{"gene":"GTF2E2","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1987,"finding":"TFIIE (containing the TFIIEβ/p34 subunit) was purified from HeLa nuclear extracts and shown to be absolutely required, together with TFIIA, TFIID, TFIIB, and RNA polymerase II, for specific transcription initiation at class II promoters. TFIIE was found to interact independently with TFIIB and with purified RNA polymerase II, but not RNA polymerase III, establishing its role as a basal initiation factor.","method":"Biochemical purification, glycerol gradient sedimentation, in vitro transcription reconstitution","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with purified components, multiple functional assays","pmids":["3029109"],"is_preprint":false},{"year":1991,"finding":"Human TFIIE is a heterodimer composed of two subunits (TFIIEα/p56 and TFIIEβ/p34, the latter encoded by GTF2E2). Both subunits are essential to form a stable preinitiation complex and to reconstitute basal-level and Sp1-activated transcription in vitro. Sequence analysis revealed structural motifs relevant to transcription initiation.","method":"cDNA cloning, recombinant protein expression, in vitro transcription reconstitution, preinitiation complex assembly assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — reconstituted transcription with purified recombinant subunits, both subunits individually tested","pmids":["1956398"],"is_preprint":false},{"year":1994,"finding":"TFIIE (via its 56-kD subunit TFIIEα) binds selectively to the nonphosphorylated form of RNA polymerase II (IIa), interacts with TBP/TFIID and TFIIF subunits, and recruits TFIIH to the transcription complex through a direct interaction with ERCC3 (XPB subunit of TFIIH). The small subunit of TFIIE (TFIIEβ/p34, encoded by GTF2E2) also participates in TFIIF interaction. This supports a model in which TFIIE plays a role in promoter clearance and recruitment of TFIIH.","method":"Protein affinity binding assays, affinity resin pulldowns, in vitro transcription","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding assays with purified proteins, functional transcription reconstitution","pmids":["7926747"],"is_preprint":false},{"year":1994,"finding":"TFIIE negatively modulates the helicase activity of TFIIH through a direct interaction between TFIIE and the ERCC3 (XPB) subunit of TFIIH, as demonstrated in transcription and DNA repair reconstitution assays.","method":"In vitro transcription/repair reconstitution, direct protein interaction assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with purified components showing functional consequence","pmids":["8152490"],"is_preprint":false},{"year":1995,"finding":"The p34 subunit of TFIIE (TFIIEβ, encoded by GTF2E2) was found to bind specifically to the DNA repair/transcription coupling protein XPA, in competition with the p56 subunit of TFIIE. Separately, the coactivator p100 bound both subunits (p56 and p34) of TFIIE independently in vitro, suggesting TFIIEβ is accessible for protein interactions relevant to transcription activation.","method":"Protein binding/affinity assays, co-immunoprecipitation, in vitro binding with translated subunits","journal":"The Journal of biological chemistry / Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct binding assays, single-lab studies each with one main method","pmids":["7876263","7651391"],"is_preprint":false},{"year":1997,"finding":"MDM2 directly binds the small subunit of TFIIE (TFIIEβ/p34, encoded by GTF2E2) through its inhibitory domain (amino acids 50–222). This interaction, along with MDM2 binding to monomeric TBP, contributes to direct repression of basal transcription, suggesting MDM2 interferes with preinitiation complex function via TFIIEβ.","method":"Protein affinity binding, GST pulldown, in vitro transcription with MDM2 domain fusions","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding mapped to specific domain with functional transcription repression readout, single lab","pmids":["9271120"],"is_preprint":false},{"year":1997,"finding":"CSB (ERCC6), the transcription-repair coupling factor, binds the p34 subunit of TFIIE (TFIIEβ, encoded by GTF2E2) as well as XPA and TFIIH, suggesting TFIIEβ participates in protein interaction networks linking transcription initiation and DNA repair.","method":"Direct protein binding assays with purified recombinant CSB and TFIIE subunits","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct biochemical binding demonstrated with purified proteins, single lab","pmids":["8999876"],"is_preprint":false},{"year":1997,"finding":"During transcription initiation, TFIIH requires TFIIE to maintain the open transcription bubble only during formation of the first three phosphodiester bonds (up to a 4-nt RNA). After this second transition, the open complex is no longer sensitive to ATPγS, indicating TFIIE and TFIIH cooperate specifically during early stages of transcript synthesis.","method":"In vitro transcription with stalled complexes, ATPγS sensitivity assays, defined-position stalling on adenovirus major late promoter","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with purified homogeneous proteins, mechanistic transitions precisely mapped","pmids":["9405375"],"is_preprint":false},{"year":2000,"finding":"TFIIH's ERCC3 (XPB) subunit, which mediates ATP-dependent promoter