in the authoring session; writing one by hand under a provider name is prohibited). Open questions: whether the fission-yeast Start trigger is best modeled as Cdc2-Cig2 phosphorylation of MBF components or of Rum1; and the extent to which metazoan cyclin E-CDK2 versus cyclin D-CDK4/6 is rate-limiting for Rb inactivation in vivo.

8Nodes
4Parts
1Variant Sets
3Variants
11Annotons
8Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:g1_s_transition deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

27 gene-function check(s) reflected in core functions · 0 conflict(s) · 17 evidence or coverage gap(s) (45 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
g1_cdk CDK4
UniProtKB:P11802
Family Representative 		cyclin-dependent protein serine/threonine kinase activity
GO:0004693 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g1_cdk Cdc28
UniProtKB:P00546
Family Representative 		cyclin-dependent protein serine/threonine kinase activity
GO:0004693 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g1_cdk cdc2
UniProtKB:P04551
Family Representative 		cyclin-dependent protein serine/threonine kinase activity
GO:0004693 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g1_cyclin CCND1
UniProtKB:P24385
Family Representative 		cyclin-dependent protein serine/threonine kinase regulator activity
GO:0016538 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g1_cyclin Cln3
UniProtKB:P13365
Family Representative 		cyclin-dependent protein serine/threonine kinase regulator activity
GO:0016538 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g1_cyclin puc1
UniProtKB:P25009
Family Representative 		cyclin-dependent protein serine/threonine kinase regulator activity
GO:0016538 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
rb_corepressor RB1
UniProtKB:P06400
Family Representative 		transcription corepressor activity
GO:0003714 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
e2f_activator E2F1
UniProtKB:Q01094
Family Representative 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
whi5_corepressor Whi5
UniProtKB:Q12416
Family Representative 		transcription corepressor activity
GO:0003714 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sbf_mbf Swi4
UniProtKB:P25302
Family Representative 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sbf_mbf Swi6
UniProtKB:P09959
Family Representative 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Function Unreviewed
No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
sbf_mbf Mbp1
UniProtKB:P39678
Family Representative 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mbf_cdc10 cdc10
UniProtKB:P01129
Family Representative 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Contributes Only
The review records contribution to this activity, not independent enabling. Check whether the module participant should be a complex.
mbf_cdc10 res1
UniProtKB:P33520
Family Representative 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mbf_cdc10 res2
UniProtKB:P41412
Family Representative 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g1s_cdk CDK2
UniProtKB:P24941
Family Representative 		cyclin-dependent protein serine/threonine kinase activity
GO:0004693 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g1s_cdk Cdc28
UniProtKB:P00546
Family Representative 		cyclin-dependent protein serine/threonine kinase activity
GO:0004693 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g1s_cdk cdc2
UniProtKB:P04551
Family Representative 		cyclin-dependent protein serine/threonine kinase activity
GO:0004693 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g1s_cyclin CCNE1
UniProtKB:P24864
Family Representative 		cyclin-dependent protein serine/threonine kinase regulator activity
GO:0016538 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g1s_cyclin Cln2
UniProtKB:P20438
Family Representative 		cyclin-dependent protein serine/threonine kinase regulator activity
GO:0016538 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g1s_cyclin Clb5
UniProtKB:P30283
Family Representative 		cyclin-dependent protein serine/threonine kinase regulator activity
GO:0016538 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g1s_cyclin cig2
UniProtKB:P36630
Family Representative 		cyclin-dependent protein serine/threonine kinase regulator activity
GO:0016538 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cki CDKN1B (p27/Kip1)
UniProtKB:P46527
Family Representative 		cyclin-dependent protein serine/threonine kinase inhibitor activity
GO:0004861 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cki Sic1
UniProtKB:P38634
Family Representative 		cyclin-dependent protein serine/threonine kinase inhibitor activity
GO:0004861 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cki rum1
UniProtKB:P40380
Family Representative 		cyclin-dependent protein serine/threonine kinase inhibitor activity
GO:0004861 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
scf_ligase PROTEIN_COMPLEX
Gene 		ubiquitin protein ligase activity
GO:0061630 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
scf_ligase/scf_fbox SKP2
UniProtKB:Q13309
Family Representative 		ubiquitin-like ligase-substrate adaptor activity
GO:1990756 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
scf_ligase/scf_fbox Cdc4
UniProtKB:P07834
Family Representative 		ubiquitin-like ligase-substrate adaptor activity
GO:1990756 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
scf_ligase/scf_fbox pop1
UniProtKB:P87060
Family Representative 		ubiquitin-like ligase-substrate adaptor activity
GO:1990756 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
scf_ligase/scf_fbox pop2
UniProtKB:O14170
