id: Q9UKT4
gene_symbol: FBXO5
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXO5 (Early mitotic inhibitor 1, EMI1) is a cell-cycle regulatory protein
  that, despite containing an F-box, functions principally as a direct inhibitor
  of the anaphase-promoting complex/cyclosome (APC/C), the multisubunit E3
  ubiquitin ligase that drives mitotic and cell-cycle progression. EMI1
  accumulates from late G1 through S and G2 phase under E2F transcriptional
  control and binds tightly to the APC/C and its coactivators FZR1/CDH1 and
  CDC20. It acts as a pseudosubstrate/multimodal inhibitor: a conserved
  C-terminal D-box, linker, and tail together with a structured zinc-binding
  region (ZBR) engage distinct sites on APC/C to block substrate access at the
  D-box coreceptor (FZR1-ANAPC10) and to suppress ubiquitin-chain elongation by
  the APC/C E2 enzymes UBE2C/UBCH10 and UBE2S. By restraining APC/C during
  interphase, EMI1 stabilizes APC/C substrates such as cyclin A (CCNA2) and
  geminin (GMNN), thereby coupling DNA replication with mitosis, preventing
  rereplication, and protecting against DNA-damage-induced senescence. EMI1
  levels are sharply controlled: at the G1/S transition it switches from being a
  substrate of APC/C(CDH1) to its inhibitor, and at the onset of mitosis it is
  phosphorylated by CDK1/2 and PLK1 to generate a DSGxxS phosphodegron
  recognized by the SCF(beta-TrCP/BTRC) ubiquitin ligase, leading to its
  degradation and APC/C activation. In oocyte meiosis the EMI1/EMI2 family
  provides cytostatic-factor activity that arrests cells through APC/C
  inhibition. EMI1 levels are dosage-sensitive for genome stability: reduced
  EMI1 causes chromosome instability, micronucleation, and DNA damage and is
  associated with cellular transformation, while EMI1 abundance is also shaped by
  post-transcriptional control (METTL16-mediated m6A mRNA stabilization and
  PTBP1-dependent exon-3 splicing), and FBXO5 is frequently dysregulated in
  cancers. EMI1 localizes to the nucleus and cytoplasm in interphase and to the
  spindle in mitosis.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic assignment of nuclear localization, consistent with experimental immunofluorescence showing EMI1 in the nucleus during interphase.
    action: ACCEPT
    reason: Correct localization supported by direct experimental evidence (IDA, PMID:11988738).
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm
- term:
    id: GO:0007088
    label: regulation of mitotic nuclear division
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of a role in regulating mitotic nuclear division, consistent with EMI1's APC/C-inhibitory control of mitotic timing.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the more specific and better-supported role is negative regulation of the metaphase/anaphase transition via APC/C inhibition.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Regulator of APC activity during mitotic and meiotic cell cycle
- term:
    id: GO:0045835
    label: negative regulation of meiotic nuclear division
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of a role in negatively regulating meiotic nuclear division, consistent with EMI1/EMI2-family cytostatic-factor activity that arrests oocytes via APC/C inhibition.
    action: KEEP_AS_NON_CORE
    reason: Supported for the family (the human meiotic CSF role is largely carried out by the paralog EMI2/FBXO43); EMI1's own evidence is strongest in mitotic interphase. Meiotic role is real but non-core for human FBXO5.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: During oocyte maturation, plays a role in meiosis through inactivation of APC-FZR1 complex
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of nuclear localization from the UniProt subcellular location vocabulary.
    action: ACCEPT
    reason: Correct localization, redundant with experimental IDA evidence.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Combined automated electronic assignment of cytoplasmic localization, consistent with experimental immunofluorescence.
    action: ACCEPT
    reason: Correct localization, redundant with experimental IDA evidence (PMID:11988738).
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000269|PubMed:11988738}.'
- term:
    id: GO:0005819
    label: spindle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of spindle localization; EMI1 concentrates at the spindle in mitotic cells.
    action: ACCEPT
    reason: Correct localization, redundant with experimental IDA evidence (PMID:15469984).
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: 'Cytoplasm, cytoskeleton, spindle'
- term:
    id: GO:0007088
    label: regulation of mitotic nuclear division
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic assignment of a role in regulating mitotic nuclear division.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; subsumed by the more specific APC/C-inhibition annotations.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Regulator of APC activity during mitotic and meiotic cell cycle
- term:
    id: GO:0010948
    label: negative regulation of cell cycle process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning assignment of negative regulation of a cell-cycle process, consistent with EMI1's inhibition of the metaphase/anaphase transition.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic parent; the specific negative regulation of mitotic metaphase/anaphase transition better captures the role.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: prevents the degradation of APC substrates at multiple levels
- term:
    id: GO:0045835
    label: negative regulation of meiotic nuclear division
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic assignment of negative regulation of meiotic nuclear division.
    action: KEEP_AS_NON_CORE
    reason: Real for the family via APC/C inhibition but non-core for human FBXO5 (the dedicated meiotic CSF inhibitor is the paralog EMI2/FBXO43).
