RUNX3

id: Q13761
gene_symbol: RUNX3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'RUNX3 encodes Runt-related transcription factor 3, a nuclear Runt-domain DNA-binding transcription
  factor that heterodimerizes with CBFβ/core-binding factor complexes to regulate RNA polymerase II target-gene
  programs. Its core function is sequence-specific regulatory DNA and chromatin binding for context-dependent
  transcriptional activation or repression, with important downstream roles in development, TGF-beta/Wnt/Hippo
  signaling, CD8 T-cell biology, and cancer-associated mislocalization or degradation.'
existing_annotations:
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: RNA polymerase II cis-regulatory region sequence-specific DNA binding is supported by
      RUNX3 Runt-domain sequence-specific DNA binding.
    action: ACCEPT
    reason: Sequence-specific regulatory-region DNA binding is central to RUNX3 transcription factor
      function.
    supported_by: &id003
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX3 is **not an enzyme** and does not catalyze a chemical reaction; its
        primary function is as a **sequence-specific DNA-binding transcription factor** that
        regulates gene expression programs by binding target regulatory elements via the **Runt
        domain**, typically stabilized by heterodimerization with **CBFβ**.
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: The target protein is **human RUNX3** (gene symbol **RUNX3**, UniProt
        **Q13761**), described in UniProt as *Runt-related transcription factor 3* with a conserved
        **Runt (AML1_Runt) DNA-binding domain** and C-terminal RUNX interaction region. In the
        literature retrieved here, the entity called RUNX3 is consistently described as a
        **Runt-domain transcription factor that heterodimerizes with CBFβ (core-binding factor β)**
        and regulates gene expression through sequence-specific DNA binding—matching the defining
        biochemical/structural properties expected for UniProt Q13761.
- term:
    id: GO:0001503
    label: ossification
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ossification is consistent with RUNX3 developmental or disease-associated
      transcriptional programs but is not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: These developmental, cell-cycle, or tissue-level outcomes are downstream consequences of
      RUNX3 transcription factor activity and should not be treated as the core function itself.
    supported_by: &id001
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: '**RUNX3 is a master developmental transcription factor** whose dysregulation can
        impact multiple hallmark pathways (TGF-β, Wnt/β-catenin, Hippo-YAP, Notch/MAPK, etc.).'
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: A 2024 review of RUNX transcription factors synthesizes RUNX3 as a regulator
        embedded in major cancer-relevant pathways, including **TGF-β/SMAD**, **Wnt/β-catenin**, and
        **Hippo–YAP** crosstalk, and emphasizes frequent RUNX3 inactivation through **promoter
        hypermethylation, histone modifications, and mislocalization**.
- term:
    id: GO:0030097
    label: hemopoiesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: hemopoiesis is consistent with RUNX3 developmental or disease-associated
      transcriptional programs but is not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: These developmental, cell-cycle, or tissue-level outcomes are downstream consequences of
      RUNX3 transcription factor activity and should not be treated as the core function itself.
    supported_by: *id001
- term:
    id: GO:0030182
    label: neuron differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: neuron differentiation is consistent with RUNX3 developmental or disease-associated
      transcriptional programs but is not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: These developmental, cell-cycle, or tissue-level outcomes are downstream consequences of
      RUNX3 transcription factor activity and should not be treated as the core function itself.
    supported_by: *id001
- term:
    id: GO:0045595
    label: regulation of cell differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: regulation of cell differentiation is consistent with RUNX3 developmental or
      disease-associated transcriptional programs but is not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: These developmental, cell-cycle, or tissue-level outcomes are downstream consequences of
      RUNX3 transcription factor activity and should not be treated as the core function itself.
    supported_by: *id001
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Regulation of transcription by RNA polymerase II is a core RUNX3 biological process.
    action: ACCEPT
    reason: RUNX3 regulates gene-expression programs as a nuclear sequence-specific transcription
      factor.
    supported_by: &id002
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX3 is **not an enzyme** and does not catalyze a chemical reaction; its
        primary function is as a **sequence-specific DNA-binding transcription factor** that
        regulates gene expression programs by binding target regulatory elements via the **Runt
        domain**, typically stabilized by heterodimerization with **CBFβ**.
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX family proteins (RUNX1/2/3) are sequence-specific transcription factors
        defined by a conserved **Runt DNA-binding domain**; they functionally **heterodimerize with
        CBFβ**, a non–DNA-binding partner that stabilizes RUNX binding to target DNA elements and
        modulates transcriptional activity.
