{"gene":"GTF2E1","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1991,"finding":"Human TFIIE is a heterodimer composed of two subunits (56 kDa and 34 kDa; GTF2E1 encodes the large 56 kDa subunit). Both subunits are required to form a stable preinitiation complex and to reconstitute basal-level and Sp1-activated transcription in vitro. cDNA cloning revealed structural motifs including zinc-finger-like sequences in the large subunit.","method":"cDNA cloning, recombinant protein purification, in vitro transcription reconstitution assay, preinitiation complex assembly","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — reconstitution of transcription with purified recombinant subunits, functional mutagenesis context, original discovery paper","pmids":["1956398"],"is_preprint":false},{"year":1987,"finding":"TFIIE (large subunit GTF2E1-containing complex) is absolutely required, together with TFIIA, TFIIB, TFIID, and RNA polymerase II, for specific transcription initiation at the adenovirus major late promoter and other class II promoters. TFIIE forms independent interactions with TFIIB and with RNA polymerase II but not RNA polymerase III, establishing its specificity for the pol II machinery.","method":"Biochemical purification from HeLa nuclear extracts, in vitro transcription assay, glycerol gradient sedimentation, preinitiation complex (heparin-resistant) formation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro transcription system with purified factors; replicated in subsequent studies","pmids":["3029109"],"is_preprint":false},{"year":1994,"finding":"TFIIE directly interacts with the ERCC3 (XPB) subunit of TFIIH, and this interaction negatively modulates the helicase activity of TFIIH. This places TFIIE (and its large subunit GTF2E1) as a regulator of TFIIH helicase activity during transcription initiation.","method":"Extensive purification of TFIIH, in vitro DNA excision repair complementation assays, direct interaction assays between TFIIE and ERCC3 subunit of TFIIH","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro interaction demonstrated and helicase modulation assayed; highly cited foundational study","pmids":["8152490"],"is_preprint":false},{"year":1996,"finding":"TFIIE is required for Tat-stimulated HIV-1 transcription in vitro. Tat interacts with a TFIIH-containing complex and stimulates TFIIH kinase-mediated phosphorylation of the RNA pol II CTD; TFIIE participates in the complex supporting this CTD phosphorylation and enhanced processivity.","method":"In vitro transcription assay, CTD phosphorylation assay, immunoprecipitation of TFIIH-containing complexes","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 — clean biochemical dissection with purified factors; TFIIE role inferred from requirement in reconstituted system","pmids":["8934526"],"is_preprint":false},{"year":1997,"finding":"TFIIE (containing GTF2E1) is co-purified with the RNA polymerase II holoenzyme. Immunopurification of BRCA1 complexes specifically co-purifies transcriptionally active RNA pol II and TFIIE, placing GTF2E1-containing TFIIE as a stable holoenzyme-associated component.","method":"Multi-step chromatographic co-purification, immunopurification with anti-hSRB7 antibody, co-immunoprecipitation with anti-BRCA1 antibody","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-purification across multiple steps; single study","pmids":["9159119"],"is_preprint":false},{"year":1997,"finding":"Analysis of transcription initiation revealed that TFIIE (GTF2E1-containing) is required for the ATP-dependent open complex formation (first transition). TFIIH helicase activity, which is regulated by TFIIE, is needed to maintain the open region only during formation of the first three phosphodiester bonds (up to the second transition at 4-nucleotide RNA).","method":"In vitro transcription with purified homogeneous proteins, stalling of pol II complex at defined positions, KMnO4 footprinting of open region, ATPγS inhibition experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro system with defined positions and chemical probing; rigorous mechanistic dissection","pmids":["9405375"],"is_preprint":false},{"year":1995,"finding":"The novel cellular coactivator p100, which mediates EBNA2 transcriptional activation, directly binds TFIIE. Both the p56 (GTF2E1) and p34 subunits of TFIIE independently bind to p100 in vitro, identifying GTF2E1 as a target for a viral/cellular coactivator.","method":"Affinity purification of p100 using EBNA2 acidic domain, bacterially expressed p100 adsorption of TFIIE from nuclear extracts, in vitro binding with translated TFIIE subunits, co-immunoprecipitation from EBV-transformed lymphocyte extracts","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal binding assays (pulldown + CoIP + in vitro translation); single laboratory","pmids":["7651391"],"is_preprint":false},{"year":2000,"finding":"TFIIH ERCC3 subunit (XPB helicase) interacts with DNA downstream of the promoter melting region rather than within it. TFIIE, by interacting with ERCC3, participates in a 'molecular wrench' mechanism where TFIIH rotates downstream DNA relative to fixed upstream protein-DNA contacts to generate torsional stress that melts the promoter.","method":"Site-specific protein-DNA photocrosslinking, DNase I footprinting