Family Representative 		ubiquitin-like ligase-substrate adaptor activity
GO:1990756 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g1_cdk G1 cyclin-dependent kinase (CDK4/6, Cdc28, Cdc2)
PANTHER:PTHR24056
Family 		cyclin-dependent protein serine/threonine kinase activity
GO:0004693 		Family Function Unreviewed
Family review leaves GO:0004693 UNRESOLVED. CDK7 assays and cyclin-H/MAT1 regulation support cyclin-dependent kinase activity; CDK1 and CDK2 supply other positive branches. The inventory also explicitly includes CDKL1, CDKL2, CDKL3, CDKL4 and CDKL5. The present sources do not establish that their kinase reactions require cyclin association, so the cyclin-dependent qualifier is not inferred from the kinase fold or CDK-like name alone. This is a specific unresolved regulatory boundary, not a claim that these proteins lack kinase activity. CDK5 p35/p39 regulation is not used as a negative GO:0004693 counterexample.
g1_cyclin G1 cyclin (cyclin D, Cln3, Puc1)
PANTHER:PTHR10177
Family 		cyclin-dependent protein serine/threonine kinase regulator activity
GO:0016538 		Family Function Unreviewed
Family review leaves GO:0016538 UNRESOLVED. Fly CycA contributes to mitotic cell-cycle progression and cyclin-mediated CDK substrate recognition (PMID:2564316; PMID:17431409). The native CycA-PC sequence differs from the reviewed 491-residue form by only Gln66 and retains the entire cyclin domain, supporting kinase regulation for this isoform. The broader family includes cyclins with distinct partners and regulatory outputs; kinase regulation is not intrinsic kinase catalysis. The complete set with direct CDK-regulator activity is unresolved beyond these positively supported branches.
rb_corepressor Retinoblastoma pocket proteins (RB1, RBL1, RBL2)
PANTHER:PTHR13742
Family 		transcription corepressor activity
GO:0003714 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR13742.
e2f_activator Activator E2F (E2F1-3) with its DP partner
PANTHER:PTHR12081:SF43
Family 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR12081:SF43.
whi5_corepressor Whi5 G1/S transcriptional repressor
PANTHER:PTHR28246
Family 		transcription corepressor activity
GO:0003714 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR28246.
sbf_mbf SBF/MBF subunits (Swi4, Mbp1 DNA-binding; Swi6 shared)
PANTHER:PTHR43828
Family 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR43828.
mbf_cdc10 MBF subunits Cdc10, Res1, Res2
PANTHER:PTHR43828
Family 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR43828.
g1s_cdk G1/S cyclin-dependent kinase (CDK2, Cdc28, Cdc2)
PANTHER:PTHR24056
Family 		cyclin-dependent protein serine/threonine kinase activity
GO:0004693 		Family Function Unreviewed
Family review leaves GO:0004693 UNRESOLVED. CDK7 assays and cyclin-H/MAT1 regulation support cyclin-dependent kinase activity; CDK1 and CDK2 supply other positive branches. The inventory also explicitly includes CDKL1, CDKL2, CDKL3, CDKL4 and CDKL5. The present sources do not establish that their kinase reactions require cyclin association, so the cyclin-dependent qualifier is not inferred from the kinase fold or CDK-like name alone. This is a specific unresolved regulatory boundary, not a claim that these proteins lack kinase activity. CDK5 p35/p39 regulation is not used as a negative GO:0004693 counterexample.
g1s_cyclin G1/S cyclin (cyclin E, Cln1/2 and Clb5/6, Cig2)
PANTHER:PTHR10177
Family 		cyclin-dependent protein serine/threonine kinase regulator activity
GO:0016538 		Family Function Unreviewed
Family review leaves GO:0016538 UNRESOLVED. Fly CycA contributes to mitotic cell-cycle progression and cyclin-mediated CDK substrate recognition (PMID:2564316; PMID:17431409). The native CycA-PC sequence differs from the reviewed 491-residue form by only Gln66 and retains the entire cyclin domain, supporting kinase regulation for this isoform. The broader family includes cyclins with distinct partners and regulatory outputs; kinase regulation is not intrinsic kinase catalysis. The complete set with direct CDK-regulator activity is unresolved beyond these positively supported branches.
g1s_cyclin G1/S cyclin (cyclin E, Cln1/2 and Clb5/6, Cig2)
PANTHER:PTHR21615
Family 		cyclin-dependent protein serine/threonine kinase regulator activity
GO:0016538 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR21615.
cki G1/S CDK inhibitor (p27/Kip1, Sic1, Rum1)
Family 		cyclin-dependent protein serine/threonine kinase inhibitor activity
GO:0004861 		Family Id Missing
The family has no identifier linking it to a curated family review.
scf_fbox F-box substrate adaptor for the CKI (Skp2 for p27; Cdc4 for Sic1; Pop1/Pop2 for Rum1)
PANTHER:PTHR16134
Family 		ubiquitin-like ligase-substrate adaptor activity
GO:1990756 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR16134.
scf_fbox F-box substrate adaptor for the CKI (Skp2 for p27; Cdc4 for Sic1; Pop1/Pop2 for Rum1)
PANTHER:PTHR19854
Family 		ubiquitin-like ligase-substrate adaptor activity
GO:1990756 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR19854.
scf_fbox F-box substrate adaptor for the CKI (Skp2 for p27; Cdc4 for Sic1; Pop1/Pop2 for Rum1)
PANTHER:PTHR44129
Family 		ubiquitin-like ligase-substrate adaptor activity
GO:1990756 		Family Function Unreviewed
The family review has no applicable adjudication supporting or excluding GO:1990756.
scf_fbox F-box substrate adaptor for the CKI (Skp2 for p27; Cdc4 for Sic1; Pop1/Pop2 for Rum1)
PANTHER:PTHR44156
Family 		ubiquitin-like ligase-substrate adaptor activity
GO:1990756 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR44156.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