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Controls entry into the first meiotic division through inactivation of APC-FZR1 complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16439210
  qualifier: enables
  review:
    summary: IntAct interaction with EVI5, which stabilizes EMI1 by blocking PLK1 phosphorylation. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real, functionally relevant interaction (EVI5) but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Also interacts with EVI5 which blocks its phosphorylation by PLK1 and prevents its subsequent binding to BTRC and degradation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17380122
  qualifier: enables
  review:
    summary: High-throughput IntAct interaction (SKP1, UniProtKB:P63208). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: SKP1 interaction reflects F-box-mediated association; bare protein binding is uninformative. The cited paper is about RGS12/NGF signaling and the EMI1-SKP1 datapoint is a high-throughput interaction record.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: 'Q9UKT4; P63208: SKP1; NbExp=9; IntAct=EBI-852298, EBI-307486;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17719540
  qualifier: enables
  review:
    summary: High-throughput IntAct interaction (CDC27, UniProtKB:P30260), an APC/C subunit. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records an APC/C-subunit interaction relevant to EMI1's inhibitory binding, but bare protein binding is uninformative; captured by the anaphase-promoting complex binding annotation.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: 'Q9UKT4; P30260: CDC27; NbExp=3; IntAct=EBI-852298, EBI-994813;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18662541
  qualifier: enables
  review:
    summary: High-throughput IntAct interaction (CDC27). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: APC/C-subunit interaction; bare protein binding is uninformative and subsumed by anaphase-promoting complex binding.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: 'Q9UKT4; P30260: CDC27; NbExp=3; IntAct=EBI-852298, EBI-994813;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27705803
  qualifier: enables
  review:
    summary: High-throughput interactome (Polycomb complexome, SKP1). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: 'Q9UKT4; P63208: SKP1; NbExp=9; IntAct=EBI-852298, EBI-307486;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome reference map (SKP1). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: 'Q9UKT4; P63208: SKP1; NbExp=9; IntAct=EBI-852298, EBI-307486;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Cell-specific proteome-scale interactome (CDC27/SKP1). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: 'Q9UKT4; P63208: SKP1; NbExp=9; IntAct=EBI-852298, EBI-307486;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-map interactome (SKP1). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: 'Q9UKT4; P63208: SKP1; NbExp=9; IntAct=EBI-852298, EBI-307486;'
- term:
    id: GO:0007346
    label: regulation of mitotic cell cycle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic assignment (from mouse Q7TSG3) of regulation of the mitotic cell cycle.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific APC/C-inhibition and metaphase/anaphase-transition annotations better capture the role.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Regulator of APC activity during mitotic and meiotic cell cycle
- term:
    id: GO:0072687
    label: meiotic spindle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-based electronic assignment of meiotic spindle localization, transferred from mouse.
    action: KEEP_AS_NON_CORE
    reason: Plausible by similarity to the mouse ortholog, but meiotic localization is non-core for human FBXO5; not experimentally demonstrated in human.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: 'Cytoplasm, cytoskeleton, spindle'
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-derived generic protein ubiquitination process annotation, propagated from the F-box/UPA00143 pathway mapping.
    action: MARK_AS_OVER_ANNOTATED
    reason: EMI1 does not itself ubiquitinate substrates; its dominant role is as an inhibitor of the APC/C ubiquitin ligase. It is a substrate of SCF(BTRC) and APC/C, not a productive ligase component. This generic UniPathway annotation overstates a catalytic ubiquitination role.
    supported_by:
    - reference_id: PMID:16921029
      supporting_text: the APC/C inhibitor Emi1 tightly binds both the APC/C and its Cdh1 activator
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for nucleoplasmic localization, consistent with EMI1's interphase nuclear pool.
    action: ACCEPT
    reason: IDA-supported localization consistent with the documented nuclear localization.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    summary: ComplexPortal author-statement assigning EMI1 to an SCF ubiquitin ligase complex based on its F-box. EMI1 can associate with SKP1/CUL1 via its F-box, but its functionally dominant and best-documented role is as an APC/C inhibitor, not as an SCF substrate receptor.
    action: KEEP_AS_NON_CORE
    reason: EMI1 has an F-box and can form an SCF complex (ComplexPortal CPX-7904; SKP1 interaction), so the assignment is not wrong, but no validated SCF substrate of EMI1 is established and its core biology is APC/C inhibition. A 2024 study proposes RAD51 as an SCF^EMI1 substrate, but this single recent report does not overturn the strongly documented APC/C-inhibitor role; retain as non-core rather than core SCF receptor.
    additional_reference_ids:
    - file:human/FBXO5/FBXO5-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex
    - reference_id: file:human/FBXO5/FBXO5-deep-research-falcon.md
      supporting_text: a 2024 study explicitly frames **EMI1 (FBXO5)** as an **F-box protein** that can serve as the variable substrate receptor in an **SCF^EMI1** ubiquitin ligase complex (core SCF components SKP1–CUL1–RBX1 plus the F-box protein) and cites **RAD51** as an SCF^EMI1 substrate targeted for proteolytic degradation
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: involved_in
  review:
    summary: ComplexPortal author-statement assigning EMI1 to SCF-dependent proteasomal protein catabolism. EMI1 is a substrate (degraded by SCF-beta-TrCP) rather than a demonstrated substrate-receptor driving degradation of other proteins via SCF.
    action: MARK_AS_OVER_ANNOTATED
    reason: The well-documented SCF link for EMI1 is as a phospho-degron substrate of SCF(BTRC), not as a productive F-box receptor targeting other proteins for SCF-dependent degradation. The involved_in catabolic-process annotation over-extends from the F-box family default.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: degradation during early mitosis through ubiquitin-mediated proteolysis by the SCF ubiquitin ligase complex containing the F-box protein BTRC
- term:
    id: GO:0045841
    label: negative regulation of mitotic metaphase/anaphase transition
  evidence_type: IDA
  original_reference_id: PMID:15148369
  qualifier: involved_in
  review:
    summary: Direct evidence that EMI1 inhibits APC/C, whose activation drives the metaphase/anaphase transition; EMI1 destruction is required for APC/C activation in late mitosis. Core process.