before and after open complex formation, mutational analysis","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — mechanistic dissection using site-specific crosslinking and footprinting; highly cited; defines mechanism involving TFIIE-TFIIH interaction","pmids":["10827951"],"is_preprint":false},{"year":2007,"finding":"Systematic affinity purification-mass spectrometry of the human transcription machinery identified GTF2E1 (TFIIE large subunit) as part of a high-confidence protein interaction network, confirming its stable associations within the RNA pol II transcription complex.","method":"Protein affinity purification coupled to mass spectrometry (AP-MS) of tagged transcription/RNA-processing factors","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 — large-scale MS interactome with high-confidence scoring; confirms known and reveals novel interactions","pmids":["17643375"],"is_preprint":false},{"year":2012,"finding":"Selective inhibition of Cdk7 (part of TFIIH) increases TFIIE retention on promoter-proximal paused RNA pol II complexes and prevents DSIF recruitment, demonstrating that TFIIE eviction from the elongating complex is dependent on Cdk7 activity within TFIIH — a process in which GTF2E1-containing TFIIE acts as a barrier to elongation factor engagement.","method":"Analog-sensitive kinase inhibition (Cdk7 inhibitor), ChIP-seq for TFIIE occupancy, nascent RNA analysis, DSIF recruitment assays in human cells","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 — clean chemical genetic approach with multiple orthogonal readouts in human cells; defines TFIIE role in initiation-to-elongation transition","pmids":["23064645"],"is_preprint":false},{"year":2016,"finding":"Cryo-EM structures of the human pre-initiation complex (PIC) at near-atomic resolution provided the first structural visualization of TFIIE (including GTF2E1/TFIIEα) within the PIC. TFIIE is positioned to contact both TFIIH and RNA pol II, and comparison of closed, open, and initially transcribing complex states reveals that TFIIE helps stabilize the transcription bubble during open complex formation.","method":"Cryo-electron microscopy (cryo-EM) of human PIC assembled on promoter DNA, structures of closed state, open state, and initially transcribing complex","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — near-atomic cryo-EM structures with functional state comparison; defines structural role of GTF2E1 in PIC","pmids":["27193682"],"is_preprint":false}],"current_model":"GTF2E1 encodes the large (α) subunit of the general transcription factor TFIIE, which is essential for RNA polymerase II transcription initiation: TFIIE (as a GTF2E1/GTF2E2 heterodimer) joins the pre-initiation complex by contacting both RNA pol II and TFIIH, negatively modulates TFIIH's XPB helicase activity to regulate ATP-dependent promoter melting via a molecular-wrench mechanism, stabilizes the transcription bubble during open complex formation (as seen by cryo-EM), must be evicted in a Cdk7-dependent manner to allow DSIF recruitment and transition to productive elongation, and serves as a direct binding target for transcriptional coactivators such as the EBNA2-associated protein p100."},"narrative":{"teleology":[{"year":1987,"claim":"Establishing that TFIIE is an obligatory general transcription factor for RNA pol II — biochemical fractionation showed that TFIIE is absolutely required for specific initiation at class II promoters and interacts independently with TFIIB and RNA pol II, defining it as a core PIC component.","evidence":"Purification from HeLa nuclear extracts with in vitro transcription reconstitution at the adenovirus major late promoter","pmids":["3029109"],"confidence":"High","gaps":["Subunit composition of TFIIE not yet determined","Molecular identity of TFIIE polypeptides unknown","Mechanism by which TFIIE contributes to initiation undefined"]},{"year":1991,"claim":"Revealing the heterodimeric architecture of TFIIE — cDNA cloning identified GTF2E1 as the large (56 kDa) subunit containing zinc-finger-like motifs, and reconstitution with recombinant subunits showed both subunits are required for PIC assembly and basal plus activated transcription.","evidence":"cDNA cloning, recombinant protein expression, in vitro transcription reconstitution","pmids":["1956398"],"confidence":"High","gaps":["Functional significance of zinc-finger-like motifs not tested by mutagenesis","Structural basis of subunit heterodimerization unknown"]},{"year":1994,"claim":"Connecting TFIIE to TFIIH regulation — the discovery that TFIIE directly binds the XPB/ERCC3 helicase subunit of TFIIH and negatively modulates its helicase activity established TFIIE as a regulator of the enzymatic activities needed for promoter melting.","evidence":"Direct interaction assays between purified TFIIE and ERCC3, helicase activity modulation assays in vitro","pmids":["8152490"],"confidence":"High","gaps":["Which subunit of TFIIE (α or β) mediates helicase inhibition not resolved","In vivo relevance of helicase modulation not demonstrated"]},{"year":1995,"claim":"Identifying GTF2E1 as a direct target for transcriptional coactivators — p100, an EBNA2-associated coactivator, was shown to bind both TFIIE subunits independently, revealing that basal factor contacts can be exploited for