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX3 can bind DNA and **mononucleosomes**, and RUNX3 loss alters chromatin
        accessibility and transcriptional programs (ATAC-seq/RNA-seq integration).
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: DNA-binding transcription factor activity, RNA polymerase II-specific is the
      best-supported core molecular function of RUNX3.
    action: ACCEPT
    reason: RUNX3 is a sequence-specific Runt-domain transcription factor that regulates RNA
      polymerase II transcription through DNA/chromatin binding and CBFβ-associated complexes.
    supported_by: *id002
- term:
    id: GO:0002062
    label: chondrocyte differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: chondrocyte differentiation is consistent with RUNX3 developmental or
      disease-associated transcriptional programs but is not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: These developmental, cell-cycle, or tissue-level outcomes are downstream consequences of
      RUNX3 transcription factor activity and should not be treated as the core function itself.
    supported_by: *id001
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Generic DNA binding is directionally correct but less precise than RUNX3
      sequence-specific regulatory DNA binding.
    action: MODIFY
    reason: RUNX3 is not merely a generic DNA-binding protein; its supported molecular role is
      sequence-specific Runt-domain binding at regulatory regions.
    proposed_replacement_terms:
    - id: GO:1990837
      label: sequence-specific double-stranded DNA binding
    - id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
    supported_by: *id003
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Generic DNA-binding transcription factor activity is correct but less precise than the
      RNA polymerase II-specific term already present.
    action: MODIFY
    reason: RUNX3 functions as a sequence-specific RNA polymerase II transcription factor, so the
      more specific term is preferred.
    proposed_replacement_terms: &id010
    - id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
    supported_by: *id002
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: ATP binding is not supported as a RUNX3 molecular function.
    action: REMOVE
    reason: RUNX3 is a non-enzymatic DNA-binding transcription factor; ATP-dependent
      chromatin-remodeling context should not be transferred to RUNX3 as ATP binding.
    supported_by: &id011
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX3 is **not an enzyme** and does not catalyze a chemical reaction; its
        primary function is as a **sequence-specific DNA-binding transcription factor** that
        regulates gene expression programs by binding target regulatory elements via the **Runt
        domain**, typically stabilized by heterodimerization with **CBFβ**.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: nucleus localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: &id005
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX3’s canonical site of action is the **nucleus**, where it binds chromatin
        and regulates transcription. Multiple studies emphasize that **cytoplasmic mislocalization**
        can functionally inactivate RUNX3 by preventing nuclear activity; oxidative stress provides
        a mechanistic route for nuclear export via Src phosphorylation and JAB1/CRM1 export
        machinery.
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: Because RUNX3 is a transcription factor, **nuclear localization** is
        essential for its canonical function. A recurring cancer mechanism is **functional
        inactivation by cytoplasmic mislocalization** (i.e., preventing nuclear transcriptional
        regulation).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: cytoplasm localization is supported, but mainly as a mislocalization/export or
      degradation context rather than the canonical site of RUNX3 function.
    action: KEEP_AS_NON_CORE
    reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic
      localization is best treated as a regulated non-core or inactivation-associated state.
    supported_by: &id006
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX3’s canonical site of action is the **nucleus**, where it binds chromatin
        and regulates transcription. Multiple studies emphasize that **cytoplasmic mislocalization**
        can functionally inactivate RUNX3 by preventing nuclear activity; oxidative stress provides
        a mechanistic route for nuclear export via Src phosphorylation and JAB1/CRM1 export
        machinery.
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: This provides a mechanistic explanation for the often-cited phenomenon of
        RUNX3 cytoplasmic mislocalization as a route to functional loss.
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Generic regulation of DNA-templated transcription is supported but should be captured
      with the RNA polymerase II-specific process.
    action: MODIFY
    reason: RUNX3 target-gene regulation is best represented by regulation of transcription by RNA
      polymerase II.
    proposed_replacement_terms: &id012
    - id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    supported_by: *id002
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Positive regulation of DNA-templated transcription is supported in context-specific
      RUNX3 target-gene programs.
    action: ACCEPT
    reason: RUNX3 can activate transcriptional targets, although the direction of regulation is
      context dependent.
    supported_by: &id008
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX3 is **not an enzyme** and does not catalyze a chemical reaction; its
        primary function is as a **sequence-specific DNA-binding transcription factor** that
        regulates gene expression programs by binding target regulatory elements via the **Runt
        domain**, typically stabilized by heterodimerization with **CBFβ**.