  • rb_corepressor ⊣ e2f_activator [input]
    rb_corepressor is a negative regulator with no upstream edge (not described as feedback)
  • whi5_corepressor ⊣ sbf_mbf [input]
    whi5_corepressor is a negative regulator with no upstream edge (not described as feedback)

Gene-review completeness (36/36 grounded genes reviewed)

33 complete review(s) · 35 with deep research · 0 missing review · 1 reviewed but lacking deep research

Gene Review Complete Deep research
CCND1 P24385 ✓ ✓ ✓
CCNE1 P24864 ✓ ✓ ✓
cdc10 P01129 ✓ ✓ ✓
cdc2 P04551 ✓ ✓ ✗
CDC28 P00546 ✓ ✓ ✓
CDC4 P07834 ✓ ✓ ✓
CDC53 Q12018 ✓ ✓ ✓
CDK2 P24941 ✓ ✓ ✓
CDK4 P11802 ✓ ✓ ✓
CDKN1B P46527 ✓ 210/214 ✓
cig2 P36630 ✓ ✓ ✓
CLB5 P30283 ✓ 35/36 ✓
CLN2 P20438 ✓ ✓ ✓
CLN3 P13365 ✓ ✓ ✓
cul1 O13790 ✓ ✓ ✓
CUL1 Q13616 ✓ ✓ ✓
E2F1 Q01094 ✓ ✓ ✓
HRT1 Q08273 ✓ ✓ ✓
MBP1 P39678 ✓ ✓ ✓
pop1 P87060 ✓ ✓ ✓
pop2 O14170 ✓ ✓ ✓
puc1 P25009 ✓ ✓ ✓
RB1 P06400 ✓ ✓ ✓
rbx1 O13959 ✓ ✓ ✓
RBX1 P62877 ✓ ✓ ✓
res1 P33520 ✓ ✓ ✓
res2 P41412 ✓ ✓ ✓
rum1 P40380 ✓ ✓ ✓
SIC1 P38634 ✓ ✓ ✓
SKP1 P52286 ✓ ✓ ✓
SKP1 P63208 ✓ ✓ ✓
skp1 Q9Y709 ✓ 67/68 ✓
SKP2 Q13309 ✓ ✓ ✓
SWI4 P25302 ✓ ✓ ✓
SWI6 P09959 ✓ ✓ ✓
WHI5 Q12416 ✓ ✓ ✓

Details

Context
EukaryotaNCBITaxon:2759
nucleusGO:0005634
G1/S transition (Start / restriction point)Biological Processg1_s_transition

Growth-coupled G1 cyclin-CDK activity releases the G1/S transcription program from its corepressor; the resulting G1/S cyclin-CDK destroys the CDK inhibitor through SCF-dependent proteolysis, committing the cell to S phase.