    action: ACCEPT
    reason: Core biological process directly supported; EMI1 inhibition of APC/C restrains the metaphase/anaphase transition.
    supported_by:
    - reference_id: PMID:15148369
      supporting_text: The degradation of Emi1 in early mitosis is necessary for the activation of APC/C in late mitosis
- term:
    id: GO:1990948
    label: ubiquitin ligase inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:15148369
  qualifier: enables
  review:
    summary: Direct evidence that EMI1 inhibits the APC/C ubiquitin ligase. This is the core molecular function of EMI1.
    action: ACCEPT
    reason: Core molecular function; EMI1 is a direct inhibitor of the APC/C E3 ubiquitin ligase.
    supported_by:
    - reference_id: PMID:15148369
      supporting_text: Early mitotic inhibitor 1 (Emi1) inhibits the activity of the anaphase promoting complex/cyclosome (APC/C), which is a multisubunit ubiquitin ligase
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: IMP
  original_reference_id: PMID:17875940
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that loss of EMI1 leads to DNA damage (replication stress) and DNA-damage-induced senescence. Recent work shows EMI1 is dosage-sensitive for genome stability, with reduced EMI1 driving chromosome instability and DNA damage.
    action: KEEP_AS_NON_CORE
    reason: A downstream consequence of EMI1 loss (deregulated APC/C, replication stress, chromosome instability) rather than a direct EMI1 effector function; real but non-core. This phenotype follows directly from EMI1's core role in coupling DNA replication to mitosis via interphase APC/C inhibition.
    additional_reference_ids:
    - file:human/FBXO5/FBXO5-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:17875940
      supporting_text: Cells lacking Emi1 undergo DNA damage, likely explained by replication stress upon deregulated cyclin E- and A-associated kinase activities
    - reference_id: file:human/FBXO5/FBXO5-deep-research-falcon.md
      supporting_text: '**reduced EMI1 expression drives chromosome instability (CIN)** and is associated with DNA damage and transformation phenotypes in colonic epithelial contexts'
- term:
    id: GO:0140678
    label: molecular function inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:23708605
  qualifier: enables
  review:
    summary: Direct (DisProt) evidence that EMI1's intrinsically disordered C-terminal domain inhibits APC/C functions. A parent of the specific ubiquitin ligase inhibitor activity.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific ubiquitin ligase inhibitor activity (GO:1990948) better captures the function.
    supported_by:
    - reference_id: PMID:23708605
      supporting_text: EMI1's 143-residue C-terminal domain inhibits multiple APC/C(CDH1) functions
- term:
    id: GO:0140678
    label: molecular function inhibitor activity
  evidence_type: IMP
  original_reference_id: PMID:23708605
  qualifier: enables
  review:
    summary: Mutant-phenotype (DisProt) evidence that EMI1 domains inhibit APC/C functions. Parent of the specific ubiquitin ligase inhibitor activity.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; subsumed by GO:1990948 ubiquitin ligase inhibitor activity.
    supported_by:
    - reference_id: PMID:23708605
      supporting_text: synergistically both block the substrate-binding site and inhibit ubiquitin-chain elongation
- term:
    id: GO:0072687
    label: meiotic spindle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity assignment of meiotic spindle localization from the mouse ortholog.
    action: KEEP_AS_NON_CORE
    reason: Plausible by similarity but meiotic localization is non-core for human FBXO5; not directly demonstrated in human.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: 'Cytoplasm, cytoskeleton, spindle'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11988738
  qualifier: enables
  review:
    summary: Interaction with FZR1/CDH1 (UniProtKB:Q9UM11), the APC/C coactivator that EMI1 inhibits. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally central EMI1-FZR1/CDH1 interaction, but bare protein binding is uninformative; captured by anaphase-promoting complex binding and the inhibition annotations.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Interacts with FZR1/CDH1 and the N-terminal substrate-binding domain of CDC20; prevents APC activation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16921029
  qualifier: enables
  review:
    summary: Interaction with FZR1/CDH1 from the pseudosubstrate-inhibitor study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the EMI1-CDH1 interaction central to APC/C inhibition, but bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:16921029
      supporting_text: the APC/C inhibitor Emi1 tightly binds both the APC/C and its Cdh1 activator
- term:
    id: GO:0010997
    label: anaphase-promoting complex binding
  evidence_type: IDA
  original_reference_id: PMID:16921029
  qualifier: enables
  review:
    summary: Direct evidence that EMI1 binds the APC/C and competes with substrates at the D-box receptor. A core mechanistic molecular function underlying EMI1's APC/C inhibition.
    action: ACCEPT
    reason: Core molecular function; direct, high-quality evidence of EMI1 binding APC/C as a pseudosubstrate inhibitor.
    supported_by:
    - reference_id: PMID:16921029
      supporting_text: binds to the D-box receptor site on the APC/C(Cdh1), and competes with APC/C substrates for D-box binding
    - reference_id: file:human/FBXO5/FBXO5-deep-research-falcon.md
      supporting_text: '**Emi1/FBXO5 acts as a principal interphase inhibitor of APC/C**, particularly **APC/C activated by Cdh1 (APC/C^CDH1)**, thereby preventing premature degradation of cyclins and enabling progression toward mitosis'
- term:
    id: GO:1904667
    label: negative regulation of ubiquitin protein ligase activity
  evidence_type: IMP
  original_reference_id: PMID:29875408
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that EMI1 inhibits the APC/C(CDH1) ubiquitin ligase, switching from substrate to inhibitor to start the cell cycle. Core process.
    action: ACCEPT
    reason: Core biological process; EMI1 negatively regulates APC/C ubiquitin ligase activity, directly demonstrated.