gene-specific activation.","evidence":"Affinity purification, in vitro binding with translated subunits, co-immunoprecipitation from EBV-transformed lymphocytes","pmids":["7651391"],"confidence":"Medium","gaps":["Functional consequence of p100–TFIIE interaction on transcription output not quantified","Binding interface not mapped at residue level","Not independently confirmed by a second laboratory"]},{"year":1997,"claim":"Defining the temporal requirement for TFIIE in open complex formation — reconstitution experiments showed TFIIE is required for the first ATP-dependent transition (promoter melting) but that continued TFIIH helicase activity regulated by TFIIE is needed only until the first few phosphodiester bonds are formed.","evidence":"In vitro transcription with stalling at defined positions, KMnO4 footprinting, ATPγS inhibition","pmids":["9405375"],"confidence":"High","gaps":["Structural basis of how TFIIE senses the length of nascent RNA is unknown","Mechanism of TFIIE release after initial transcription not addressed"]},{"year":2000,"claim":"Elucidating the molecular-wrench mechanism — site-specific crosslinking showed that TFIIH/XPB contacts downstream DNA and, together with TFIIE, generates torsional stress to melt the promoter rather than threading DNA through the helicase, resolving how TFIIE–TFIIH cooperation drives strand separation.","evidence":"Site-specific protein–DNA photocrosslinking, DNase I footprinting of closed and open complexes","pmids":["10827951"],"confidence":"High","gaps":["Exact contribution of TFIIE versus TFIIH to torque generation not quantified","No high-resolution structure of the TFIIE–XPB interface available"]},{"year":2012,"claim":"Establishing TFIIE as a gatekeeper of the initiation-to-elongation transition — chemical genetic inhibition of Cdk7 caused TFIIE retention on promoter-proximal complexes and blocked DSIF recruitment, demonstrating that Cdk7-dependent TFIIE eviction is a prerequisite for productive elongation.","evidence":"Analog-sensitive Cdk7 inhibition, ChIP-seq for TFIIE occupancy, DSIF recruitment assays in human cells","pmids":["23064645"],"confidence":"High","gaps":["Whether Cdk7 directly phosphorylates TFIIE or acts indirectly via CTD phosphorylation is unresolved","Genome-wide heterogeneity in TFIIE eviction kinetics not explored"]},{"year":2016,"claim":"Visualizing GTF2E1 within the PIC at near-atomic resolution — cryo-EM structures of the human PIC in closed, open, and initially transcribing states revealed how TFIIE bridges RNA pol II and TFIIH and stabilizes the transcription bubble, providing the first structural framework for its regulatory functions.","evidence":"Cryo-EM of human PIC assembled on promoter DNA at multiple functional states","pmids":["27193682"],"confidence":"High","gaps":["Dynamics of TFIIE conformational changes during the transition from closed to open complex not captured","Structure of TFIIE in the eviction/elongation transition state unavailable"]},{"year":null,"claim":"The mechanism by which Cdk7 activity triggers TFIIE release — whether through direct phosphorylation of GTF2E1/GTF2E2 or indirectly via CTD phosphorylation-induced conformational changes — remains unresolved, as does the structural basis of TFIIE's role as a barrier to elongation factor engagement.","evidence":"","pmids":[],"confidence":"High","gaps":["No identification of specific phosphorylation sites on TFIIE subunits relevant to eviction","No time-resolved structural data capturing TFIIE departure from the PIC","In vivo consequences of GTF2E1 loss-of-function in human cells not systematically characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140223","term_label":"general transcription initiation factor activity","supporting_discovery_ids":[0,1,5,10]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[7,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,7]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[9,10]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,5,7,9,10]}],"complexes":["TFIIE (GTF2E1/GTF2E2 heterodimer)","RNA polymerase II pre-initiation complex (PIC)"],"partners":["GTF2E2","ERCC3","GTF2B","POLR2A","SND1"],"other_free_text":[]},"mechanistic_narrative":"GTF2E1 encodes the large (α/56 kDa) subunit of general transcription factor IIE, an essential component of the RNA polymerase II pre-initiation complex that functions as a heterodimer with GTF2E2 to drive promoter opening and regulate the transition from initiation to elongation. TFIIE enters the PIC through direct contacts with both RNA pol II and the XPB helicase subunit of TFIIH, negatively modulating XPB helicase activity and participating in a molecular-wrench mechanism that generates torsional stress to melt promoter DNA during ATP-dependent open complex formation [PMID:8152490, PMID:10827951, PMID:9405375]. Cryo-EM structures show that TFIIE stabilizes the transcription bubble in the open and initially transcribing states, and Cdk7-dependent eviction of TFIIE from the elongating complex is required for DSIF recruitment and the transition to productive elongation [PMID:27193682, PMID:23064645]. GTF2E1 also serves as a direct binding target for the transcriptional coactivator p100, linking basal transcription factor architecture to gene-specific activation programs [PMID:7651391]."