{"gene":"GTF3C6","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2007,"finding":"GTF3C6 (TFIIIC35) was identified and cloned as the sixth subunit of human TFIIIC, the last of the six TFIIIC subunits conserved from yeast. Affinity-purified TFIIIC from an epitope-tagged TFIIIC35 cell line was active in binding to and transcribing the VA1 gene in vitro, confirming its incorporation into a functional complex. TFIIIC35 was shown to interact directly and specifically with TFIIIC subunit TFIIIC63, and to a lesser extent with TFIIIC90, in vitro.","method":"Molecular cloning, affinity purification, in vitro transcription assay, in vitro binding/interaction assays, phylogenetic analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro transcription reconstitution plus direct binding assays; single lab with multiple orthogonal methods","pmids":["17409385"],"is_preprint":false},{"year":2024,"finding":"GTF3C6 expression is driven by KRAS mutation via the PI3K signaling pathway in lung adenocarcinoma (LUAD). GTF3C6 promotes anchorage-independent proliferation, migration, and invasion of LUAD cells, and its downstream effector is the FAK (focal adhesion kinase) pathway, as GTF3C6 regulates FAK phosphorylation. GTF3C6 knockdown reverses the malignant phenotype of KRAS-mutant LUAD cells in vitro and suppresses tumor growth in vivo.","method":"Western blot, qRT-PCR, immunofluorescence, immunohistochemistry, gene knockdown/overexpression, LSL-KrasG12D/+;LSL-p53-/- mouse model, patient-derived organoids, in vivo tumor growth assays","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined cellular and in vivo phenotype and pathway placement, single lab with multiple methods","pmids":["38685529"],"is_preprint":false}],"current_model":"GTF3C6 (TFIIIC35) is the sixth subunit of human transcription factor TFIIIC, required for RNA Pol III-dependent transcription, directly interacting with TFIIIC63 within the complex; in cancer contexts, its expression is driven by KRAS mutation via PI3K signaling and it promotes malignant phenotypes through downstream FAK pathway activation."},"narrative":{"teleology":[{"year":2007,"claim":"Identification of GTF3C6 as the sixth TFIIIC subunit resolved the complete subunit composition of human TFIIIC and established that the complex requires this conserved component for promoter binding and RNA Pol III transcription.","evidence":"Molecular cloning, affinity purification of TFIIIC from epitope-tagged TFIIIC35-expressing cells, in vitro transcription of the VA1 gene, and direct in vitro binding assays with individual TFIIIC subunits","pmids":["17409385"],"confidence":"High","gaps":["Structural basis of the GTF3C6–TFIIIC63 interaction is unresolved","Contribution of GTF3C6 to TFIIIC assembly or stability in vivo has not been dissected","Whether GTF3C6 contacts DNA or other Pol III machinery components is unknown"]},{"year":2024,"claim":"Linking GTF3C6 to KRAS-driven oncogenesis established a non-canonical, cancer-relevant function: KRAS activates GTF3C6 expression via PI3K, and GTF3C6 in turn promotes malignant phenotypes through FAK pathway activation.","evidence":"Knockdown and overexpression in LUAD cell lines, LSL-KrasG12D/+;LSL-p53−/− mouse model, patient-derived organoids, in vivo tumor growth assays, Western blot for FAK phosphorylation","pmids":["38685529"],"confidence":"Medium","gaps":["Whether FAK activation by GTF3C6 is direct or mediated through Pol III-dependent transcription of specific targets is unknown","Independent replication in additional KRAS-mutant cancer models has not been reported","Mechanism by which PI3K signaling upregulates GTF3C6 expression is not defined"]},{"year":null,"claim":"The structural role of GTF3C6 within the TFIIIC complex and the mechanistic link between its canonical Pol III transcription function and its oncogenic activity remain open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structural data for GTF3C6 within TFIIIC exist","Whether the cancer phenotype depends on GTF3C6's role in Pol III transcription or an independent function is untested","Genome-wide identification of GTF3C6-dependent Pol III transcripts has not been performed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140223","term_label":"general transcription initiation factor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0]}],"complexes":["TFIIIC"],"partners":["GTF3C2","GTF3C4"],"other_free_text":[]},"mechanistic_narrative":"GTF3C6 (TFIIIC35) is the sixth and final subunit of human transcription factor IIIC (TFIIIC), the multi-subunit complex required for promoter recognition and RNA polymerase III-dependent transcription. Affinity-purified TFIIIC containing epitope-tagged GTF3C6 is active in binding and transcribing the VA1 gene in vitro, and GTF3C6 interacts directly with the TFIIIC63 subunit and more weakly with TFIIIC90 [PMID:17409385]. In lung adenocarcinoma, GTF3C6 expression is upregulated downstream of oncogenic KRAS via PI3K signaling, and GTF3C6 promotes anchorage-independent growth, migration, and invasion through activation of FAK phosphorylation; its knockdown suppresses tumor growth in vivo [PMID:38685529]."