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: A 2024 study (Cancer Research Communications) presented evidence that RUNX3
        can be **pro-metastatic** in a gastric cancer model (HGC-27), where CRISPR KO reduced
        migration/invasion/anchorage-independent growth and suppressed liver metastasis in vivo.
        Multi-omic mapping (ChIP-seq, HiChIP) supported direct transcriptional control of
        metastasis-associated targets including **WNT5A**, **CD44**, and **VIM**, with WNT5A
        functioning as a major effector.
- term:
    id: GO:1990837
    label: sequence-specific double-stranded DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: sequence-specific double-stranded DNA binding is supported by RUNX3 Runt-domain
      sequence-specific DNA binding.
    action: ACCEPT
    reason: Sequence-specific regulatory-region DNA binding is central to RUNX3 transcription factor
      function.
    supported_by: *id003
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18772112
  review:
    summary: Protein binding is supported in many RUNX3 contexts but is too generic to describe the
      main function.
    action: MARK_AS_OVER_ANNOTATED
    reason: RUNX3 has specific partner interactions such as CBFβ, MYC, TLE/corepressors, SMADs, and
      chromatin factors, but the unqualified protein binding term is not informative for curation.
    supported_by: &id004
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX family proteins (RUNX1/2/3) are sequence-specific transcription factors
        defined by a conserved **Runt DNA-binding domain**; they functionally **heterodimerize with
        CBFβ**, a non–DNA-binding partner that stabilizes RUNX binding to target DNA elements and
        modulates transcriptional activity.
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: 'A key 2023 advance demonstrated a **direct protein–protein mechanism** linking
        RUNX3 to oncogene control: RUNX3 binds **MYC** directly via the **Runt domain**, disrupts MYC’s
        transcriptionally active complexes (MYC–MAX and MYC–MIZ1), increases **GSK3β-mediated phosphorylation
        of MYC at T58**, and promotes **FBXW7-dependent K48-linked ubiquitination** and proteasomal degradation
        of MYC.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24229708
  review:
    summary: Protein binding is supported in many RUNX3 contexts but is too generic to describe the
      main function.
    action: MARK_AS_OVER_ANNOTATED
    reason: RUNX3 has specific partner interactions such as CBFβ, MYC, TLE/corepressors, SMADs, and
      chromatin factors, but the unqualified protein binding term is not informative for curation.
    supported_by: *id004
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: Protein binding is supported in many RUNX3 contexts but is too generic to describe the
      main function.
    action: MARK_AS_OVER_ANNOTATED
    reason: RUNX3 has specific partner interactions such as CBFβ, MYC, TLE/corepressors, SMADs, and
      chromatin factors, but the unqualified protein binding term is not informative for curation.
    supported_by: *id004
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:38424632
  review:
    summary: Protein binding is supported in many RUNX3 contexts but is too generic to describe the
      main function.
    action: MARK_AS_OVER_ANNOTATED
    reason: RUNX3 has specific partner interactions such as CBFβ, MYC, TLE/corepressors, SMADs, and
      chromatin factors, but the unqualified protein binding term is not informative for curation.
    supported_by: *id004
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9751710
  review:
    summary: Protein binding is supported in many RUNX3 contexts but is too generic to describe the
      main function.
    action: MARK_AS_OVER_ANNOTATED
    reason: RUNX3 has specific partner interactions such as CBFβ, MYC, TLE/corepressors, SMADs, and
      chromatin factors, but the unqualified protein binding term is not informative for curation.
    supported_by: *id004
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: cytosol localization is supported, but mainly as a mislocalization/export or
      degradation context rather than the canonical site of RUNX3 function.
    action: KEEP_AS_NON_CORE
    reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic
      localization is best treated as a regulated non-core or inactivation-associated state.
    supported_by: *id006
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:20591170
  review:
    summary: Regulation of transcription by RNA polymerase II is a core RUNX3 biological process.
    action: ACCEPT
    reason: RUNX3 regulates gene-expression programs as a nuclear sequence-specific transcription
      factor.
    supported_by: *id002
- term:
    id: GO:0001222
    label: transcription corepressor binding
  evidence_type: IPI
  original_reference_id: PMID:9751710
  review:
    summary: Transcription corepressor binding is supported by RUNX/Runt-domain recruitment of
      TLE/Groucho corepressors.
    action: ACCEPT
    reason: This is a more informative binding annotation than generic protein binding for
      RUNX3-associated transcriptional repression.
    supported_by:
    - reference_id: PMID:9751710
      supporting_text: The mammalian AML/CBFalpha runt domain (RD) transcription factors regulate
        hematopoiesis and osteoblast differentiation. Like their Drosophila counterparts, most
        mammalian RD proteins terminate in a common pentapeptide, VWRPY, which serves to recruit the
        corepressor Groucho (Gro).