},"prefetch_data":{"uniprot":{"accession":"P29083","full_name":"General transcription factor IIE subunit 1","aliases":["General transcription factor IIE 56 kDa subunit","Transcription initiation factor IIE subunit alpha","TFIIE-alpha"],"length_aa":439,"mass_kda":49.5,"function":"Recruits TFIIH to the initiation complex and stimulates the RNA polymerase II C-terminal domain kinase and DNA-dependent ATPase activities of TFIIH. Both TFIIH and TFIIE are required for promoter clearance by RNA polymerase","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P29083/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/GTF2E1","classification":"Common Essential","n_dependent_lines":1193,"n_total_lines":1208,"dependency_fraction":0.9875827814569537},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GTF2E1","total_profiled":1310},"omim":[{"mim_id":"616943","title":"TRICHOTHIODYSTROPHY 6, NONPHOTOSENSITIVE; TTD6","url":"https://www.omim.org/entry/616943"},{"mim_id":"613644","title":"ACTIVATING TRANSCRIPTION FACTOR 7-INTERACTING PROTEIN; ATF7IP","url":"https://www.omim.org/entry/613644"},{"mim_id":"604328","title":"STRUCTURE-SPECIFIC RECOGNITION PROTEIN 1; SSRP1","url":"https://www.omim.org/entry/604328"},{"mim_id":"602955","title":"TAF6 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 80-KD; TAF6","url":"https://www.omim.org/entry/602955"},{"mim_id":"600475","title":"TAF10 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 30-KD; TAF10","url":"https://www.omim.org/entry/600475"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GTF2E1"},"hgnc":{"alias_symbol":["TFIIE-A","FE"],"prev_symbol":[]},"alphafold":{"accession":"P29083","domains":[{"cath_id":"1.10.10.10","chopping":"13-96_197-213","consensus_level":"medium","plddt":78.5556,"start":13,"end":213},{"cath_id":"3.30.40.10","chopping":"106-192","consensus_level":"medium","plddt":81.0278,"start":106,"end":192},{"cath_id":"-","chopping":"396-437","consensus_level":"high","plddt":85.5833,"start":396,"end":437}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P29083","model_url":"https://alphafold.ebi.ac.uk/files/AF-P29083-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P29083-F1-predicted_aligned_error_v6.png","plddt_mean":66.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GTF2E1","jax_strain_url":"https://www.jax.org/strain/search?query=GTF2E1"},"sequence":{"accession":"P29083","fasta_url":"https://rest.uniprot.org/uniprotkb/P29083.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P29083/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P29083"}},"corpus_meta":[{"pmid":"20547883","id":"PMC_20547883","title":"Humans 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America","url":"https://pubmed.ncbi.nlm.nih.gov/9159119","citation_count":405,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17643375","id":"PMC_17643375","title":"Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme.","date":"2007","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/17643375","citation_count":367,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34079125","id":"PMC_34079125","title":"A proximity-dependent biotinylation map of a human cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23064645","id":"PMC_23064645","title":"Cyclin-dependent kinase control of the initiation-to-elongation switch of RNA polymerase II.","date":"2012","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23064645","citation_count":326,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23251661","id":"PMC_23251661","title":"Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23251661","citation_count":312,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22863883","id":"PMC_22863883","title":"A high-throughput approach for measuring temporal changes in the interactome.","date":"2012","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/22863883","citation_count":273,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"3029109","id":"PMC_3029109","title":"Factors involved in specific transcription by mammalian RNA polymerase II. Purification and functional analysis of initiation factors IIB and IIE.","date":"1987","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3029109","citation_count":249,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8934526","id":"PMC_8934526","title":"Enhanced processivity of RNA polymerase II triggered by Tat-induced phosphorylation of its carboxy-terminal domain.","date":"1996","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/8934526","citation_count":245,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27193682","id":"PMC_27193682","title":"Near-atomic resolution visualization of human transcription promoter opening.","date":"2016","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/27193682","citation_count":241,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30033366","id":"PMC_30033366","title":"Mapping the Genetic Landscape of Human Cells.","date":"2018","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/30033366","citation_count":225,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10827951","id":"PMC_10827951","title":"Mechanism of ATP-dependent promoter melting by transcription factor IIH.","date":"2000","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/10827951","citation_count":221,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7651391","id":"PMC_7651391","title":"The