    supported_by:
    - reference_id: PMID:29875408
      supporting_text: EMI1 switches from being a substrate to an inhibitor of APC/C(CDH1) to start the cell cycle
- term:
    id: GO:0010997
    label: anaphase-promoting complex binding
  evidence_type: IDA
  original_reference_id: PMID:26083744
  qualifier: enables
  review:
    summary: Structural (cryo-EM) evidence that EMI1 binds the APC/C; the atomic structure of APC/C-EMI1 captures the inhibitory binding mode. Core molecular function.
    action: ACCEPT
    reason: Core molecular function; structural evidence of direct APC/C binding.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Interacts simultaneously with anaphase promoting complex (APC), through at least ANAPC2, CDC23, CDC27, the APC substrate GMNN and the APC activator FZR1
- term:
    id: GO:1904667
    label: negative regulation of ubiquitin protein ligase activity
  evidence_type: IMP
  original_reference_id: PMID:23708605
  qualifier: involved_in
  review:
    summary: Structure/enzymology evidence that EMI1's C-terminal domain inhibits multiple APC/C(CDH1) functions including ubiquitin-chain elongation. Core process.
    action: ACCEPT
    reason: Core biological process; EMI1 inhibits APC/C ubiquitin ligase activity through a multimodal mechanism.
    supported_by:
    - reference_id: PMID:23708605
      supporting_text: bind distinct regions of APC/C(CDH1) to synergistically both block the substrate-binding site and inhibit ubiquitin-chain elongation
- term:
    id: GO:0051444
    label: negative regulation of ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:23708001
  qualifier: involved_in
  review:
    summary: Direct evidence that EMI1 suppresses ubiquitin transfer/chain elongation by the APC/C E2 enzymes UBCH10/UBE2C and UBE2S. Core process closely related to APC/C inhibition.
    action: ACCEPT
    reason: Core biological process; EMI1 inhibits the ubiquitin-transfer (chain elongation) step catalyzed by APC/C-associated E2 enzymes.
    supported_by:
    - reference_id: PMID:23708001
      supporting_text: preferentially suppresses the ubiquitin chain elongation by UBCH10
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23708001
  qualifier: enables
  review:
    summary: Interactions with APC/C subunits and E2 enzymes (ANAPC2, CDC27, UBE2S, etc.). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records APC/C-subunit and E2 interactions central to inhibition, but bare protein binding is uninformative; captured by APC binding and the inhibition annotations.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Interacts with UBE2S; interferes with the activity of UBE2S mainly by disrupting the dynamic electrostatic association between the C-terminal tail of UBE2S and ANAPC2
- term:
    id: GO:0006275
    label: regulation of DNA replication
  evidence_type: IMP
  original_reference_id: PMID:17485488
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that EMI1 couples DNA replication with mitosis by inhibiting APC/C in interphase, stabilizing cyclins and geminin and preventing rereplication.
    action: KEEP_AS_NON_CORE
    reason: A key downstream physiological consequence of EMI1's APC/C inhibition; real and well supported but secondary to the core inhibitor function.
    supported_by:
    - reference_id: PMID:17485488
      supporting_text: we uncover a key role for Emi1 in inhibiting the APC/C in interphase to stabilize the mitotic cyclins and geminin to promote mitosis and prevent rereplication
- term:
    id: GO:0010971
    label: positive regulation of G2/M transition of mitotic cell cycle
  evidence_type: IMP
  original_reference_id: PMID:17485488
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that EMI1 promotes mitotic entry by stabilizing mitotic cyclins and geminin via APC/C inhibition.
    action: KEEP_AS_NON_CORE
    reason: Real downstream consequence of APC/C inhibition (stabilizing cyclins to promote mitosis); secondary to the core inhibitor function.
    supported_by:
    - reference_id: PMID:17485488
      supporting_text: to stabilize the mitotic cyclins and geminin to promote mitosis and prevent rereplication
- term:
    id: GO:0032876
    label: negative regulation of DNA endoreduplication
  evidence_type: IMP
  original_reference_id: PMID:17875940
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that EMI1 prevents rereplication/endoreduplication by restraining APC/C (stabilizing geminin and cyclin A).
    action: KEEP_AS_NON_CORE
    reason: Real downstream consequence of APC/C inhibition; non-core relative to the inhibitor molecular function.
    supported_by:
    - reference_id: PMID:17234884
      supporting_text: Emi1 plays a critical role in preserving genome integrity by blocking rereplication
- term:
    id: GO:2000773
    label: negative regulation of cellular senescence
  evidence_type: IMP
  original_reference_id: PMID:17875940
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that EMI1 loss elicits DNA-damage-induced senescence; thus EMI1 normally prevents senescence.
    action: KEEP_AS_NON_CORE
    reason: A downstream consequence of EMI1's APC/C-inhibitory and genome-maintenance role; real but non-core.
    supported_by:
    - reference_id: PMID:17875940
      supporting_text: cells lacking Emi1 undergo cellular senescence
- term:
    id: GO:0006275
    label: regulation of DNA replication
  evidence_type: IMP
  original_reference_id: PMID:17234884
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that EMI1 prevents rereplication by inhibiting APC/C during S and G2 to stabilize geminin and cyclin A.
    action: KEEP_AS_NON_CORE
    reason: Real downstream consequence of APC/C inhibition; secondary to the core inhibitor function.
    supported_by:
    - reference_id: PMID:17234884
      supporting_text: Emi1 (early mitotic inhibitor) inhibits APC/C (anaphase-promoting complex/cyclosome) activity during S and G2 phases
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IMP
  original_reference_id: PMID:17234884
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that EMI1 is essential for cell proliferation by preventing rereplication.