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX3 is **not an enzyme** and does not catalyze a chemical reaction; its
        primary function is as a **sequence-specific DNA-binding transcription factor** that
        regulates gene expression programs by binding target regulatory elements via the **Runt
        domain**, typically stabilized by heterodimerization with **CBFβ**.
- term:
    id: GO:1990837
    label: sequence-specific double-stranded DNA binding
  evidence_type: IDA
  original_reference_id: PMID:28473536
  review:
    summary: sequence-specific double-stranded DNA binding is supported by RUNX3 Runt-domain
      sequence-specific DNA binding.
    action: ACCEPT
    reason: Sequence-specific regulatory-region DNA binding is central to RUNX3 transcription factor
      function.
    supported_by: *id003
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: ISA
  original_reference_id: GO_REF:0000113
  review:
    summary: Chromatin localization is supported by RUNX3 DNA, mononucleosome, and
      chromatin-remodeler-associated activity.
    action: ACCEPT
    reason: RUNX3 binds chromatin-associated regulatory DNA as part of its transcription factor
      function.
    supported_by: &id009
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX3 can bind DNA and **mononucleosomes**, and RUNX3 loss alters chromatin
        accessibility and transcriptional programs (ATAC-seq/RNA-seq integration).
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX3 associates with **CBFβ** and chromatin remodeler machinery including
        SWI/SNF components; the **Runt domain** is implicated as critical for interactions with
        chromatin factors in this metastatic gastric cancer model.
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: ISA
  original_reference_id: GO_REF:0000113
  review:
    summary: DNA-binding transcription factor activity, RNA polymerase II-specific is the
      best-supported core molecular function of RUNX3.
    action: ACCEPT
    reason: RUNX3 is a sequence-specific Runt-domain transcription factor that regulates RNA
      polymerase II transcription through DNA/chromatin binding and CBFβ-associated complexes.
    supported_by: *id002
- term:
    id: GO:0016513
    label: core-binding factor complex
  evidence_type: TAS
  original_reference_id: PMID:18258917
  review:
    summary: Core-binding factor complex is the canonical RUNX3 transcription factor complex
      context.
    action: ACCEPT
    reason: RUNX3 heterodimerizes with CBFβ, placing it in the core-binding factor complex for
      DNA-binding transcriptional regulation.
    supported_by:
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX family proteins (RUNX1/2/3) are sequence-specific transcription factors
        defined by a conserved **Runt DNA-binding domain**; they functionally **heterodimerize with
        CBFβ**, a non–DNA-binding partner that stabilizes RUNX binding to target DNA elements and
        modulates transcriptional activity.
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX3 associates with **CBFβ** and chromatin remodeler machinery including
        SWI/SNF components; the **Runt domain** is implicated as critical for interactions with
        chromatin factors in this metastatic gastric cancer model.
- term:
    id: GO:0043371
    label: negative regulation of CD4-positive, alpha-beta T cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: negative regulation of CD4-positive, alpha-beta T cell differentiation is a supported
      RUNX3 biological role, especially in immune differentiation, but it is downstream of the
      transcription factor core function.
    action: KEEP_AS_NON_CORE
    reason: T-cell differentiation phenotypes reflect RUNX3-regulated transcriptional programs
      rather than a separate core molecular activity.
    supported_by: &id007
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX3 is a key regulator of **CD8+ T-cell differentiation, infiltration,
        effector/memory fate, and residency**.
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: '**RUNX3 is a master developmental transcription factor** whose dysregulation can
        impact multiple hallmark pathways (TGF-β, Wnt/β-catenin, Hippo-YAP, Notch/MAPK, etc.).'