Epstein-Barr virus nuclear protein 2 acidic domain forms a complex with a novel cellular coactivator that can interact with TFIIE.","date":"1995","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7651391","citation_count":212,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29568061","id":"PMC_29568061","title":"An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29568061","citation_count":201,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1956398","id":"PMC_1956398","title":"Structure and functional properties of human general transcription factor IIE.","date":"1991","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/1956398","citation_count":188,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23602568","id":"PMC_23602568","title":"The protein interaction landscape of the human CMGC kinase group.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/23602568","citation_count":174,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9405375","id":"PMC_9405375","title":"Three transitions in the RNA polymerase II transcription complex during initiation.","date":"1997","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9405375","citation_count":161,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32416067","id":"PMC_32416067","title":"Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer.","date":"2020","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/32416067","citation_count":159,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":42843,"output_tokens":142,"usd":0.065329},"stage2":{"model":"","input_tokens":0,"output_tokens":0,"usd":0.0},"total_usd":0.311717,"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":53669,"output_tokens":3486,"usd":0.106648},"round2_rules_fired":"R1","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6397,"output_tokens":2447,"usd":0.13974}},"stage1_raw":"Looking through all 100 abstracts, I need to identify papers about GTF2E1 (General Transcription Factor IIE Subunit 1, also known as TFIIE alpha). After carefully reviewing all abstracts, none of them describe GTF2E1/TFIIE. The entire corpus appears to be about iron-sulfur (Fe-S) cluster biology, iron chemistry, and related topics — with no papers about the transcription factor GTF2E1.\n\n```json\n{\n  \"discoveries\": [],\n  \"current_model\": \"No mechanistic findings in the available literature.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to identify papers actually about GTF2E1 (the large subunit of TFIIE, a general transcription factor for RNA polymerase II).\n\n**Classification:**\n\nThe 100 retrieved papers are almost entirely about Fe-S cluster biology, iron chemistry, and unrelated topics — clear contamination with \"Fe\" symbol collisions. None of these describe GTF2E1.\n\nThe 30 gene2pubmed-curated papers contain the relevant GTF2E1 papers. Let me identify KEEP papers:\n\n- PMID 8946909: General transcription factors of RNA pol II — KEEP (GTF2E1 is TFIIE large subunit)\n- PMID 8152490: TFIIH dual role, direct interaction between TFIIE and ERCC3/XPB — KEEP\n- PMID 3029109: Purification of TFIIB and TFIIE, functional analysis — KEEP\n- PMID 1956398: Structure and functional properties of human TFIIE, cDNA cloning of both subunits — KEEP\n- PMID 9159119: BRCA1 in RNA pol II holoenzyme, co-purifies TFIIE — KEEP\n- PMID 10827951: TFIIH mechanism of promoter melting — KEEP (TFIIE context)\n- PMID 8934526: Tat/TFIIH/CTD phosphorylation — KEEP (TFIIE involvement)\n- PMID 9405375: Three transitions in pol II transcription complex — KEEP\n- PMID 27193682: Cryo-EM of human PIC including TFIIE structure — KEEP\n- PMID 23064645: Cdk7/TFIIH/TFIIE in initiation-to-elongation switch — KEEP\n- PMID 17643375: Survey of transcription machinery interactions — KEEP\n- PMID 7651391: EBNA2/p100 coactivator interacts with TFIIE — KEEP\n- PMID 28514442, 33961781, 26496610, 22939629, 26344197, 34079125, 29568061: Interactome/proteome maps — these identify GTF2E1 interactions by MS; KEEP as interaction evidence\n- PMID 12477932: MGC cDNA sequencing — KEEP (sequence identification)\n- PMID 21873635, 16344560, 8125298, 20211142, 23251661, 22863883, 30033366, 23602568, 32416067: GWAS, promoter atlas, kinase interactome, CRISPR screens — mostly expression/association, EXCLUDE unless mechanistic\n\nLet me focus on mechanistic findings:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"Human TFIIE is a heterodimer composed of two subunits (56 kDa and 34 kDa; GTF2E1 encodes the large 56 kDa subunit). Both subunits are required to form a stable preinitiation complex and to reconstitute basal-level and Sp1-activated transcription in vitro. cDNA cloning revealed structural motifs including zinc-finger-like sequences in the large subunit.\",\n      \"method\": \"cDNA cloning, recombinant protein purification, in vitro transcription reconstitution assay, preinitiation complex assembly\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution of transcription with purified recombinant subunits, functional mutagenesis context, original discovery paper\",\n      \"pmids\": [\"1956398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"TFIIE (large subunit GTF2E1-containing complex) is absolutely required, together with TFIIA, TFIIB, TFIID, and RNA polymerase II, for specific transcription initiation at the adenovirus major late promoter and other class II promoters. TFIIE forms independent interactions with TFIIB and with RNA polymerase II but not RNA polymerase III, establishing its specificity for the pol II machinery.