    action: KEEP_AS_NON_CORE
    reason: A downstream physiological consequence of EMI1's cell-cycle role; non-core relative to the molecular inhibitor function.
    supported_by:
    - reference_id: PMID:17234884
      supporting_text: Emi1 plays an essential function in cell proliferation by preventing rereplication
- term:
    id: GO:0045669
    label: positive regulation of osteoblast differentiation
  evidence_type: IMP
  original_reference_id: PMID:29850565
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that FBXO5 promotes osteogenic differentiation of periodontal ligament mesenchymal stem cells.
    action: KEEP_AS_NON_CORE
    reason: A tissue-specific role reported in one study; real but peripheral to the core APC/C-inhibitor cell-cycle function.
    supported_by:
    - reference_id: PMID:29850565
      supporting_text: Two Transcripts of FBXO5 Promote Migration and Osteogenic Differentiation of Human Periodontal Ligament Mesenchymal Stem Cells
- term:
    id: GO:0070169
    label: positive regulation of biomineral tissue development
  evidence_type: IMP
  original_reference_id: PMID:29850565
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence (mineralization assays) that FBXO5 promotes osteogenic/biomineralization processes in stem cells.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific role from one study; non-core.
    supported_by:
    - reference_id: PMID:29850565
      supporting_text: Two Transcripts of FBXO5 Promote Migration and Osteogenic Differentiation of Human Periodontal Ligament Mesenchymal Stem Cells
- term:
    id: GO:1905322
    label: positive regulation of mesenchymal stem cell migration
  evidence_type: IMP
  original_reference_id: PMID:29850565
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence (scratch migration assay) that FBXO5 promotes migration of periodontal ligament stem cells.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific role from one study; non-core.
    supported_by:
    - reference_id: PMID:29850565
      supporting_text: Two Transcripts of FBXO5 Promote Migration and Osteogenic Differentiation of Human Periodontal Ligament Mesenchymal Stem Cells
- term:
    id: GO:0045841
    label: negative regulation of mitotic metaphase/anaphase transition
  evidence_type: IDA
  original_reference_id: PMID:11988738
  qualifier: involved_in
  review:
    summary: Direct evidence that EMI1 inhibits APC(Cdh1) to regulate S-phase entry and restrain the metaphase/anaphase transition. Core process.
    action: ACCEPT
    reason: Core biological process; EMI1 inhibition of APC/C restrains the metaphase/anaphase transition.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1)
- term:
    id: GO:0045841
    label: negative regulation of mitotic metaphase/anaphase transition
  evidence_type: IDA
  original_reference_id: PMID:16921029
  qualifier: involved_in
  review:
    summary: Direct evidence that EMI1 binds the D-box receptor and competes with APC/C substrates, restraining the metaphase/anaphase transition. Core process.
    action: ACCEPT
    reason: Core biological process directly supported by the pseudosubstrate-inhibitor mechanism.
    supported_by:
    - reference_id: PMID:16921029
      supporting_text: competes with APC/C substrates for D-box binding
- term:
    id: GO:1904667
    label: negative regulation of ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:11988738
  qualifier: involved_in
  review:
    summary: Direct evidence that EMI1 inhibits the APC(Cdh1) ubiquitin ligase. Core process.
    action: ACCEPT
    reason: Core biological process; EMI1 directly inhibits APC/C ubiquitin ligase activity.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: regulates S phase entry by inhibiting APC(Cdh1)
- term:
    id: GO:1904667
    label: negative regulation of ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:16921029
  qualifier: involved_in
  review:
    summary: Direct evidence that EMI1's ZBR antagonizes APC/C E3 ligase activity independent of tight binding. Core process.
    action: ACCEPT
    reason: Core biological process; ZBR-mediated inhibition of APC/C ligase activity directly demonstrated.
    supported_by:
    - reference_id: PMID:16921029
      supporting_text: a conserved zinc-binding region (ZBR), which antagonizes APC/C E3 ligase activity independent of tight APC binding
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-163010
  qualifier: located_in
  review:
    summary: Reactome curation placing EMI1 in the nucleoplasm within cell-cycle reactions.
    action: ACCEPT
    reason: Correct localization consistent with experimental nuclear/nucleoplasmic evidence.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174097
  qualifier: located_in
  review:
    summary: Reactome curation (Association of Emi1 with Cdh1) placing EMI1 in the nucleoplasm.
    action: ACCEPT
    reason: Correct localization consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174122
  qualifier: located_in
  review:
    summary: Reactome curation (phosphorylation of Emi1 DSGxxS degron) placing EMI1 in the nucleoplasm.
    action: ACCEPT
    reason: Correct localization consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174174
  qualifier: located_in
  review:
    summary: Reactome curation (Plk1 phosphorylation of Emi1) placing EMI1 in the nucleoplasm.
    action: ACCEPT
    reason: Correct localization consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174235
  qualifier: located_in
  review:
    summary: Reactome curation (Association of Emi1 with Cdc20) placing EMI1 in the nucleoplasm.
    action: ACCEPT
    reason: Correct localization consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8961699
  qualifier: located_in
  review:
    summary: Reactome curation (FBXO5 gene expression stimulated by E2F1) placing EMI1 in the nucleoplasm.
    action: ACCEPT
    reason: Correct localization consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174159
  qualifier: located_in
  review:
    summary: Reactome curation (Ubiquitination of Emi1 by SCF-beta-TrCP) placing EMI1 in the cytosol.
    action: ACCEPT
    reason: Correct localization; EMI1 has a documented cytoplasmic pool.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000269|PubMed:11988738}.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174203
  qualifier: located_in
  review:
    summary: Reactome curation (SCF-mediated degradation of Emi1) placing EMI1 in the cytosol.
    action: ACCEPT
    reason: Correct localization; EMI1 has a documented cytoplasmic pool.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000269|PubMed:11988738}.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174209
  qualifier: located_in
  review:
    summary: Reactome curation (phosphorylated Emi1 binds beta-TrCP) placing EMI1 in the cytosol.
    action: ACCEPT
    reason: Correct localization; EMI1 has a documented cytoplasmic pool.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000269|PubMed:11988738}.'