- term:
    id: GO:0043378
    label: positive regulation of CD8-positive, alpha-beta T cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: positive regulation of CD8-positive, alpha-beta T cell differentiation is a supported
      RUNX3 biological role, especially in immune differentiation, but it is downstream of the
      transcription factor core function.
    action: KEEP_AS_NON_CORE
    reason: T-cell differentiation phenotypes reflect RUNX3-regulated transcriptional programs
      rather than a separate core molecular activity.
    supported_by: *id007
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952419
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952399
  review:
    summary: cytosol localization is supported, but mainly as a mislocalization/export or
      degradation context rather than the canonical site of RUNX3 function.
    action: KEEP_AS_NON_CORE
    reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic
      localization is best treated as a regulated non-core or inactivation-associated state.
    supported_by: *id006
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952408
  review:
    summary: cytosol localization is supported, but mainly as a mislocalization/export or
      degradation context rather than the canonical site of RUNX3 function.
    action: KEEP_AS_NON_CORE
    reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic
      localization is best treated as a regulated non-core or inactivation-associated state.
    supported_by: *id006
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952382
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952399
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8951966
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8951977
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952058
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952062
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952069
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8937792
  review:
    summary: cytosol localization is supported, but mainly as a mislocalization/export or
      degradation context rather than the canonical site of RUNX3 function.
    action: KEEP_AS_NON_CORE
    reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic
      localization is best treated as a regulated non-core or inactivation-associated state.
    supported_by: *id006
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8937807
  review:
    summary: cytosol localization is supported, but mainly as a mislocalization/export or
      degradation context rather than the canonical site of RUNX3 function.
    action: KEEP_AS_NON_CORE
    reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic
      localization is best treated as a regulated non-core or inactivation-associated state.
    supported_by: *id006
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8937814
  review:
    summary: cytosol localization is supported, but mainly as a mislocalization/export or
      degradation context rather than the canonical site of RUNX3 function.
    action: KEEP_AS_NON_CORE
    reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic
      localization is best treated as a regulated non-core or inactivation-associated state.
    supported_by: *id006
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8865454
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8878117
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8878143
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8878178
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8878193
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8878220
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8878237
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8937814
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8949335
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8951428
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8951676
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8951910
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8951951
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952128
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952226
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952371
  review:
    summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20599712
  review:
    summary: Protein binding is supported in many RUNX3 contexts but is too generic to describe the
      main function.
    action: MARK_AS_OVER_ANNOTATED
    reason: RUNX3 has specific partner interactions such as CBFβ, MYC, TLE/corepressors, SMADs, and
      chromatin factors, but the unqualified protein binding term is not informative for curation.
    supported_by: *id004
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:20599712
  review:
    summary: nucleus localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:20599712
  review:
    summary: cytoplasm localization is supported, but mainly as a mislocalization/export or
      degradation context rather than the canonical site of RUNX3 function.
    action: KEEP_AS_NON_CORE
    reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic
      localization is best treated as a regulated non-core or inactivation-associated state.
    supported_by: *id006
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:20599712
  review:
    summary: Positive regulation of DNA-templated transcription is supported in context-specific
      RUNX3 target-gene programs.
    action: ACCEPT
    reason: RUNX3 can activate transcriptional targets, although the direction of regulation is
      context dependent.
    supported_by: *id008
- term:
    id: GO:0071559
    label: response to transforming growth factor beta
  evidence_type: IDA
  original_reference_id: PMID:20599712
  review:
    summary: Response to transforming growth factor beta is supported as a pathway context for RUNX3
      transcriptional regulation.
    action: KEEP_AS_NON_CORE
    reason: TGF-beta/SMAD effects are important context-specific biology, but the core function
      remains nuclear sequence-specific transcriptional regulation.
    supported_by:
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: A 2024 review of RUNX transcription factors synthesizes RUNX3 as a regulator
        embedded in major cancer-relevant pathways, including **TGF-β/SMAD**, **Wnt/β-catenin**, and
        **Hippo–YAP** crosstalk, and emphasizes frequent RUNX3 inactivation through **promoter
        hypermethylation, histone modifications, and mislocalization**.
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: '**RUNX3 is a master developmental transcription factor** whose dysregulation can
        impact multiple hallmark pathways (TGF-β, Wnt/β-catenin, Hippo-YAP, Notch/MAPK, etc.).'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17377532
  review:
    summary: Protein binding is supported in many RUNX3 contexts but is too generic to describe the
      main function.
    action: MARK_AS_OVER_ANNOTATED
    reason: RUNX3 has specific partner interactions such as CBFβ, MYC, TLE/corepressors, SMADs, and
      chromatin factors, but the unqualified protein binding term is not informative for curation.
    supported_by: *id004
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Chromatin localization is supported by RUNX3 DNA, mononucleosome, and
      chromatin-remodeler-associated activity.