\",\n      \"method\": \"Biochemical purification from HeLa nuclear extracts, in vitro transcription assay, glycerol gradient sedimentation, preinitiation complex (heparin-resistant) formation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro transcription system with purified factors; replicated in subsequent studies\",\n      \"pmids\": [\"3029109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"TFIIE directly interacts with the ERCC3 (XPB) subunit of TFIIH, and this interaction negatively modulates the helicase activity of TFIIH. This places TFIIE (and its large subunit GTF2E1) as a regulator of TFIIH helicase activity during transcription initiation.\",\n      \"method\": \"Extensive purification of TFIIH, in vitro DNA excision repair complementation assays, direct interaction assays between TFIIE and ERCC3 subunit of TFIIH\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro interaction demonstrated and helicase modulation assayed; highly cited foundational study\",\n      \"pmids\": [\"8152490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"TFIIE is required for Tat-stimulated HIV-1 transcription in vitro. Tat interacts with a TFIIH-containing complex and stimulates TFIIH kinase-mediated phosphorylation of the RNA pol II CTD; TFIIE participates in the complex supporting this CTD phosphorylation and enhanced processivity.\",\n      \"method\": \"In vitro transcription assay, CTD phosphorylation assay, immunoprecipitation of TFIIH-containing complexes\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean biochemical dissection with purified factors; TFIIE role inferred from requirement in reconstituted system\",\n      \"pmids\": [\"8934526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"TFIIE (containing GTF2E1) is co-purified with the RNA polymerase II holoenzyme. Immunopurification of BRCA1 complexes specifically co-purifies transcriptionally active RNA pol II and TFIIE, placing GTF2E1-containing TFIIE as a stable holoenzyme-associated component.\",\n      \"method\": \"Multi-step chromatographic co-purification, immunopurification with anti-hSRB7 antibody, co-immunoprecipitation with anti-BRCA1 antibody\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-purification across multiple steps; single study\",\n      \"pmids\": [\"9159119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Analysis of transcription initiation revealed that TFIIE (GTF2E1-containing) is required for the ATP-dependent open complex formation (first transition). TFIIH helicase activity, which is regulated by TFIIE, is needed to maintain the open region only during formation of the first three phosphodiester bonds (up to the second transition at 4-nucleotide RNA).\",\n      \"method\": \"In vitro transcription with purified homogeneous proteins, stalling of pol II complex at defined positions, KMnO4 footprinting of open region, ATPγS inhibition experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro system with defined positions and chemical probing; rigorous mechanistic dissection\",\n      \"pmids\": [\"9405375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The novel cellular coactivator p100, which mediates EBNA2 transcriptional activation, directly binds TFIIE. Both the p56 (GTF2E1) and p34 subunits of TFIIE independently bind to p100 in vitro, identifying GTF2E1 as a target for a viral/cellular coactivator.\",\n      \"method\": \"Affinity purification of p100 using EBNA2 acidic domain, bacterially expressed p100 adsorption of TFIIE from nuclear extracts, in vitro binding with translated TFIIE subunits, co-immunoprecipitation from EBV-transformed lymphocyte extracts\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal binding assays (pulldown + CoIP + in vitro translation); single laboratory\",\n      \"pmids\": [\"7651391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TFIIH ERCC3 subunit (XPB helicase) interacts with DNA downstream of the promoter melting region rather than within it. TFIIE, by interacting with ERCC3, participates in a 'molecular wrench' mechanism where TFIIH rotates downstream DNA relative to fixed upstream protein-DNA contacts to generate torsional stress that melts the promoter.\",\n      \"method\": \"Site-specific protein-DNA photocrosslinking, DNase I footprinting before and after open complex formation, mutational analysis\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mechanistic dissection using site-specific crosslinking and footprinting; highly cited; defines mechanism involving TFIIE-TFIIH interaction\",\n      \"pmids\": [\"10827951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Systematic affinity purification-mass spectrometry of the human transcription machinery identified GTF2E1 (TFIIE large subunit) as part of a high-confidence protein interaction network, confirming its stable associations within the RNA pol II transcription complex.