},"prefetch_data":{"uniprot":{"accession":"Q969F1","full_name":"General transcription factor 3C polypeptide 6","aliases":["Transcription factor IIIC 35 kDa subunit","TFIIIC 35 kDa subunit","TFIIIC35","Transcription factor IIIC subunit 6"],"length_aa":213,"mass_kda":24.0,"function":"Involved in RNA polymerase III-mediated transcription. Integral, tightly associated component of the DNA-binding TFIIIC2 subcomplex that directly binds tRNA and virus-associated RNA promoters","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q969F1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GTF3C6","classification":"Not Classified","n_dependent_lines":269,"n_total_lines":1208,"dependency_fraction":0.222682119205298},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GTF3C6","total_profiled":1310},"omim":[{"mim_id":"611784","title":"GENERAL TRANSCRIPTION FACTOR 3C, POLYPEPTIDE 6; GTF3C6","url":"https://www.omim.org/entry/611784"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GTF3C6"},"hgnc":{"alias_symbol":["bA397G5.3","TFIIIC35"],"prev_symbol":["C6orf51"]},"alphafold":{"accession":"Q969F1","domains":[{"cath_id":"2.60.40","chopping":"19-69_99-111_125-145","consensus_level":"medium","plddt":85.3345,"start":19,"end":145}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969F1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969F1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969F1-F1-predicted_aligned_error_v6.png","plddt_mean":66.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GTF3C6","jax_strain_url":"https://www.jax.org/strain/search?query=GTF3C6"},"sequence":{"accession":"Q969F1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969F1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969F1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969F1"}},"corpus_meta":[{"pmid":"17409385","id":"PMC_17409385","title":"Identification, 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Deficit in Energy Metabolism Caused by FH Loss in RPE Cells.","date":"2021","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34943047","citation_count":22,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34687317","id":"PMC_34687317","title":"Interactome profiling reveals interaction of SARS-CoV-2 NSP13 with host factor STAT1 to suppress interferon signaling.","date":"2021","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/34687317","citation_count":18,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35563538","id":"PMC_35563538","title":"Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling.","date":"2022","source":"International journal of molecular 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adhesion.","date":"2014","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/25437307","citation_count":13,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"37314216","id":"PMC_37314216","title":"USP9X deubiquitinates and stabilizes CDC123 to promote breast carcinogenesis through regulating cell cycle.","date":"2023","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/37314216","citation_count":8,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":2985,"output_tokens":737,"usd":0.010005},"stage2":{"model":"claude-opus-4-6","input_tokens":3919,"output_tokens":2390,"usd":0.119017},"total_usd":0.228129,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":13946,"output_tokens":939,"usd":0.027962},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":4111,"output_tokens":1075,"usd":0.071145}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"GTF3C6 (TFIIIC35) was identified as the sixth subunit of human TFIIIC transcription factor complex; affinity-purified TFIIIC from epitope-tagged TFIIIC35 cells is active in binding to and transcribing the VA1 gene in vitro, establishing its role in RNA polymerase III-dependent transcription.\",\n      \"method\": \"Molecular cloning, epitope-tag affinity purification, in vitro transcription assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro transcription reconstitution with affinity-purified complex, single rigorous paper with multiple orthogonal methods\",\n      \"pmids\": [\"17409385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TFIIIC35 (GTF3C6) directly interacts with human TFIIIC subunits TFIIIC63 and, to a lesser extent, TFIIIC90 in vitro, placing it within the TFIIIC complex architecture.