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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: RNA polymerase II cis-regulatory region sequence-specific DNA binding is supported by RUNX3 Runt-domain sequence-specific DNA binding. Reason: Sequence-specific regulatory-region DNA binding is central to RUNX3 transcription factor function. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0001503 ossification | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: ossification is consistent with RUNX3 developmental or disease-associated transcriptional programs but is not the core molecular function. 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. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md **RUNX3 is a master developmental transcription factor** whose dysregulation can impact multiple hallmark pathways (TGF-β, Wnt/β-catenin, Hippo-YAP, Notch/MAPK, etc.). file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. |
| GO:0030097 hemopoiesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: hemopoiesis is consistent with RUNX3 developmental or disease-associated transcriptional programs but is not the core molecular function. 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. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md **RUNX3 is a master developmental transcription factor** whose dysregulation can impact multiple hallmark pathways (TGF-β, Wnt/β-catenin, Hippo-YAP, Notch/MAPK, etc.). file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. |
| GO:0030182 neuron differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: neuron differentiation is consistent with RUNX3 developmental or disease-associated transcriptional programs but is not the core molecular function. 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. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md **RUNX3 is a master developmental transcription factor** whose dysregulation can impact multiple hallmark pathways (TGF-β, Wnt/β-catenin, Hippo-YAP, Notch/MAPK, etc.). file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. |
| GO:0045595 regulation of cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: regulation of cell differentiation is consistent with RUNX3 developmental or disease-associated transcriptional programs but is not the core molecular function. 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. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md **RUNX3 is a master developmental transcription factor** whose dysregulation can impact multiple hallmark pathways (TGF-β, Wnt/β-catenin, Hippo-YAP, Notch/MAPK, etc.). file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: Regulation of transcription by RNA polymerase II is a core RUNX3 biological process. Reason: RUNX3 regulates gene-expression programs as a nuclear sequence-specific transcription factor. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md RUNX3 can bind DNA and **mononucleosomes**, and RUNX3 loss alters chromatin accessibility and transcriptional programs (ATAC-seq/RNA-seq integration). |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: DNA-binding transcription factor activity, RNA polymerase II-specific is the best-supported core molecular function of RUNX3. Reason: RUNX3 is a sequence-specific Runt-domain transcription factor that regulates RNA polymerase II transcription through DNA/chromatin binding and CBFβ-associated complexes. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md RUNX3 can bind DNA and **mononucleosomes**, and RUNX3 loss alters chromatin accessibility and transcriptional programs (ATAC-seq/RNA-seq integration). |
| GO:0002062 chondrocyte differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: chondrocyte differentiation is consistent with RUNX3 developmental or disease-associated transcriptional programs but is not the core molecular function. 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. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md **RUNX3 is a master developmental transcription factor** whose dysregulation can impact multiple hallmark pathways (TGF-β, Wnt/β-catenin, Hippo-YAP, Notch/MAPK, etc.). file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. |
| GO:0003677 DNA binding | IEA GO_REF:0000120 | MODIFY | Summary: Generic DNA binding is directionally correct but less precise than RUNX3 sequence-specific regulatory DNA binding. Reason: RUNX3 is not merely a generic DNA-binding protein; its supported molecular role is sequence-specific Runt-domain binding at regulatory regions. Proposed replacements: sequence-specific double-stranded DNA binding RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic DNA-binding transcription factor activity is correct but less precise than the RNA polymerase II-specific term already present. Reason: RUNX3 functions as a sequence-specific RNA polymerase II transcription factor, so the more specific term is preferred. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md RUNX3 can bind DNA and **mononucleosomes**, and RUNX3 loss alters chromatin accessibility and transcriptional programs (ATAC-seq/RNA-seq integration). |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | REMOVE | Summary: ATP binding is not supported as a RUNX3 molecular function. Reason: RUNX3 is a non-enzymatic DNA-binding transcription factor; ATP-dependent chromatin-remodeling context should not be transferred to RUNX3 as ATP binding. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: nucleus localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: cytoplasm localization is supported, but mainly as a mislocalization/export or degradation context rather than the canonical site of RUNX3 function. Reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic localization is best treated as a regulated non-core or inactivation-associated state. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md This provides a mechanistic explanation for the often-cited phenomenon of RUNX3 cytoplasmic mislocalization as a route to functional loss. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | MODIFY | Summary: Generic regulation of DNA-templated transcription is supported but should be captured with the RNA polymerase II-specific process. Reason: RUNX3 target-gene regulation is best represented by regulation of transcription by RNA polymerase II. Proposed replacements: regulation of transcription by RNA polymerase II Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md RUNX3 can bind DNA and **mononucleosomes**, and RUNX3 loss alters chromatin accessibility and transcriptional programs (ATAC-seq/RNA-seq integration). |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000117 | ACCEPT | Summary: Positive regulation of DNA-templated transcription is supported in context-specific RUNX3 target-gene programs. Reason: RUNX3 can activate transcriptional targets, although the direction of regulation is context dependent. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:1990837 sequence-specific double-stranded DNA binding | IEA GO_REF:0000117 | ACCEPT | Summary: sequence-specific double-stranded DNA binding is supported by RUNX3 Runt-domain sequence-specific DNA binding. Reason: Sequence-specific regulatory-region DNA binding is central to RUNX3 transcription factor function. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0005515 protein binding | IPI PMID:18772112 RUNX3 attenuates beta-catenin/T cell factors in intestinal t... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported in many RUNX3 contexts but is too generic to describe the main function. 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. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0005515 protein binding | IPI PMID:24229708 Runx3 inactivation is a crucial early event in the developme... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported in many RUNX3 contexts but is too generic to describe the main function. 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. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported in many RUNX3 contexts but is too generic to describe the main function. 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. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0005515 protein binding | IPI PMID:38424632 Ubiquitylation of RUNX3 by RNA-binding ubiquitin ligase MEX3... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported in many RUNX3 contexts but is too generic to describe the main function. 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. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0005515 protein binding | IPI PMID:9751710 Transcriptional repression by AML1 and LEF-1 is mediated by ... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported in many RUNX3 contexts but is too generic to describe the main function. 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. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: cytosol localization is supported, but mainly as a mislocalization/export or degradation context rather than the canonical site of RUNX3 function. Reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic localization is best treated as a regulated non-core or inactivation-associated state. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md This provides a mechanistic explanation for the often-cited phenomenon of RUNX3 cytoplasmic mislocalization as a route to functional loss. |
| GO:0006357 regulation of transcription by RNA polymerase II | IDA PMID:20591170 The Runx transcriptional co-activator, CBFbeta, is essential... | ACCEPT | Summary: Regulation of transcription by RNA polymerase II is a core RUNX3 biological process. Reason: RUNX3 regulates gene-expression programs as a nuclear sequence-specific transcription factor. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md RUNX3 can bind DNA and **mononucleosomes**, and RUNX3 loss alters chromatin accessibility and transcriptional programs (ATAC-seq/RNA-seq integration). |
| GO:0001222 transcription corepressor binding | IPI PMID:9751710 Transcriptional repression by AML1 and LEF-1 is mediated by ... | ACCEPT | Summary: Transcription corepressor binding is supported by RUNX/Runt-domain recruitment of TLE/Groucho corepressors. Reason: This is a more informative binding annotation than generic protein binding for RUNX3-associated transcriptional repression. Supporting Evidence: PMID:9751710 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). file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: sequence-specific double-stranded DNA binding is supported by RUNX3 Runt-domain sequence-specific DNA binding. Reason: Sequence-specific regulatory-region DNA binding is central to RUNX3 transcription factor function. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: Chromatin localization is supported by RUNX3 DNA, mononucleosome, and chromatin-remodeler-associated activity. Reason: RUNX3 binds chromatin-associated regulatory DNA as part of its transcription factor function. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md RUNX3 can bind DNA and **mononucleosomes**, and RUNX3 loss alters chromatin accessibility and transcriptional programs (ATAC-seq/RNA-seq integration). file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: DNA-binding transcription factor activity, RNA polymerase II-specific is the best-supported core molecular function of RUNX3. Reason: RUNX3 is a sequence-specific Runt-domain transcription factor that regulates RNA polymerase II transcription through DNA/chromatin binding and CBFβ-associated complexes. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md RUNX3 can bind DNA and **mononucleosomes**, and RUNX3 loss alters chromatin accessibility and transcriptional programs (ATAC-seq/RNA-seq integration). |