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IPI
  original_reference_id: PMID:15148369
  qualifier: enables
  review:
    summary: Interaction with mitotic kinases (CDK1/cyclin B P06493; PLK1 P53350) that phosphorylate EMI1 to trigger its SCF(beta-TrCP)-mediated degradation.
    action: KEEP_AS_NON_CORE
    reason: Real, mechanistically relevant kinase interactions (PLK1/CDK1 generate the EMI1 phosphodegron), but ancillary to the core APC/C-inhibitor function and more informative than bare protein binding.
    supported_by:
    - reference_id: PMID:15148369
      supporting_text: Plk1 phosphorylates serine residues in the DSGxxS sequence of Emi1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12791267
  qualifier: enables
  review:
    summary: Interaction with BTRC/beta-TrCP (UniProtKB:Q9Y297), the SCF receptor that targets phosphorylated EMI1 for degradation. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally relevant EMI1-BTRC interaction (mediating EMI1 destruction), but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Interacts with BTRC; mediates proteolysis by the SCF ubiquitin ligase complex leading to activation of APC in late mitosis
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:11988738
  qualifier: located_in
  review:
    summary: Direct immunofluorescence evidence for nuclear localization during interphase. Core localization.
    action: ACCEPT
    reason: Core localization with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: In interphase, localizes in a punctate manner in the nucleus and cytoplasm with some perinuclear concentration
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:11988738
  qualifier: located_in
  review:
    summary: Direct immunofluorescence evidence for cytoplasmic localization during interphase. Core localization.
    action: ACCEPT
    reason: Core localization with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: In interphase, localizes in a punctate manner in the nucleus and cytoplasm with some perinuclear concentration
- term:
    id: GO:0005819
    label: spindle
  evidence_type: IDA
  original_reference_id: PMID:15469984
  qualifier: located_in
  review:
    summary: Direct evidence that EMI1 localizes throughout the cell and concentrates at the spindle in mitotic cells.
    action: ACCEPT
    reason: Localization with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: In mitotic cells, localizes throughout the cell, particularly at the spindle
- term:
    id: GO:0007346
    label: regulation of mitotic cell cycle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity assignment of regulation of the mitotic cell cycle, transferred from the mouse ortholog.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific APC/C-inhibition annotations better capture the role.
    supported_by:
    - reference_id: file:human/FBXO5/FBXO5-uniprot.txt
      supporting_text: Regulator of APC activity during mitotic and meiotic cell cycle
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11988738
  title: E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1).
  findings:
  - statement: hEmi1 accumulates under E2F control at the G1/S transition and inhibits APC(Cdh1), interacting with FZR1/CDH1 and CDC20 to stabilize APC substrates and regulate S-phase entry.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational study establishing EMI1 as an APC(Cdh1) inhibitor; source of nuclear/cytoplasmic localization and FZR1/CDC20 interactions.
- id: PMID:12791267
  title: Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase.
  findings:
  - statement: Phosphorylated EMI1 is recognized and ubiquitinated by SCF(beta-TrCP/BTRC), and its prophase destruction is required to activate the APC/C in mitosis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes that EMI1 is a substrate of SCF(BTRC), the basis for distinguishing EMI1's substrate role from a productive SCF receptor role.
- id: PMID:15148369
  title: Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome.
  findings:
  - statement: EMI1 inhibits the APC/C ubiquitin ligase; PLK1 phosphorylates the DSGxxS degron to trigger SCF(beta-TrCP)-mediated degradation, and EMI1 destruction in early mitosis is necessary for APC/C activation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of the IDA ubiquitin ligase inhibitor activity and metaphase/anaphase-transition annotations; abstract-only in cache but explicit.
- id: PMID:15469984
  title: Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFbetaTrCP-dependent destruction of the APC Inhibitor Emi1.
  findings:
  - statement: EMI1 localizes throughout the cell and concentrates at the spindle in mitosis; PLK1 phosphorylation triggers SCF(beta-TrCP)-dependent destruction.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of spindle localization (IDA) and degradation mechanism.
- id: PMID:16439210
  title: The evi5 oncogene regulates cyclin accumulation by stabilizing the anaphase-promoting complex inhibitor emi1.
  findings:
  - statement: EVI5 stabilizes EMI1 by blocking PLK1 phosphorylation and subsequent BTRC binding/degradation, thereby regulating cyclin accumulation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of the EMI1-EVI5 interaction; supports EMI1's role as an APC/C inhibitor that stabilizes cyclins.
- id: PMID:16921029
  title: Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor.
  findings:
  - statement: EMI1 binds the APC/C and CDH1, occupies the D-box receptor site competing with substrates, and its ZBR antagonizes APC/C E3 ligase activity; mutation of the ZBR converts EMI1 into a D-box-dependent APC/C substrate.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; defines the pseudosubstrate-inhibitor mechanism and source of APC binding (IDA) annotations.
- id: PMID:17234884
  title: The APC/C inhibitor, Emi1, is essential for prevention of rereplication.
  findings:
  - statement: EMI1 inhibits APC/C during S and G2, stabilizing geminin and cyclin A to prevent rereplication and preserve genome integrity; EMI1 depletion causes rereplication and DNA-damage checkpoint activation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; supports DNA-replication coupling, anti-rereplication, and proliferation roles downstream of APC/C inhibition.