    action: ACCEPT
    reason: RUNX3 binds chromatin-associated regulatory DNA as part of its transcription factor
      function.
    supported_by: *id009
- term:
    id: GO:0000977
    label: RNA polymerase II transcription regulatory region sequence-specific DNA binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: RNA polymerase II transcription regulatory region sequence-specific DNA binding is
      supported by RUNX3 Runt-domain sequence-specific DNA binding.
    action: ACCEPT
    reason: Sequence-specific regulatory-region DNA binding is central to RUNX3 transcription factor
      function.
    supported_by: *id003
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Negative regulation of transcription by RNA polymerase II is supported for RUNX3 in
      repressive target-gene and Wnt/TCF contexts.
    action: ACCEPT
    reason: RUNX3 can repress transcriptional outputs through protein complexes and target-gene
      regulation.
    supported_by:
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX3 is **not an enzyme** and does not catalyze a chemical reaction; its
        primary function is as a **sequence-specific DNA-binding transcription factor** that
        regulates gene expression programs by binding target regulatory elements via the **Runt
        domain**, typically stabilized by heterodimerization with **CBFβ**.
    - reference_id: PMID:18772112
      supporting_text: Here we found that RUNX3, a gastric tumor suppressor, forms a ternary complex
        with beta-catenin/TCF4 and attenuates Wnt signaling activity.
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: DNA-binding transcription factor activity, RNA polymerase II-specific is the
      best-supported core molecular function of RUNX3.
    action: ACCEPT
    reason: RUNX3 is a sequence-specific Runt-domain transcription factor that regulates RNA
      polymerase II transcription through DNA/chromatin binding and CBFβ-associated complexes.
    supported_by: *id002
- term:
    id: GO:0048935
    label: peripheral nervous system neuron development
  evidence_type: TAS
  original_reference_id: PMID:20096094
  review:
    summary: peripheral nervous system neuron development is consistent with RUNX3 developmental or
      disease-associated transcriptional programs but is not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: These developmental, cell-cycle, or tissue-level outcomes are downstream consequences of
      RUNX3 transcription factor activity and should not be treated as the core function itself.
    supported_by: *id001
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:20100835
  review:
    summary: nucleus localization is central to RUNX3 canonical transcription factor activity.
    action: ACCEPT
    reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription.
    supported_by: *id005
- term:
    id: GO:0006468
    label: protein phosphorylation
  evidence_type: IDA
  original_reference_id: PMID:20100835
  review:
    summary: Protein phosphorylation is not supported as a process carried out by RUNX3.
    action: REMOVE
    reason: The cited biology describes Src-mediated phosphorylation of RUNX3, making RUNX3 the
      substrate rather than the kinase or causal gene product for protein phosphorylation.
    supported_by:
    - reference_id: PMID:20100835
      supporting_text: In this study, we found that the overexpression of Src results in the
        tyrosine phosphorylation and cytoplasmic localization of RUNX3.
    - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
      supporting_text: RUNX3’s canonical site of action is the **nucleus**, where it binds chromatin
        and regulates transcription. Multiple studies emphasize that **cytoplasmic mislocalization**
        can functionally inactivate RUNX3 by preventing nuclear activity; oxidative stress provides
        a mechanistic route for nuclear export via Src phosphorylation and JAB1/CRM1 export
        machinery.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20100835
  review:
    summary: Protein binding is supported in many RUNX3 contexts but is too generic to describe the
      main function.
    action: MARK_AS_OVER_ANNOTATED
    reason: RUNX3 has specific partner interactions such as CBFβ, MYC, TLE/corepressors, SMADs, and
      chromatin factors, but the unqualified protein binding term is not informative for curation.
    supported_by: *id004
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:20100835
  review:
    summary: cytoplasm localization is supported, but mainly as a mislocalization/export or
      degradation context rather than the canonical site of RUNX3 function.
    action: KEEP_AS_NON_CORE
    reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic
      localization is best treated as a regulated non-core or inactivation-associated state.
    supported_by: *id006
- term:
    id: GO:0045786
    label: negative regulation of cell cycle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: negative regulation of cell cycle is consistent with RUNX3 developmental or
      disease-associated transcriptional programs but is not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: These developmental, cell-cycle, or tissue-level outcomes are downstream consequences of
      RUNX3 transcription factor activity and should not be treated as the core function itself.