G1/S transition of mitotic cell cycleGO:0000082
Context
EukaryotaNCBITaxon:2759
nucleusGO:0005634

Connections

G1 cyclin-CDK phosphorylation of the corepressor (Rb, Whi5) releases the G1/S transcription factor.
The released transcription program produces the G1/S cyclins that activate the G1/S CDK.
Positive feedback: G1/S cyclin-CDK reinforces corepressor phosphorylation (cyclin E-CDK2 on Rb; Cln1/2-Cdc28 on Whi5), making commitment switch-like and irreversible.
G1/S CDK multisite phosphorylation of the CKI creates the phosphodegron recognized by the SCF F-box adaptor.
cki_destruction -> g1s_cdk_activation Positively Regulates
Destruction of the CKI releases S-phase cyclin-CDK activity, completing the commitment positive feedback loop.
Part 1: G1 cyclin-CDK activation
Growth-coupled G1 cyclin-CDK activationRegulatory Stepg1_cdk_priming

The G1 cyclin accumulates with cell growth and mitogenic input (cyclin D in metazoa, Cln3 in budding yeast, Puc1 and the Cig cyclins in fission yeast) and activates its CDK partner, whose first substrate is the transcriptional corepressor of the G1/S program.

Annotons

G1 CDK catalytic subunit
g1_cdk
Participant: Family: G1 cyclin-dependent kinase (CDK4/6, Cdc28, Cdc2)
Family:
G1 cyclin-dependent kinase (CDK4/6, Cdc28, Cdc2)PANTHER:PTHR24056 Metazoa use the dedicated CDK4/CDK6 paralogs with cyclin D; both yeasts use the single essential CDK (Cdc28, Cdc2) with G1 cyclins.
Representative Members: CDK4UniProtKB:P11802 Cdc28UniProtKB:P00546 cdc2UniProtKB:P04551

Function

cyclin-dependent protein serine/threonine kinase activityGO:0004693
Targets: G1/S transcriptional corepressor (Rb, Whi5)

Processes

G1/S transition of mitotic cell cycleGO:0000082

Locations

nucleusGO:0005634

Catalytic subunit of the G1 cyclin-CDK that initiates hypo-phosphorylation of the Rb/Whi5 corepressor.

G1 cyclin regulatory subunit
g1_cyclin
Participant: Family: G1 cyclin (cyclin D, Cln3, Puc1)
Family:
G1 cyclin (cyclin D, Cln3, Puc1)PANTHER:PTHR10177 Growth- and mitogen-responsive cyclin whose abundance couples cell size or extracellular signals to G1 CDK activation.
Representative Members: CCND1UniProtKB:P24385 Cln3UniProtKB:P13365 puc1UniProtKB:P25009

Function

cyclin-dependent protein serine/threonine kinase regulator activityGO:0016538

Regulatory subunit that activates and confers substrate preference on the G1 CDK.

PMID:3062366
Cln3 (DAF1/WHI1) sets cell size at Start in budding yeast.
Part 2: release of the G1/S transcription program
Release of the G1/S transcription factor from its corepressorRegulatory Stepg1s_transcription_release

Phosphorylation of the corepressor by G1 cyclin-CDK dissociates it from the G1/S transcription factor, which then activates the G1/S gene cluster (G1/S cyclins, replication factors). The corepressor-transcription factor pair is lineage-specific and is modeled as a taxon variant set.

Variant set: G1/S corepressor and transcription factor by taxon (Exactly One)
Metazoan Rb-E2F/DPRegulatory Stepmetazoan_rb_e2f
Context
MetazoaNCBITaxon:33208

Annotons

Rb pocket-protein corepressor
rb_corepressor
Participant: Family: Retinoblastoma pocket proteins (RB1, RBL1, RBL2)
Family:
Retinoblastoma pocket proteins (RB1, RBL1, RBL2)PANTHER:PTHR13742
Representative Members: RB1UniProtKB:P06400

Function

transcription corepressor activityGO:0003714
Targets: E2F-DP activator

Locations

chromatinGO:0000785

Hypophosphorylated Rb binds activator E2Fs and recruits chromatin repressors; cyclin D-CDK4/6 then cyclin E-CDK2 phosphorylation releases E2F.