\",\n      \"method\": \"In vitro protein-protein interaction assay (pulldown/binding assay)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct in vitro binding assay with defined subunit specificity, supported by functional complex purification\",\n      \"pmids\": [\"17409385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KRAS mutation drives GTF3C6 expression through the PI3K pathway, and GTF3C6 in turn promotes LUAD malignant phenotype (anchorage-independent proliferation, migration, invasion) via regulation of FAK phosphorylation (FAK pathway activation).\",\n      \"method\": \"Western blot, qRT-PCR, gene knockdown/overexpression, immunofluorescence, LUAD mouse models, patient-derived organoids, in vivo tumor growth assay\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods and models but single lab, pathway placement via knockdown with defined phenotypic readouts\",\n      \"pmids\": [\"38685529\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GTF3C6 (TFIIIC35) is the sixth subunit of the human TFIIIC complex, directly binding TFIIIC63 and enabling RNA polymerase III-dependent transcription; additionally, in lung adenocarcinoma, KRAS-mutant signaling through PI3K upregulates GTF3C6 expression, which then promotes tumor cell proliferation, migration, and invasion by activating FAK pathway phosphorylation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEEP papers.\n\n**Classification:**\n\n- Paper [1] PMID:17409385 — KEEP: Direct study of GTF3C6 (TFIIIC35), the sixth subunit of human TFIIIC.\n- Paper [2] PMID:27663376 — EXCLUDE: GTF3C6 is only identified as an incidental yeast two-hybrid hit with a viral protein; no mechanistic study of GTF3C6 itself.\n- Paper [3] PMID:38685529 — KEEP: Direct mechanistic study of GTF3C6 in LUAD, including pathway placement (KRAS/PI3K → GTF3C6 → FAK).\n- Additional papers [1]-[25]: All are about unrelated genes/topics (RBPs, cDNA collections, interactomes not focused on GTF3C6, BRCA1, CDC123, etc.) — EXCLUDE. None describe GTF3C6 mechanistically.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"GTF3C6 (TFIIIC35) was identified and cloned as the sixth subunit of human TFIIIC, the last of the six TFIIIC subunits conserved from yeast. Affinity-purified TFIIIC from an epitope-tagged TFIIIC35 cell line was active in binding to and transcribing the VA1 gene in vitro, confirming its incorporation into a functional complex. TFIIIC35 was shown to interact directly and specifically with TFIIIC subunit TFIIIC63, and to a lesser extent with TFIIIC90, in vitro.\",\n      \"method\": \"Molecular cloning, affinity purification, in vitro transcription assay, in vitro binding/interaction assays, phylogenetic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro transcription reconstitution plus direct binding assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17409385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GTF3C6 expression is driven by KRAS mutation via the PI3K signaling pathway in lung adenocarcinoma (LUAD). GTF3C6 promotes anchorage-independent proliferation, migration, and invasion of LUAD cells, and its downstream effector is the FAK (focal adhesion kinase) pathway, as GTF3C6 regulates FAK phosphorylation. GTF3C6 knockdown reverses the malignant phenotype of KRAS-mutant LUAD cells in vitro and suppresses tumor growth in vivo.\",\n      \"method\": \"Western blot, qRT-PCR, immunofluorescence, immunohistochemistry, gene knockdown/overexpression, LSL-KrasG12D/+;LSL-p53-/- mouse model, patient-derived organoids, in vivo tumor growth assays\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cellular and in vivo phenotype and pathway placement, single lab with multiple methods\",\n      \"pmids\": [\"38685529\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GTF3C6 (TFIIIC35) is the sixth subunit of human transcription factor TFIIIC, required for RNA Pol III-dependent transcription, directly interacting with TFIIIC63 within the complex; in cancer contexts, its expression is driven by KRAS mutation via PI3K signaling and it promotes malignant phenotypes through downstream FAK pathway activation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GTF3C6 (also called TFIIIC35) is the sixth and smallest subunit of the human general transcription factor IIIC (TFIIIC) complex, directly interacting with TFIIIC63 and TFIIIC90 to assemble a functional complex that binds DNA promoter elements and supports RNA polymerase III-dependent transcription in vitro [PMID:17409385]. In KRAS-mutant lung adenocarcinoma, PI3K-dependent signaling upregulates GTF3C6 expression, which promotes tumor cell proliferation, migration, and invasion through activation of FAK phosphorylation [PMID:38685529].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of GTF3C6 as the sixth TFIIIC subunit resolved the complete composition of human TFIIIC and established that this subunit is required for promoter binding and RNA polymerase III transcription.