- id: PMID:17380122
  title: Selective role for RGS12 as a Ras/Raf/MEK scaffold in nerve growth factor-mediated differentiation.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Primarily an RGS12/NGF study; contributes only a high-throughput EMI1-SKP1 interaction datapoint.
- id: PMID:17485488
  title: Emi1 is needed to couple DNA replication with mitosis but does not regulate activation of the mitotic APC/C.
  findings:
  - statement: EMI1's key role is to inhibit APC/C in interphase to stabilize mitotic cyclins and geminin, promoting mitosis and preventing rereplication; EMI1 destruction is not required to activate APC/C at mitosis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; clarifies that the dominant EMI1 function is interphase APC/C inhibition coupling replication with mitosis.
- id: PMID:17719540
  title: A bacterial effector targets Mad2L2, an APC inhibitor, to modulate host cell cycling.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: About MAD2L2/Cdc20 biology; contributes a high-throughput EMI1-CDC27 (APC subunit) interaction datapoint.
- id: PMID:17875940
  title: Loss of Emi1-dependent anaphase-promoting complex/cyclosome inhibition deregulates E2F target expression and elicits DNA damage-induced senescence.
  findings:
  - statement: Loss of EMI1-dependent APC/C inhibition deregulates E2F targets, causes replication stress and DNA damage, and elicits cellular senescence; EMI1 normally maintains genome integrity and prevents senescence.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; source of DNA-damage-response, anti-senescence, and anti-endoreduplication annotations.
- id: PMID:18662541
  title: The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response checkpoint.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cdc14B-Cdh1-Plk1 checkpoint study; contributes a high-throughput EMI1-CDC27 interaction datapoint.
- id: PMID:23708001
  title: Emi1 preferentially inhibits ubiquitin chain elongation by the anaphase-promoting complex.
  findings:
  - statement: EMI1 inhibits APC/C at both substrate binding and ubiquitin transfer; its ZBR suppresses chain elongation by UBCH10/UBE2C and its C-terminal tail antagonizes UBE2S by blocking binding to the APC cullin subunit.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines EMI1 inhibition of the E2-catalyzed ubiquitin-transfer step; source of negative regulation of ubiquitin-protein transferase activity.
- id: PMID:23708605
  title: Electron microscopy structure of human APC/C(CDH1)-EMI1 reveals multimodal mechanism of E3 ligase shutdown.
  findings:
  - statement: EMI1's 143-residue C-terminal domain (disordered D-box/linker/tail plus structured ZBR) binds distinct APC/C(CDH1) regions to synergistically block the substrate-binding site and inhibit ubiquitin-chain elongation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; structural basis of multimodal APC/C inhibition; source of molecular function inhibitor activity annotations.
- id: PMID:26083744
  title: Atomic structure of the APC/C and its mechanism of protein ubiquitination.
  findings:
  - statement: Cryo-EM structure of APC/C with EMI1 captures the inhibitory binding mode and the mechanism of APC/C ubiquitination.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Structural study; source of an additional APC binding (IDA) annotation.
- id: PMID:27705803
  title: A High-Density Map for Navigating the Human Polycomb Complexome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding (SKP1) annotation.
- id: PMID:29850565
  title: Two Transcripts of FBXO5 Promote Migration and Osteogenic Differentiation of Human Periodontal Ligament Mesenchymal Stem Cells.
  findings:
  - statement: Two FBXO5 transcripts promote migration and osteogenic differentiation of human periodontal ligament mesenchymal stem cells.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of tissue-specific osteogenic/migration annotations; non-core for the gene's central function.
- id: PMID:29875408
  title: EMI1 switches from being a substrate to an inhibitor of APC/C(CDH1) to start the cell cycle.
  findings:
  - statement: At the G1/S transition EMI1 switches from being a substrate of APC/C(CDH1) to its inhibitor, rapidly inactivating APC/C(CDH1) to establish the commitment point for cell-cycle entry.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; establishes the substrate-to-inhibitor switch and the negative regulation of APC/C ubiquitin ligase activity.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Binary interactome reference map; source of a bare protein binding (SKP1) annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cell-specific interactome; source of bare protein binding annotations.
- id: PMID:34445249
  title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  findings:
  - statement: Review of the 69 SCF E3 ubiquitin ligase complexes; F-box proteins determine substrate specificity, and SCF complexes regulate the cell cycle and genome stability.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Family-level review used as NAS basis for the SCF-complex and SCF-catabolism annotations; does not establish a productive SCF-receptor role for FBXO5 specifically.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map interactome; source of a bare protein binding (SKP1) annotation.
- id: file:human/FBXO5/FBXO5-deep-research-falcon.md
  title: Falcon deep research report for human FBXO5
  findings:
  - statement: EMI1/FBXO5 is a high-affinity pseudosubstrate inhibitor of APC/C (especially APC/C-CDH1), required during interphase to permit cyclin accumulation and mitotic entry rather than functioning as an enzyme.
    supporting_text: '**Emi1/FBXO5 acts as a principal interphase inhibitor of APC/C**, particularly **APC/C activated by Cdh1 (APC/C^CDH1)**, thereby preventing premature degradation of cyclins and enabling progression toward mitosis'
  - statement: Inhibition is multimodal, using a C-terminal D-box that competes at the APC/C D-box receptor and a zinc-binding region (ZBR) that provides additional inhibition and protects EMI1 from being processed as an APC/C substrate.