melting, interacts with DNA downstream of the melting region (not the region undergoing melting itself). TFIIE is positioned upstream and its fixed protein-DNA interactions provide the fulcrum for TFIIH's proposed molecular wrench mechanism for promoter opening.","method":"DNA footprinting, protein-DNA crosslinking, in vitro transcription with mutant templates","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — mechanistic dissection by multiple orthogonal methods in vitro","pmids":["10827951"],"is_preprint":false},{"year":2012,"finding":"Selective inhibition of Cdk7 (part of TFIIH) increases TFIIE retention at promoters and prevents DRB sensitivity-inducing factor (DSIF) recruitment, attenuating pausing in human cells. This places TFIIE (including TFIIEβ) downstream of Cdk7 phosphorylation in the initiation-to-elongation switch, where TFIIE must be evicted before elongation factors can engage.","method":"Selective Cdk7 inhibition (analog-sensitive kinase), ChIP, in vivo functional assays in human cells","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 — clean chemical-genetic inhibition with ChIP readout, mechanistic pathway placement in human cells","pmids":["23064645"],"is_preprint":false},{"year":2016,"finding":"Cryo-EM structures of the human pre-initiation complex (PIC) in closed, open, and initially transcribing states provided near-atomic resolution views of TFIIE (both subunits, including TFIIEβ/GTF2E2) within the PIC. TFIIE is shown to stabilize the transcription bubble and undergoes conformational changes during the transition from closed to open complex, with TFIIB playing a key role in bubble stabilization.","method":"Cryo-electron microscopy at near-atomic resolution, comparison of three PIC states","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures of multiple PIC states with functional interpretation","pmids":["27193682"],"is_preprint":false},{"year":2016,"finding":"Homozygous missense mutations in GTF2E2 (p.Ala150Pro and p.Asp187Tyr in TFIIEβ) cause trichothiodystrophy (TTD) without a DNA repair defect (normal NER). These mutations decrease protein levels of both TFIIE subunits (TFIIEα and TFIIEβ), reduce phosphorylation of TFIIEα, and destabilize the TFIIE complex, establishing that TFIIE mutations cause TTD through impaired transcription rather than NER.","method":"Patient cell studies, immunoblotting, UV damage repair assays (NER normal), phosphorylation analysis, clinical genetics","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — disease-causing mutations characterized with multiple cellular assays, NER exclusion, two independent patients","pmids":["26996949"],"is_preprint":false},{"year":2021,"finding":"Knockdown of GTF2E2 in lung adenocarcinoma cells inhibits proliferation, migration, invasion, and promotes apoptosis in vitro, and attenuates tumor growth in vivo. LC-MS/MS identified RPS4X as a physical interaction partner of GTF2E2, and GTF2E2 was found to promote tumor development by activating RPS4X-mediated mTOR pathway signaling.","method":"shRNA knockdown, in vitro proliferation/migration/invasion/apoptosis assays, xenograft mouse model, LC-MS/MS interactome, mTOR pathway analysis","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2–3 — loss-of-function with defined cellular phenotypes and MS-identified interaction, single lab, pathway placement partially indirect","pmids":["33757492"],"is_preprint":false}],"current_model":"GTF2E2 encodes TFIIEβ (p34), the small subunit of the general transcription factor TFIIE, which heterodimerizes with TFIIEα (p56) and is essential for RNA polymerase II preinitiation complex assembly, promoter opening, and the transition from initiation to elongation: TFIIEβ participates in binding RNA pol IIa and in recruiting TFIIH to the promoter (via TFIIEα–ERCC3 interaction), cooperates with TFIIH to maintain the open transcription bubble during early transcript synthesis, must be evicted (via Cdk7-dependent phosphorylation) for productive elongation to proceed, and its destabilization by missense mutations causes the multisystem developmental disorder trichothiodystrophy through impaired transcription rather than DNA repair defects."},"narrative":{"teleology":[{"year":1987,"claim":"Establishing that TFIIE (containing the future-named TFIIEβ subunit) is an indispensable basal transcription factor for RNA polymerase II resolved its requirement alongside TFIIA, TFIIB, TFIID, and Pol II for specific promoter-directed initiation.","evidence":"Biochemical purification from HeLa nuclear extracts and reconstituted in vitro transcription","pmids":["3029109"],"confidence":"High","gaps":["Individual subunit contributions not yet separated","Mechanism of TFIIE action within the PIC unknown"]},{"year":1991,"claim":"Identification and cloning of the two TFIIE subunits (α/p56 and β/p34) demonstrated that both are individually required for preinitiation complex assembly and basal transcription, defining the heterodimeric architecture of the factor.","evidence":"cDNA cloning, recombinant protein expression, reconstituted transcription assays","pmids":["1956398"],"confidence":"High","gaps":["Protein–protein interactions within the PIC not mapped","Structural basis of heterodimerization unknown"]},{"year":1994,"claim":"Mapping interaction partners showed that TFIIEα selectively binds