    supported_by: *id001
- term:
    id: GO:0050680
    label: negative regulation of epithelial cell proliferation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: negative regulation of epithelial cell proliferation is consistent with RUNX3
      developmental or disease-associated transcriptional programs but is not the core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: These developmental, cell-cycle, or tissue-level outcomes are downstream consequences of
      RUNX3 transcription factor activity and should not be treated as the core function itself.
    supported_by: *id001
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: TAS
  original_reference_id: PMID:7607690
  review:
    summary: Generic DNA-binding transcription factor activity is correct but less precise than the
      RNA polymerase II-specific term already present.
    action: MODIFY
    reason: RUNX3 functions as a sequence-specific RNA polymerase II transcription factor, so the
      more specific term is preferred.
    proposed_replacement_terms: *id010
    supported_by: *id002
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: NAS
  original_reference_id: PMID:7835892
  review:
    summary: ATP binding is not supported as a RUNX3 molecular function.
    action: REMOVE
    reason: RUNX3 is a non-enzymatic DNA-binding transcription factor; ATP-dependent
      chromatin-remodeling context should not be transferred to RUNX3 as ATP binding.
    supported_by: *id011
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: NAS
  original_reference_id: PMID:7622058
  review:
    summary: Generic regulation of DNA-templated transcription is supported but should be captured
      with the RNA polymerase II-specific process.
    action: MODIFY
    reason: RUNX3 target-gene regulation is best represented by regulation of transcription by RNA
      polymerase II.
    proposed_replacement_terms: *id012
    supported_by: *id002
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: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:0000113
  title: Gene Ontology annotation of human sequence-specific DNA binding transcription factors
    (DbTFs) based on the TFClass database
  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:17377532
  title: Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1.
  findings: []
- id: PMID:18258917
  title: Repression of the transcription factor Th-POK by Runx complexes in cytotoxic T cell
    development.
  findings: []
- id: PMID:18772112
  title: RUNX3 attenuates beta-catenin/T cell factors in intestinal tumorigenesis.
  findings: []
- id: PMID:20096094
  title: Brn3a regulates neuronal subtype specification in the trigeminal ganglion by promoting Runx
    expression during sensory differentiation.
  findings: []
- id: PMID:20100835
  title: Src kinase phosphorylates RUNX3 at tyrosine residues and localizes the protein in the
    cytoplasm.
  findings: []
- id: PMID:20591170
  title: The Runx transcriptional co-activator, CBFbeta, is essential for invasion of breast cancer
    cells.
  findings: []
- id: PMID:20599712
  title: Tumor suppressor, AT motif binding factor 1 (ATBF1), translocates to the nucleus with runt
    domain transcription factor 3 (RUNX3) in response to TGF-beta signal transduction.
  findings: []
- id: PMID:24229708
  title: Runx3 inactivation is a crucial early event in the development of lung adenocarcinoma.
  findings: []
- id: PMID:28473536
  title: Impact of cytosine methylation on DNA binding specificities of human transcription factors.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:38424632
  title: Ubiquitylation of RUNX3 by RNA-binding ubiquitin ligase MEX3C promotes tumorigenesis in
    lung adenocarcinoma.
  findings: []
- id: PMID:7607690
  title: Identification of a new murine runt domain-containing gene, Cbfa3, and localization of the
    human homolog, CBFA3, to chromosome 1p35-pter.
  findings: []
- id: PMID:7622058
  title: Cloning, mapping and expression of PEBP2 alpha C, a third gene encoding the mammalian Runt
    domain.
  findings: []
- id: PMID:7835892
  title: 'AML1, AML2, and AML3, the human members of the runt domain gene-family: cDNA structure, expression,
    and chromosomal localization.'
  findings: []
- id: PMID:9751710
  title: Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors.