PMID:9694791
pRB-family proteins bind and repress E2F; CDK phosphorylation releases E2F.
Activator E2F transcription factor
e2f_activator
Participant: Family: Activator E2F (E2F1-3) with its DP partner
Family:
Activator E2F (E2F1-3) with its DP partnerPANTHER:PTHR12081:SF43 Functions as an E2F-DP heterodimer; the DP partner (TFDP1, PTHR12548) is not separately modeled.
Representative Members: E2F1UniProtKB:Q01094

Function

DNA-binding transcription factor activity, RNA polymerase II-specificGO:0000981

Locations

chromatinGO:0000785

Activates the G1/S gene cluster (cyclin E, cyclin A, CDC6, CDT1, MCMs, E2F1 itself) once released from Rb.

Connections

rb_corepressor -> e2f_activator Negatively Regulates
Rb binds and represses activator E2F until phosphorylated by G1 cyclin-CDK.
Budding-yeast Whi5-SBF/MBFRegulatory Stepbudding_yeast_whi5_sbf
Context
Saccharomyces cerevisiaeNCBITaxon:4932

Annotons

Whi5 corepressor
whi5_corepressor
Participant: Family: Whi5 G1/S transcriptional repressor
Family:
Whi5 G1/S transcriptional repressorPANTHER:PTHR28246 Functional analog, not homolog, of metazoan Rb; a Saccharomycotina-specific family.
Representative Members: Whi5UniProtKB:Q12416

Function

transcription corepressor activityGO:0003714
Targets: SBF (Swi4-Swi6)

Locations

chromatinGO:0000785

SBF-bound repressor of G1/S transcription; multisite phosphorylation by Cln3-Cdc28 (reinforced by Cln1/2-Cdc28) drives its nuclear export and releases SBF.

PMID:15210111
Whi5 is an SBF-bound inhibitor of G1/S transcription antagonized by CDK activity.
PMID:15210110
Cln3-Cdc28 phosphorylates Whi5 to activate G1-specific transcription.
SBF/MBF transcription factor
sbf_mbf
Participant: Family: SBF/MBF subunits (Swi4, Mbp1 DNA-binding; Swi6 shared)
Family:
SBF/MBF subunits (Swi4, Mbp1 DNA-binding; Swi6 shared)PANTHER:PTHR43828 PANTHER family PTHR43828 groups the ankyrin-repeat G1/S transcription-factor subunits Swi4, Swi6, Mbp1 and fission-yeast Cdc10/Res1/Res2; the family's PANTHER name is dominated by an unrelated member. SBF = Swi4-Swi6 (SCB elements); MBF = Mbp1-Swi6 (MCB elements).
Representative Members: Swi4UniProtKB:P25302 Swi6UniProtKB:P09959 Mbp1UniProtKB:P39678

Function

DNA-binding transcription factor activity, RNA polymerase II-specificGO:0000981

Locations

chromatinGO:0000785

Activates the ~200-gene G1/S cluster including CLN1, CLN2, CLB5 and CLB6 once Whi5 is released.

PMID:8372350
Mbp1 and Swi4 are the DNA-binding subunits of MBF and SBF required for G1 to S progression.
PMID:1832338
SWI4 and SWI6 are required for G1 cyclin transcription.

Connections

whi5_corepressor -> sbf_mbf Negatively Regulates
Whi5 represses SBF-bound promoters until phosphorylated by Cln-Cdc28.
Fission-yeast MBF (Cdc10-Res1-Res2)Regulatory Stepfission_yeast_mbf

Fission yeast has no Rb/Whi5-type corepressor; MBF activity at Start depends on Cdc2-cyclin activity and is later shut off by the MBF-dependent corepressor Nrm1. The direct CDK trigger is a knowledge gap and no corepressor annoton is asserted.

Context
Schizosaccharomyces pombeNCBITaxon:4896

Annotons

MBF transcription factor (Cdc10-Res1-Res2)
mbf_cdc10
Participant: Family: MBF subunits Cdc10, Res1, Res2
Family:
MBF subunits Cdc10, Res1, Res2PANTHER:PTHR43828 Same PANTHER family as budding-yeast Swi4/Swi6/Mbp1; Cdc10 is the Swi6-like shared subunit, Res1/Res2 the Swi4/Mbp1-like DNA-binding subunits. The activator Rep2 is unclassified in PANTHER and not modeled.
Representative Members: cdc10UniProtKB:P01129 res1UniProtKB:P33520 res2UniProtKB:P41412

Function

DNA-binding transcription factor activity, RNA polymerase II-specificGO:0000981

Locations

chromatinGO:0000785

Activates MCB-driven G1/S genes (cig2, cdc18, cdt1, cdc22) at Start.