| GO:0016513 core-binding factor complex | TAS PMID:18258917 Repression of the transcription factor Th-POK by Runx comple... | ACCEPT | Summary: Core-binding factor complex is the canonical RUNX3 transcription factor complex context. Reason: RUNX3 heterodimerizes with CBFβ, placing it in the core-binding factor complex for DNA-binding transcriptional regulation. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0043371 negative regulation of CD4-positive, alpha-beta T cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | 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. Reason: T-cell differentiation phenotypes reflect RUNX3-regulated transcriptional programs rather than a separate core molecular activity. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md RUNX3 is a key regulator of **CD8+ T-cell differentiation, infiltration, effector/memory fate, and residency**. file:human/RUNX3/RUNX3-deep-research-falcon.md **RUNX3 is a master developmental transcription factor** whose dysregulation can impact multiple hallmark pathways (TGF-β, Wnt/β-catenin, Hippo-YAP, Notch/MAPK, etc.). |
| GO:0043378 positive regulation of CD8-positive, alpha-beta T cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | 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. Reason: T-cell differentiation phenotypes reflect RUNX3-regulated transcriptional programs rather than a separate core molecular activity. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md RUNX3 is a key regulator of **CD8+ T-cell differentiation, infiltration, effector/memory fate, and residency**. file:human/RUNX3/RUNX3-deep-research-falcon.md **RUNX3 is a master developmental transcription factor** whose dysregulation can impact multiple hallmark pathways (TGF-β, Wnt/β-catenin, Hippo-YAP, Notch/MAPK, etc.). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8952419 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952399 | KEEP AS NON CORE | Summary: cytosol localization is supported, but mainly as a mislocalization/export or degradation context rather than the canonical site of RUNX3 function. Reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic localization is best treated as a regulated non-core or inactivation-associated state. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md This provides a mechanistic explanation for the often-cited phenomenon of RUNX3 cytoplasmic mislocalization as a route to functional loss. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952408 | KEEP AS NON CORE | Summary: cytosol localization is supported, but mainly as a mislocalization/export or degradation context rather than the canonical site of RUNX3 function. Reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic localization is best treated as a regulated non-core or inactivation-associated state. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md This provides a mechanistic explanation for the often-cited phenomenon of RUNX3 cytoplasmic mislocalization as a route to functional loss. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8952382 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8952399 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8951966 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8951977 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8952058 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8952062 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8952069 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8937792 | KEEP AS NON CORE | Summary: cytosol localization is supported, but mainly as a mislocalization/export or degradation context rather than the canonical site of RUNX3 function. Reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic localization is best treated as a regulated non-core or inactivation-associated state. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md This provides a mechanistic explanation for the often-cited phenomenon of RUNX3 cytoplasmic mislocalization as a route to functional loss. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8937807 | KEEP AS NON CORE | Summary: cytosol localization is supported, but mainly as a mislocalization/export or degradation context rather than the canonical site of RUNX3 function. Reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic localization is best treated as a regulated non-core or inactivation-associated state. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md This provides a mechanistic explanation for the often-cited phenomenon of RUNX3 cytoplasmic mislocalization as a route to functional loss. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8937814 | KEEP AS NON CORE | Summary: cytosol localization is supported, but mainly as a mislocalization/export or degradation context rather than the canonical site of RUNX3 function. Reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic localization is best treated as a regulated non-core or inactivation-associated state. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md This provides a mechanistic explanation for the often-cited phenomenon of RUNX3 cytoplasmic mislocalization as a route to functional loss. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8865454 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8878117 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8878143 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8878178 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8878193 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8878220 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8878237 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8937814 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8949335 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8951428 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8951676 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8951910 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8951951 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8952128 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8952226 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8952371 | ACCEPT | Summary: nucleoplasm localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005515 protein binding | IPI PMID:20599712 Tumor suppressor, AT motif binding factor 1 (ATBF1), translo... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported in many RUNX3 contexts but is too generic to describe the main function. 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. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0005634 nucleus | IDA PMID:20599712 Tumor suppressor, AT motif binding factor 1 (ATBF1), translo... | ACCEPT | Summary: nucleus localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0005737 cytoplasm | IDA PMID:20599712 Tumor suppressor, AT motif binding factor 1 (ATBF1), translo... | KEEP AS NON CORE | Summary: cytoplasm localization is supported, but mainly as a mislocalization/export or degradation context rather than the canonical site of RUNX3 function. Reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic localization is best treated as a regulated non-core or inactivation-associated state. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md This provides a mechanistic explanation for the often-cited phenomenon of RUNX3 cytoplasmic mislocalization as a route to functional loss. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:20599712 Tumor suppressor, AT motif binding factor 1 (ATBF1), translo... | ACCEPT | Summary: Positive regulation of DNA-templated transcription is supported in context-specific RUNX3 target-gene programs. Reason: RUNX3 can activate transcriptional targets, although the direction of regulation is context dependent. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0071559 response to transforming growth factor beta | IDA PMID:20599712 Tumor suppressor, AT motif binding factor 1 (ATBF1), translo... | KEEP AS NON CORE | Summary: Response to transforming growth factor beta is supported as a pathway context for RUNX3 transcriptional regulation. Reason: TGF-beta/SMAD effects are important context-specific biology, but the core function remains nuclear sequence-specific transcriptional regulation. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md **RUNX3 is a master developmental transcription factor** whose dysregulation can impact multiple hallmark pathways (TGF-β, Wnt/β-catenin, Hippo-YAP, Notch/MAPK, etc.). |
| GO:0005515 protein binding | IPI PMID:17377532 Foxp3 controls regulatory T-cell function by interacting wit... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported in many RUNX3 contexts but is too generic to describe the main function. 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. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0000785 chromatin | ISS GO_REF:0000024 | ACCEPT | Summary: Chromatin localization is supported by RUNX3 DNA, mononucleosome, and chromatin-remodeler-associated activity. Reason: RUNX3 binds chromatin-associated regulatory DNA as part of its transcription factor function. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md RUNX3 can bind DNA and **mononucleosomes**, and RUNX3 loss alters chromatin accessibility and transcriptional programs (ATAC-seq/RNA-seq integration). file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | ISS GO_REF:0000024 | ACCEPT | Summary: RNA polymerase II transcription regulatory region sequence-specific DNA binding is supported by RUNX3 Runt-domain sequence-specific DNA binding. Reason: Sequence-specific regulatory-region DNA binding is central to RUNX3 transcription factor function. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: Negative regulation of transcription by RNA polymerase II is supported for RUNX3 in repressive target-gene and Wnt/TCF contexts. Reason: RUNX3 can repress transcriptional outputs through protein complexes and target-gene regulation. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. PMID:18772112 Here we found that RUNX3, a gastric tumor suppressor, forms a ternary complex with beta-catenin/TCF4 and attenuates Wnt signaling activity. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISS GO_REF:0000024 | ACCEPT | Summary: DNA-binding transcription factor activity, RNA polymerase II-specific is the best-supported core molecular function of RUNX3. Reason: RUNX3 is a sequence-specific Runt-domain transcription factor that regulates RNA polymerase II transcription through DNA/chromatin binding and CBFβ-associated complexes. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md RUNX3 can bind DNA and **mononucleosomes**, and RUNX3 loss alters chromatin accessibility and transcriptional programs (ATAC-seq/RNA-seq integration). |