  findings: []
- id: Reactome:R-HSA-8865454
  title: CBFB binds RUNX3
  findings: []
- id: Reactome:R-HSA-8878117
  title: RUNX3 binds ZFHX3
  findings: []
- id: Reactome:R-HSA-8878143
  title: RUNX3 binds SMAD3 and SMAD4
  findings: []
- id: Reactome:R-HSA-8878178
  title: The complex of RUNX3, SMAD3 and SMAD4 binds the CDKN1A gene promoter
  findings: []
- id: Reactome:R-HSA-8878193
  title: RUNX3 binds the JAG1 gene promoter
  findings: []
- id: Reactome:R-HSA-8878220
  title: RUNX3 binds the NOTCH1 coactivator complex
  findings: []
- id: Reactome:R-HSA-8878237
  title: RUNX3:NOTCH1 coactivator complex binds the HES1 gene promoter
  findings: []
- id: Reactome:R-HSA-8937792
  title: RUNX3 binds SRC
  findings: []
- id: Reactome:R-HSA-8937807
  title: SRC phosphorylates RUNX3
  findings: []
- id: Reactome:R-HSA-8937814
  title: RUNX3 translocates to the nucleus
  findings: []
- id: Reactome:R-HSA-8949335
  title: RUNX3:CBFB binds the ITGAL gene,(ITGA4 gene) promoter
  findings: []
- id: Reactome:R-HSA-8951428
  title: RUNX3 binds CTNNB1:TCF7L2,(LEF1,TCF7L1,TCF7)
  findings: []
- id: Reactome:R-HSA-8951676
  title: RUNX3 binds TEADs and YAP1
  findings: []
- id: Reactome:R-HSA-8951910
  title: RUNX3 binds the RUNX1 promoter
  findings: []
- id: Reactome:R-HSA-8951951
  title: RUNX3 binds EP300
  findings: []
- id: Reactome:R-HSA-8951966
  title: EP300 acetylates RUNX3
  findings: []
- id: Reactome:R-HSA-8951977
  title: Acetylated RUNX3 binds to BRD2
  findings: []
- id: Reactome:R-HSA-8952058
  title: CCND1 binds RUNX3 and displaces EP300
  findings: []
- id: Reactome:R-HSA-8952062
  title: CCND1 recruits HDAC4 to RUNX3
  findings: []
- id: Reactome:R-HSA-8952069
  title: HDAC4 deacetylates RUNX3
  findings: []
- id: Reactome:R-HSA-8952128
  title: RUNX3 binds TP53
  findings: []
- id: Reactome:R-HSA-8952226
  title: RUNX3 binds the BCL2L11 (BIM) gene
  findings: []
- id: Reactome:R-HSA-8952371
  title: MDM2 binds RUNX3
  findings: []
- id: Reactome:R-HSA-8952382
  title: MDM2 polyubiquitinates RUNX3
  findings: []
- id: Reactome:R-HSA-8952399
  title: Polyubiquitinated RUNX3 translocates to the cytosol
  findings: []
- id: Reactome:R-HSA-8952408
  title: Polyubiquitinated RUNX3 is degraded by the proteasome
  findings: []
- id: Reactome:R-HSA-8952419
  title: SMURFs ubiquitinate RUNX3
  findings: []
- id: file:human/RUNX3/RUNX3-deep-research-falcon.md
  title: Falcon deep research synthesis for RUNX3
  findings: []
core_functions:
- description: Nuclear Runt-domain sequence-specific transcription factor activity in
    CBFβ/core-binding factor complexes, regulating RNA polymerase II target-gene programs through
    chromatin and regulatory-region DNA binding.
  molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  directly_involved_in:
  - id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  - id: GO:0045893
    label: positive regulation of DNA-templated transcription
  - id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0005654
    label: nucleoplasm
  - id: GO:0000785
    label: chromatin
  in_complex:
    id: GO:0016513
    label: core-binding factor complex
  supported_by:
  - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
    supporting_text: RUNX3 is **not an enzyme** and does not catalyze a chemical reaction; its
      primary function is as a **sequence-specific DNA-binding transcription factor** that regulates
      gene expression programs by binding target regulatory elements via the **Runt domain**,
      typically stabilized by heterodimerization with **CBFβ**.
  - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
    supporting_text: RUNX family proteins (RUNX1/2/3) are sequence-specific transcription factors
      defined by a conserved **Runt DNA-binding domain**; they functionally **heterodimerize with
      CBFβ**, a non–DNA-binding partner that stabilizes RUNX binding to target DNA elements and
      modulates transcriptional activity.
  - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
    supporting_text: RUNX3 can bind DNA and **mononucleosomes**, and RUNX3 loss alters chromatin
      accessibility and transcriptional programs (ATAC-seq/RNA-seq integration).
  - reference_id: file:human/RUNX3/RUNX3-deep-research-falcon.md
    supporting_text: RUNX3’s canonical site of action is the **nucleus**, where it binds chromatin
      and regulates transcription. Multiple studies emphasize that **cytoplasmic mislocalization**
      can functionally inactivate RUNX3 by preventing nuclear activity; oxidative stress provides a
      mechanistic route for nuclear export via Src phosphorylation and JAB1/CRM1 export machinery.
proposed_new_terms: []
suggested_questions: []
suggested_experiments: []