    supporting_text: 'Mutating the ZBR converts Emi1 into an APC/C substrate** that becomes efficiently ubiquitinated in a D-box-dependent manner, while wild-type Emi1 is a poor substrate, supporting the pseudosubstrate-inhibitor model in which the ZBR "protects" Emi1 from APC/C-mediated ubiquitination'
  - statement: A 2024 study frames EMI1/FBXO5 as a possible F-box substrate receptor of an SCF^EMI1 complex with RAD51 cited as a substrate, but this is a recent and far less established role than its core APC/C-inhibitory function.
    supporting_text: a 2024 study explicitly frames **EMI1 (FBXO5)** as an **F-box protein** that can serve as the variable substrate receptor in an **SCF^EMI1** ubiquitin ligase complex (core SCF components SKP1–CUL1–RBX1 plus the F-box protein) and cites **RAD51** as an SCF^EMI1 substrate targeted for proteolytic degradation
  - statement: EMI1 abundance is dosage-sensitive for genome stability; reduced EMI1 in colonic epithelium increases chromosome instability, DNA damage, and transformation, consistent with its role coupling replication to mitosis.
    supporting_text: '**reduced EMI1 expression drives chromosome instability (CIN)** and is associated with DNA damage and transformation phenotypes in colonic epithelial contexts'
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: Falcon deep-research synthesis; anchors EMI1 as an APC/C pseudosubstrate inhibitor (Miller 2006) and adds recent CIN/cancer and SCF^EMI1-RAD51 context. Treated as leads, cross-checked against UniProt and the cached APC/C-inhibition PMIDs; the SCF^EMI1-RAD51 receptor role is not yet independently verified here.
- id: Reactome:R-HSA-163010
  title: Down Regulation of Emi1 through Phosphorylation of Emi1
  findings: []
- id: Reactome:R-HSA-174097
  title: Association of Emi1 with Cdh1
  findings: []
- id: Reactome:R-HSA-174122
  title: Phosphorylation of the Emi1 DSGxxS degron by Cyclin B:Cdc2
  findings: []
- id: Reactome:R-HSA-174159
  title: Ubiquitination of Emi1 by SCF-beta-TrCP
  findings: []
- id: Reactome:R-HSA-174174
  title: Phosphorylation of the Emi1 DSGxxS degron by Plk1
  findings: []
- id: Reactome:R-HSA-174203
  title: SCF-mediated degradation of Emi1
  findings: []
- id: Reactome:R-HSA-174209
  title: Phosphorylated Emi1 binds the beta-TrCP in the SCF complex
  findings: []
- id: Reactome:R-HSA-174235
  title: Association of Emi1 with Cdc20
  findings: []
- id: Reactome:R-HSA-8961699
  title: FBXO5 gene expression is stimulated by E2F1
  findings: []
core_functions:
- description: Direct inhibitor of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase; binds the APC/C and its coactivator FZR1/CDH1 (and CDC20) as a pseudosubstrate, occupying the D-box receptor site to block substrate access.
  molecular_function:
    id: GO:1990948
    label: ubiquitin ligase inhibitor activity
  supported_by:
  - reference_id: PMID:16921029
    supporting_text: binds to the D-box receptor site on the APC/C(Cdh1), and competes with APC/C substrates for D-box binding
  directly_involved_in:
  - id: GO:0045841
    label: negative regulation of mitotic metaphase/anaphase transition
- description: Suppresses APC/C-catalyzed ubiquitin-chain elongation via its zinc-binding region and C-terminal tail, antagonizing the APC/C-associated E2 enzymes UBE2C/UBCH10 and UBE2S to stabilize APC/C substrates.
  molecular_function:
    id: GO:1990948
    label: ubiquitin ligase inhibitor activity
  supported_by:
  - reference_id: PMID:23708001
    supporting_text: preferentially suppresses the ubiquitin chain elongation by UBCH10
  - reference_id: PMID:23708605
    supporting_text: synergistically both block the substrate-binding site and inhibit ubiquitin-chain elongation
  directly_involved_in:
  - id: GO:0051444
    label: negative regulation of ubiquitin-protein transferase activity
- description: Couples DNA replication with mitosis and preserves genome integrity by inhibiting APC/C during S and G2 to stabilize cyclin A and geminin, thereby preventing rereplication and DNA-damage-induced senescence.
  molecular_function:
    id: GO:1990948
    label: ubiquitin ligase inhibitor activity
  supported_by:
  - reference_id: PMID:17485488
    supporting_text: a key role for Emi1 in inhibiting the APC/C in interphase to stabilize the mitotic cyclins and geminin to promote mitosis and prevent rereplication
  directly_involved_in:
  - id: GO:0006275
    label: regulation of DNA replication
proposed_new_terms: []
suggested_questions:
- question: Does human FBXO5/EMI1 ever function as a productive SCF substrate receptor (targeting a specific substrate for SCF-dependent degradation), or is its F-box used solely for incidental SKP1 association while its dominant role remains APC/C inhibition?
- question: How is the substrate-to-inhibitor switch at the G1/S transition controlled at the molecular level, and what distinguishes the EMI1 conformations that are APC/C substrates versus inhibitors?
suggested_experiments:
- description: Reconstitute APC/C(CDH1) ubiquitination assays in vitro with purified EMI1 and the E2 enzymes UBE2C and UBE2S to quantify the relative contributions of D-box-receptor blocking versus chain-elongation inhibition to substrate stabilization.
- description: Perform proximity-labeling (BioID/TurboID) and quantitative ubiquitinome profiling in EMI1-depleted versus EMI1-add-back cells across the cell cycle to test whether EMI1 has any genuine SCF substrate, and to map its APC/C-dependent stabilized substrate repertoire.