\",\n      \"evidence\": \"Molecular cloning, epitope-tag affinity purification of TFIIIC, and in vitro VA1 gene transcription assay\",\n      \"pmids\": [\"17409385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of TFIIIC35 within the hexameric complex\",\n        \"Precise contribution of TFIIIC35 to promoter DNA recognition versus complex stability is unresolved\",\n        \"Whether TFIIIC35 has functions independent of TFIIIC is unknown\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapping the direct interaction of TFIIIC35 with TFIIIC63 (and weaker binding to TFIIIC90) placed the subunit within the TFIIIC complex architecture, suggesting it bridges specific subcomplexes.\",\n      \"evidence\": \"In vitro protein-protein pulldown/binding assays with individual TFIIIC subunits\",\n      \"pmids\": [\"17409385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vivo validation of endogenous subunit contacts (e.g., cross-linking mass spectrometry)\",\n        \"Stoichiometry of TFIIIC35 within the complex is not determined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linking KRAS-mutant signaling via PI3K to GTF3C6 upregulation and downstream FAK pathway activation revealed a non-canonical oncogenic role for this Pol III transcription factor subunit in lung adenocarcinoma.\",\n      \"evidence\": \"Gene knockdown/overexpression, qRT-PCR, Western blot, LUAD mouse models, patient-derived organoids, and in vivo tumor growth assays\",\n      \"pmids\": [\"38685529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding; independent replication in additional cohorts or model systems is lacking\",\n        \"Whether FAK activation by GTF3C6 is direct or indirect (and whether it depends on TFIIIC-mediated transcription) is unresolved\",\n        \"Mechanism by which PI3K signaling specifically upregulates GTF3C6 transcription or mRNA stability is not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No structural model of TFIIIC35 within the human TFIIIC complex exists, and it remains unknown whether GTF3C6's oncogenic functions operate through its canonical role in Pol III transcription or through a TFIIIC-independent mechanism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No cryo-EM or crystallographic structure of human TFIIIC including TFIIIC35\",\n        \"No separation-of-function mutants distinguishing Pol III transcription role from FAK signaling role\",\n        \"Genome-wide identification of Pol III targets specifically dependent on TFIIIC35 has not been performed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"TFIIIC\"],\n    \"partners\": [\"GTF3C1\", \"GTF3C2\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to correct the partners — the timeline specifically names TFIIIC63 and TFIIIC90 as direct interaction partners. Let me map those correctly: TFIIIC63 = GTF3C5, TFIIIC90 = GTF3C4. Let me also fix the pathway term_id.\n\n```json\n{\n  \"mechanistic_narrative\": \"GTF3C6 (also called TFIIIC35) is the sixth and smallest subunit of the human general transcription factor IIIC (TFIIIC) complex, directly interacting with TFIIIC63 (GTF3C5) and to a lesser extent TFIIIC90 (GTF3C4) to assemble a functional complex that binds DNA promoter elements and supports RNA polymerase III-dependent transcription in vitro [PMID:17409385]. In KRAS-mutant lung adenocarcinoma, PI3K-dependent signaling upregulates GTF3C6 expression, which promotes tumor cell proliferation, migration, and invasion through activation of FAK phosphorylation [PMID:38685529].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of GTF3C6 as the sixth TFIIIC subunit resolved the complete subunit composition of human TFIIIC and established that this subunit is required for promoter binding and RNA polymerase III transcription.\",\n      \"evidence\": \"Molecular cloning, epitope-tag affinity purification of TFIIIC, and in vitro VA1 gene transcription assay\",\n      \"pmids\": [\"17409385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of TFIIIC35 within the hexameric complex\",\n        \"Precise contribution of TFIIIC35 to promoter DNA recognition versus complex stability is unresolved\",\n        \"Whether TFIIIC35 has functions independent of the TFIIIC complex is unknown\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapping the direct interaction of TFIIIC35 with TFIIIC63 (and weaker binding to TFIIIC90) placed the subunit within the TFIIIC complex architecture, suggesting it bridges specific subcomplexes.\",\n      \"evidence\": \"In vitro protein-protein pulldown/binding assays with individual recombinant TFIIIC subunits\",\n      \"pmids\": [\"17409385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vivo validation of endogenous subunit contacts (e.g., cross-linking mass spectrometry)\",\n        \"Stoichiometry of TFIIIC35 within the complex is not determined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linking KRAS-mutant signaling via PI3K to GTF3C6 upregulation and downstream FAK pathway activation revealed a non-canonical oncogenic role for this Pol III transcription factor subunit in lung adenocarcinoma.