\",\n      \"method\": \"Protein affinity purification coupled to mass spectrometry (AP-MS) of tagged transcription/RNA-processing factors\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — large-scale MS interactome with high-confidence scoring; confirms known and reveals novel interactions\",\n      \"pmids\": [\"17643375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Selective inhibition of Cdk7 (part of TFIIH) increases TFIIE retention on promoter-proximal paused RNA pol II complexes and prevents DSIF recruitment, demonstrating that TFIIE eviction from the elongating complex is dependent on Cdk7 activity within TFIIH — a process in which GTF2E1-containing TFIIE acts as a barrier to elongation factor engagement.\",\n      \"method\": \"Analog-sensitive kinase inhibition (Cdk7 inhibitor), ChIP-seq for TFIIE occupancy, nascent RNA analysis, DSIF recruitment assays in human cells\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean chemical genetic approach with multiple orthogonal readouts in human cells; defines TFIIE role in initiation-to-elongation transition\",\n      \"pmids\": [\"23064645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cryo-EM structures of the human pre-initiation complex (PIC) at near-atomic resolution provided the first structural visualization of TFIIE (including GTF2E1/TFIIEα) within the PIC. TFIIE is positioned to contact both TFIIH and RNA pol II, and comparison of closed, open, and initially transcribing complex states reveals that TFIIE helps stabilize the transcription bubble during open complex formation.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM) of human PIC assembled on promoter DNA, structures of closed state, open state, and initially transcribing complex\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — near-atomic cryo-EM structures with functional state comparison; defines structural role of GTF2E1 in PIC\",\n      \"pmids\": [\"27193682\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GTF2E1 encodes the large (α) subunit of the general transcription factor TFIIE, which is essential for RNA polymerase II transcription initiation: TFIIE (as a GTF2E1/GTF2E2 heterodimer) joins the pre-initiation complex by contacting both RNA pol II and TFIIH, negatively modulates TFIIH's XPB helicase activity to regulate ATP-dependent promoter melting via a molecular-wrench mechanism, stabilizes the transcription bubble during open complex formation (as seen by cryo-EM), must be evicted in a Cdk7-dependent manner to allow DSIF recruitment and transition to productive elongation, and serves as a direct binding target for transcriptional coactivators such as the EBNA2-associated protein p100.\"\n}\n```","stage2_raw":"\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"GTF2E1 encodes the large (α/56 kDa) subunit of general transcription factor IIE, an essential component of the RNA polymerase II pre-initiation complex that functions as a heterodimer with GTF2E2 to drive promoter opening and regulate the transition from initiation to elongation. TFIIE enters the PIC through direct contacts with both RNA pol II and the XPB helicase subunit of TFIIH, negatively modulating XPB helicase activity and participating in a molecular-wrench mechanism that generates torsional stress to melt promoter DNA during ATP-dependent open complex formation [PMID:8152490, PMID:10827951, PMID:9405375]. Cryo-EM structures show that TFIIE stabilizes the transcription bubble in the open and initially transcribing states, and Cdk7-dependent eviction of TFIIE from the elongating complex is required for DSIF recruitment and the transition to productive elongation [PMID:27193682, PMID:23064645]. GTF2E1 also serves as a direct binding target for the transcriptional coactivator p100, linking basal transcription factor architecture to gene-specific activation programs [PMID:7651391].\",\n  \"teleology\": [\n    {\n      \"year\": 1987,\n      \"claim\": \"Establishing that TFIIE is an obligatory general transcription factor for RNA pol II — biochemical fractionation showed that TFIIE is absolutely required for specific initiation at class II promoters and interacts independently with TFIIB and RNA pol II, defining it as a core PIC component.\",\n      \"evidence\": \"Purification from HeLa nuclear extracts with in vitro transcription reconstitution at the adenovirus major late promoter\",\n      \"pmids\": [\"3029109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Subunit composition of TFIIE not yet determined\",\n        \"Molecular identity of TFIIE polypeptides unknown\",\n        \"Mechanism by which TFIIE contributes to initiation undefined\"\n      ]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Revealing the heterodimeric architecture of TFIIE — cDNA cloning identified GTF2E1 as the large (56 kDa) subunit containing zinc-finger-like motifs, and reconstitution with recombinant subunits showed both subunits are required for PIC assembly and basal plus activated transcription.\",\n      \"evidence\": \"cDNA cloning, recombinant protein expression, in vitro transcription reconstitution\",\n      \"pmids\": [\"1956398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional significance of zinc-finger-like motifs not tested by mutagenesis\",\n        \"Structural basis of subunit heterodimerization unknown\"\n      ]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Connecting TFIIE to TFIIH regulation — the discovery that TFIIE directly binds the XPB/ERCC3 helicase subunit of TFIIH and negatively modulates its helicase activity established TFIIE as a regulator of the enzymatic activities needed for promoter melting.