PMID:1734281
cdc10 controls the periodic transcription of DNA-synthesis genes at Start in fission yeast.
Part 3: G1/S cyclin-CDK activation
G1/S cyclin-CDK activationRegulatory Stepg1s_cdk_activation

The G1/S cyclins transcribed by the released program (cyclin E; Cln1/2 and Clb5/6; Cig2) bind the CDK and produce the G1/S CDK activity that phosphorylates the CDK inhibitor and reinforces corepressor inactivation.

Annotons

G1/S CDK catalytic subunit
g1s_cdk
Participant: Family: G1/S cyclin-dependent kinase (CDK2, Cdc28, Cdc2)
Family:
G1/S cyclin-dependent kinase (CDK2, Cdc28, Cdc2)PANTHER:PTHR24056
Representative Members: CDK2UniProtKB:P24941 Cdc28UniProtKB:P00546 cdc2UniProtKB:P04551

Function

cyclin-dependent protein serine/threonine kinase activityGO:0004693
Targets: CDK inhibitor (p27, Sic1, Rum1) G1/S transcriptional corepressor (Rb, Whi5)

Processes

G1/S transition of mitotic cell cycleGO:0000082

Locations

nucleusGO:0005634

G1/S CDK that multisite-phosphorylates the CKI to create the phosphodegron read by the SCF F-box adaptor.

G1/S cyclin regulatory subunit
g1s_cyclin
Participant: Family: G1/S cyclin (cyclin E, Cln1/2 and Clb5/6, Cig2)
Family:
G1/S cyclin (cyclin E, Cln1/2 and Clb5/6, Cig2) The role is split across two PANTHER families: cyclin E, Clb5/6 and Cig2 are canonical cyclins (PTHR10177), whereas the budding-yeast Start cyclins Cln1/Cln2 form a separate family (PTHR21615).
Representative Members: CCNE1UniProtKB:P24864 Cln2UniProtKB:P20438 Clb5UniProtKB:P30283 cig2UniProtKB:P36630

Function

cyclin-dependent protein serine/threonine kinase regulator activityGO:0016538

Transcriptionally induced cyclin that activates the G1/S CDK and closes the positive feedback loop on the transcription program.

PMID:8657126
Cig2-Cdc2 promotes S-phase onset in fission yeast.
PMID:1832338
SBF-dependent CLN1/CLN2 transcription is required for Start.
Part 4: CDK inhibitor destruction
SCF-dependent destruction of the CDK inhibitorRegulatory Stepcki_destruction

The stoichiometric CDK inhibitor (p27/Kip1, Sic1, Rum1) holds S-phase cyclin-CDK inactive through G1. Multisite phosphorylation by the G1/S CDK creates a phosphodegron recognized by an F-box adaptor of the SCF ubiquitin ligase, and proteasomal destruction of the inhibitor releases S-phase CDK activity irreversibly.

Annotons

Stoichiometric CDK inhibitor
cki
Participant: Family: G1/S CDK inhibitor (p27/Kip1, Sic1, Rum1)
Family:
G1/S CDK inhibitor (p27/Kip1, Sic1, Rum1) No shared PANTHER family: p27/Kip1 belongs to the Cip/Kip family PTHR10265, whereas Sic1 and Rum1 are unclassified and structurally unrelated to Cip/Kip proteins. They are functional analogs that bind and inhibit cyclin-CDK stoichiometrically.
Representative Members: CDKN1B (p27/Kip1)UniProtKB:P46527 Sic1UniProtKB:P38634 rum1UniProtKB:P40380

Function

cyclin-dependent protein serine/threonine kinase inhibitor activityGO:0004861
Targets: S-phase cyclin-CDK (cyclin E/A-CDK2, Clb5/6-Cdc28, Cig2/Cdc13-Cdc2)

Locations

nucleusGO:0005634

Inhibitor whose CDK-dependent phosphorylation and SCF-mediated destruction is the irreversible commitment event.