\",\n      \"evidence\": \"Gene knockdown/overexpression, Western blot, qRT-PCR, LUAD mouse models, patient-derived organoids, and in vivo tumor growth assays\",\n      \"pmids\": [\"38685529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding; independent replication in additional cohorts or model systems is lacking\",\n        \"Whether FAK activation by GTF3C6 is direct or indirect and whether it depends on TFIIIC-mediated transcription is unresolved\",\n        \"Mechanism by which PI3K signaling specifically upregulates GTF3C6 expression is not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No structural model of TFIIIC35 within the human TFIIIC complex exists, and it remains unknown whether GTF3C6's oncogenic functions operate through its canonical role in Pol III transcription or through a TFIIIC-independent mechanism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No cryo-EM or crystallographic structure of human TFIIIC including TFIIIC35\",\n        \"No separation-of-function mutants distinguishing Pol III transcription role from FAK signaling role\",\n        \"Genome-wide identification of Pol III target genes specifically dependent on TFIIIC35 has not been performed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"TFIIIC\"],\n    \"partners\": [\"GTF3C5\", \"GTF3C4\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"GTF3C6 (TFIIIC35) is the sixth and final subunit of human transcription factor IIIC (TFIIIC), the multi-subunit complex required for promoter recognition and RNA polymerase III-dependent transcription. Affinity-purified TFIIIC containing epitope-tagged GTF3C6 is active in binding and transcribing the VA1 gene in vitro, and GTF3C6 interacts directly with the TFIIIC63 subunit and more weakly with TFIIIC90 [PMID:17409385]. In lung adenocarcinoma, GTF3C6 expression is upregulated downstream of oncogenic KRAS via PI3K signaling, and GTF3C6 promotes anchorage-independent growth, migration, and invasion through activation of FAK phosphorylation; its knockdown suppresses tumor growth in vivo [PMID:38685529].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of GTF3C6 as the sixth TFIIIC subunit resolved the complete subunit composition of human TFIIIC and established that the complex requires this conserved component for promoter binding and RNA Pol III transcription.\",\n      \"evidence\": \"Molecular cloning, affinity purification of TFIIIC from epitope-tagged TFIIIC35-expressing cells, in vitro transcription of the VA1 gene, and direct in vitro binding assays with individual TFIIIC subunits\",\n      \"pmids\": [\"17409385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the GTF3C6–TFIIIC63 interaction is unresolved\",\n        \"Contribution of GTF3C6 to TFIIIC assembly or stability in vivo has not been dissected\",\n        \"Whether GTF3C6 contacts DNA or other Pol III machinery components is unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linking GTF3C6 to KRAS-driven oncogenesis established a non-canonical, cancer-relevant function: KRAS activates GTF3C6 expression via PI3K, and GTF3C6 in turn promotes malignant phenotypes through FAK pathway activation.\",\n      \"evidence\": \"Knockdown and overexpression in LUAD cell lines, LSL-KrasG12D/+;LSL-p53−/− mouse model, patient-derived organoids, in vivo tumor growth assays, Western blot for FAK phosphorylation\",\n      \"pmids\": [\"38685529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether FAK activation by GTF3C6 is direct or mediated through Pol III-dependent transcription of specific targets is unknown\",\n        \"Independent replication in additional KRAS-mutant cancer models has not been reported\",\n        \"Mechanism by which PI3K signaling upregulates GTF3C6 expression is not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural role of GTF3C6 within the TFIIIC complex and the mechanistic link between its canonical Pol III transcription function and its oncogenic activity remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structural data for GTF3C6 within TFIIIC exist\",\n        \"Whether the cancer phenotype depends on GTF3C6's role in Pol III transcription or an independent function is untested\",\n        \"Genome-wide identification of GTF3C6-dependent Pol III transcripts has not been performed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140223\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"TFIIIC\"],\n    \"partners\": [\"GTF3C2\", \"GTF3C4\"],\n    \"other_free_text\": []\n  }\n}\n```"}