| GO:0048935 peripheral nervous system neuron development | TAS PMID:20096094 Brn3a regulates neuronal subtype specification in the trigem... | KEEP AS NON CORE | Summary: peripheral nervous system neuron development is consistent with RUNX3 developmental or disease-associated transcriptional programs but is not the core molecular function. 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. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md **RUNX3 is a master developmental transcription factor** whose dysregulation can impact multiple hallmark pathways (TGF-β, Wnt/β-catenin, Hippo-YAP, Notch/MAPK, etc.). file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. |
| GO:0005634 nucleus | IDA PMID:20100835 Src kinase phosphorylates RUNX3 at tyrosine residues and loc... | ACCEPT | Summary: nucleus localization is central to RUNX3 canonical transcription factor activity. Reason: RUNX3 acts in the nucleus/nucleoplasm to bind chromatin and regulate transcription. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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). |
| GO:0006468 protein phosphorylation | IDA PMID:20100835 Src kinase phosphorylates RUNX3 at tyrosine residues and loc... | REMOVE | Summary: Protein phosphorylation is not supported as a process carried out by RUNX3. 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. Supporting Evidence: PMID:20100835 In this study, we found that the overexpression of Src results in the tyrosine phosphorylation and cytoplasmic localization of RUNX3. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0005515 protein binding | IPI PMID:20100835 Src kinase phosphorylates RUNX3 at tyrosine residues and loc... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported in many RUNX3 contexts but is too generic to describe the main function. 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. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. |
| GO:0005737 cytoplasm | IDA PMID:20100835 Src kinase phosphorylates RUNX3 at tyrosine residues and loc... | KEEP AS NON CORE | Summary: cytoplasm localization is supported, but mainly as a mislocalization/export or degradation context rather than the canonical site of RUNX3 function. Reason: RUNX3 core activity is nuclear transcriptional regulation; cytoplasmic/cytosolic localization is best treated as a regulated non-core or inactivation-associated state. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md This provides a mechanistic explanation for the often-cited phenomenon of RUNX3 cytoplasmic mislocalization as a route to functional loss. |
| GO:0045786 negative regulation of cell cycle | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: negative regulation of cell cycle is consistent with RUNX3 developmental or disease-associated transcriptional programs but is not the core molecular function. 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. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md **RUNX3 is a master developmental transcription factor** whose dysregulation can impact multiple hallmark pathways (TGF-β, Wnt/β-catenin, Hippo-YAP, Notch/MAPK, etc.). file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. |
| GO:0050680 negative regulation of epithelial cell proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: negative regulation of epithelial cell proliferation is consistent with RUNX3 developmental or disease-associated transcriptional programs but is not the core molecular function. 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. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md **RUNX3 is a master developmental transcription factor** whose dysregulation can impact multiple hallmark pathways (TGF-β, Wnt/β-catenin, Hippo-YAP, Notch/MAPK, etc.). file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. |
| GO:0003700 DNA-binding transcription factor activity | TAS PMID:7607690 Identification of a new murine runt domain-containing gene, ... | MODIFY | Summary: Generic DNA-binding transcription factor activity is correct but less precise than the RNA polymerase II-specific term already present. Reason: RUNX3 functions as a sequence-specific RNA polymerase II transcription factor, so the more specific term is preferred. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md RUNX3 can bind DNA and **mononucleosomes**, and RUNX3 loss alters chromatin accessibility and transcriptional programs (ATAC-seq/RNA-seq integration). |
| GO:0005524 ATP binding | NAS PMID:7835892 AML1, AML2, and AML3, the human members of the runt domain g... | REMOVE | Summary: ATP binding is not supported as a RUNX3 molecular function. Reason: RUNX3 is a non-enzymatic DNA-binding transcription factor; ATP-dependent chromatin-remodeling context should not be transferred to RUNX3 as ATP binding. Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. |
| GO:0006355 regulation of DNA-templated transcription | NAS PMID:7622058 Cloning, mapping and expression of PEBP2 alpha C, a third ge... | MODIFY | Summary: Generic regulation of DNA-templated transcription is supported but should be captured with the RNA polymerase II-specific process. Reason: RUNX3 target-gene regulation is best represented by regulation of transcription by RNA polymerase II. Proposed replacements: regulation of transcription by RNA polymerase II Supporting Evidence: file:human/RUNX3/RUNX3-deep-research-falcon.md 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**. file:human/RUNX3/RUNX3-deep-research-falcon.md 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. file:human/RUNX3/RUNX3-deep-research-falcon.md RUNX3 can bind DNA and **mononucleosomes**, and RUNX3 loss alters chromatin accessibility and transcriptional programs (ATAC-seq/RNA-seq integration). |
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