\",\n      \"evidence\": \"Direct interaction assays between purified TFIIE and ERCC3, helicase activity modulation assays in vitro\",\n      \"pmids\": [\"8152490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which subunit of TFIIE (α or β) mediates helicase inhibition not resolved\",\n        \"In vivo relevance of helicase modulation not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identifying GTF2E1 as a direct target for transcriptional coactivators — p100, an EBNA2-associated coactivator, was shown to bind both TFIIE subunits independently, revealing that basal factor contacts can be exploited for gene-specific activation.\",\n      \"evidence\": \"Affinity purification, in vitro binding with translated subunits, co-immunoprecipitation from EBV-transformed lymphocytes\",\n      \"pmids\": [\"7651391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of p100–TFIIE interaction on transcription output not quantified\",\n        \"Binding interface not mapped at residue level\",\n        \"Not independently confirmed by a second laboratory\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defining the temporal requirement for TFIIE in open complex formation — reconstitution experiments showed TFIIE is required for the first ATP-dependent transition (promoter melting) but that continued TFIIH helicase activity regulated by TFIIE is needed only until the first few phosphodiester bonds are formed.\",\n      \"evidence\": \"In vitro transcription with stalling at defined positions, KMnO4 footprinting, ATPγS inhibition\",\n      \"pmids\": [\"9405375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of how TFIIE senses the length of nascent RNA is unknown\",\n        \"Mechanism of TFIIE release after initial transcription not addressed\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Elucidating the molecular-wrench mechanism — site-specific crosslinking showed that TFIIH/XPB contacts downstream DNA and, together with TFIIE, generates torsional stress to melt the promoter rather than threading DNA through the helicase, resolving how TFIIE–TFIIH cooperation drives strand separation.\",\n      \"evidence\": \"Site-specific protein–DNA photocrosslinking, DNase I footprinting of closed and open complexes\",\n      \"pmids\": [\"10827951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Exact contribution of TFIIE versus TFIIH to torque generation not quantified\",\n        \"No high-resolution structure of the TFIIE–XPB interface available\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing TFIIE as a gatekeeper of the initiation-to-elongation transition — chemical genetic inhibition of Cdk7 caused TFIIE retention on promoter-proximal complexes and blocked DSIF recruitment, demonstrating that Cdk7-dependent TFIIE eviction is a prerequisite for productive elongation.\",\n      \"evidence\": \"Analog-sensitive Cdk7 inhibition, ChIP-seq for TFIIE occupancy, DSIF recruitment assays in human cells\",\n      \"pmids\": [\"23064645\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Cdk7 directly phosphorylates TFIIE or acts indirectly via CTD phosphorylation is unresolved\",\n        \"Genome-wide heterogeneity in TFIIE eviction kinetics not explored\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Visualizing GTF2E1 within the PIC at near-atomic resolution — cryo-EM structures of the human PIC in closed, open, and initially transcribing states revealed how TFIIE bridges RNA pol II and TFIIH and stabilizes the transcription bubble, providing the first structural framework for its regulatory functions.\",\n      \"evidence\": \"Cryo-EM of human PIC assembled on promoter DNA at multiple functional states\",\n      \"pmids\": [\"27193682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Dynamics of TFIIE conformational changes during the transition from closed to open complex not captured\",\n        \"Structure of TFIIE in the eviction/elongation transition state unavailable\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which Cdk7 activity triggers TFIIE release — whether through direct phosphorylation of GTF2E1/GTF2E2 or indirectly via CTD phosphorylation-induced conformational changes — remains unresolved, as does the structural basis of TFIIE's role as a barrier to elongation factor engagement.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No identification of specific phosphorylation sites on TFIIE subunits relevant to eviction\",\n        \"No time-resolved structural data capturing TFIIE departure from the PIC\",\n        \"In vivo consequences of GTF2E1 loss-of-function in human cells not systematically characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140223\", \"supporting_discovery_ids\": [0, 1, 5, 10]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 5, 7, 9, 10]}\n    ],\n    \"complexes\": [\n      \"TFIIE (GTF2E1/GTF2E2 heterodimer)\",\n      \"RNA polymerase II pre-initiation complex (PIC)\"\n    ],\n    \"partners\": [\n      \"GTF2E2\",\n      \"ERCC3\",\n      \"GTF2B\",\n      \"POLR2A\",\n      \"SND1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}