PANTHER:PTN004142838
PAINT node in PTHR10265 (Cip/Kip) with IBD support for cyclin-dependent protein serine/threonine kinase inhibitor activity (F:GO:0004861), seeded by human CDKN1B.
PMID:7954792
Sic1 inhibits Clb-Cdc28 and must be destroyed for S-phase entry.
PMID:8521500
Rum1 is a direct inhibitor of the Cdc2 kinase.
PMID:10385618
Cip/Kip proteins (p21, p27, p57) inhibit G1 cyclin-CDKs in mammalian cells.
SCF ubiquitin ligase with CKI-specific F-box adaptor
scf_ligase
Participant: Protein Complex: SCF (Skp1-cullin-F-box) ubiquitin ligase
Protein Complex:
SCF (Skp1-cullin-F-box) ubiquitin ligaseGO:0019005
Active units:
Cullin-1 scaffold
Participant: Family: Cullin-1 (CUL1, Cdc53, Cul1)
Family:
Cullin-1 (CUL1, Cdc53, Cul1)PANTHER:PTHR11932
Representative Members: CUL1UniProtKB:Q13616 Cdc53UniProtKB:Q12018 cul1UniProtKB:O13790
Role: scaffold bridging Skp1/F-box and the RING subunit
RING-box subunit
Participant: Family: RBX1/Hrt1/Rbx1 RING-box protein
Family:
RBX1/Hrt1/Rbx1 RING-box proteinPANTHER:PTHR11210
Representative Members: RBX1UniProtKB:P62877 Hrt1UniProtKB:Q08273 rbx1UniProtKB:O13959
Role: recruits the ubiquitin-charged E2 (Cdc34/UBE2R)
Skp1 adaptor
Participant: Family: Skp1
Family:
Skp1PANTHER:PTHR11165
Representative Members: SKP1UniProtKB:P63208 Skp1UniProtKB:P52286 skp1UniProtKB:Q9Y709
Role: links the F-box protein to the cullin
CKI-recognizing F-box adaptor
Participant: Family: F-box substrate adaptor for the CKI (Skp2 for p27; Cdc4 for Sic1; Pop1/Pop2 for Rum1)
Family:
F-box substrate adaptor for the CKI (Skp2 for p27; Cdc4 for Sic1; Pop1/Pop2 for Rum1) The adaptor is lineage-specific and non-orthologous: the leucine-rich-repeat F-box protein Skp2 recognizes phospho-p27 in metazoa, whereas the WD40 F-box proteins Cdc4 and Pop1/Pop2 recognize phospho-Sic1 and phospho-Rum1 in the yeasts. Family ids follow the local PANTHER 19.0 sequence classification (Skp2 PTHR16134, Cdc4 PTHR19854, Pop1 PTHR44129, Pop2 PTHR44156); the UniProt cross-references place the same proteins in PTHR46976, PTHR19849, PTHR19848 and PTHR22847 respectively, and PANTHER family names are dominated by other members. The PAINT SKP2 adaptor node PTN009029653 lies in the PTHR46976 slice and is cited as evidence rather than asserted as an ancestral node.
Representative Members: SKP2UniProtKB:Q13309 Cdc4UniProtKB:P07834 pop1UniProtKB:P87060 pop2UniProtKB:O14170
Role: substrate receptor for the phosphorylated CDK inhibitor
Function:
ubiquitin-like ligase-substrate adaptor activityGO:1990756
PANTHER:PTN009029653
PAINT node (PTHR46976 slice) with IBD support for ubiquitin-like ligase-substrate adaptor activity (F:GO:1990756) and SCF ubiquitin ligase complex membership (C:GO:0019005), seeded by human SKP2.
PMID:10559916
SKP2 is the F-box adaptor for phosphorylated p27.

Function

ubiquitin protein ligase activityGO:0061630
Targets: phosphorylated CDK inhibitor (p27, Sic1, Rum1)

Processes

SCF-dependent proteasomal ubiquitin-dependent protein catabolic processGO:0031146

Locations

nucleusGO:0005634

Polyubiquitinates the phosphorylated CKI for proteasomal destruction, releasing S-phase cyclin-CDK.

PMID:9346239
Cdc4-Skp1-Cdc53 ubiquitinates phosphorylated Sic1.
PMID:10559916
SKP2 is required for ubiquitin-mediated degradation of p27.
PMID:9203581
Pop1 is required for ubiquitin-proteasome degradation of Rum1.

Connections

cki -> scf_ligase Provides Input For
The phosphorylated CKI is the substrate recognized by the SCF F-box adaptor.