nonphosphorylated Pol II and recruits TFIIH via ERCC3, while TFIIEβ contacts TFIIF; additionally, TFIIE negatively modulates TFIIH helicase activity, placing TFIIE as a regulatory bridge between Pol II binding and TFIIH function.","evidence":"Affinity pulldown assays with purified proteins, in vitro transcription and DNA repair reconstitution","pmids":["7926747","8152490"],"confidence":"High","gaps":["Whether TFIIEβ directly contacts TFIIH remained unclear","Structural topology of TFIIE within the PIC not resolved"]},{"year":1995,"claim":"Discovery that TFIIEβ directly binds the NER factor XPA and the coactivator p100 expanded its interaction network beyond core PIC components, suggesting roles at the transcription–repair interface.","evidence":"In vitro protein binding and co-immunoprecipitation assays","pmids":["7876263","7651391"],"confidence":"Medium","gaps":["Functional consequences of XPA–TFIIEβ binding on transcription or repair not demonstrated","No in vivo validation"]},{"year":1997,"claim":"Binding of MDM2 and CSB to TFIIEβ identified it as a convergence point for transcriptional repression and transcription-coupled repair, while reconstitution experiments pinpointed that TFIIE–TFIIH cooperation maintains the open bubble only during synthesis of the first 3–4 nucleotides, precisely defining the temporal window of TFIIE function.","evidence":"GST pulldown with MDM2 domain fusions and in vitro transcription repression; purified protein binding for CSB; stalled-complex transcription assays with ATPγS sensitivity","pmids":["9271120","8999876","9405375"],"confidence":"High","gaps":["Whether MDM2–TFIIEβ interaction occurs at endogenous promoters in vivo unknown","Mechanism by which TFIIE is released after the transition not identified"]},{"year":2000,"claim":"DNA footprinting and crosslinking revealed that TFIIE is positioned upstream of the melting region and provides a fixed anchor (fulcrum) for TFIIH’s molecular-wrench mechanism of promoter opening, explaining how TFIIE’s protein–DNA contacts contribute to strand separation.","evidence":"DNA footprinting, protein–DNA crosslinking, mutant template analysis in vitro","pmids":["10827951"],"confidence":"High","gaps":["Exact residues of TFIIEβ contacting DNA not identified","Model inferred from footprinting, not atomic structure"]},{"year":2012,"claim":"Chemical-genetic inhibition of Cdk7 in human cells showed that TFIIE retention at promoters blocks elongation factor (DSIF) recruitment, establishing that Cdk7-dependent phosphorylation drives TFIIE eviction as a prerequisite for the initiation-to-elongation transition in vivo.","evidence":"Analog-sensitive Cdk7 inhibition, ChIP in human cells","pmids":["23064645"],"confidence":"High","gaps":["Whether Cdk7 directly phosphorylates TFIIEβ or acts indirectly (e.g., through Pol II CTD) not resolved","Genome-wide generality of TFIIE eviction requirement not tested"]},{"year":2016,"claim":"Cryo-EM structures of the human PIC in closed, open, and initially transcribing states provided near-atomic views of TFIIEβ within the complex, showing conformational rearrangements during bubble opening, while independent genetic studies demonstrated that homozygous missense mutations in GTF2E2 destabilize the TFIIE heterodimer and cause trichothiodystrophy through impaired transcription (not NER).","evidence":"Cryo-EM at near-atomic resolution of three PIC states; patient cell analysis with immunoblotting, UV-repair assays, and phosphorylation studies in two unrelated families","pmids":["27193682","26996949"],"confidence":"High","gaps":["High-resolution structure of TFIIEβ disease mutants within the PIC not available","Specific transcriptional targets affected in TTD patient cells not identified"]},{"year":2021,"claim":"Knockdown of GTF2E2 in lung adenocarcinoma cells implicated it in promoting proliferation and mTOR pathway activation through interaction with RPS4X, extending its functional relevance beyond basal transcription to cancer cell biology.","evidence":"shRNA knockdown, proliferation/migration/invasion assays, xenograft model, LC-MS/MS interactome","pmids":["33757492"],"confidence":"Medium","gaps":["RPS4X interaction not confirmed by reciprocal pulldown or structural data","Whether mTOR activation is a direct consequence of GTF2E2–RPS4X interaction or indirect transcriptional effect is unclear","Single-lab finding without independent replication"]},{"year":null,"claim":"Key unresolved questions include the identity of the direct phosphorylation event(s) that trigger TFIIE eviction during promoter escape, the structural basis of disease-causing GTF2E2 mutations within the PIC, and the specific transcriptional programs impaired in trichothiodystrophy caused by TFIIEβ deficiency.","evidence":"","pmids":[],"confidence":"High","gaps":["Direct Cdk7 substrate site(s) on TFIIE subunits not mapped","Atomic-resolution structure of mutant TFIIE in the PIC unavailable","Genome-wide transcriptional consequences of GTF2E2 mutations not profiled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140223","term_label":"general transcription initiation factor activity","supporting_discovery_ids":[0,1,7,10]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,10]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,7,9,10,11]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3,4,6]}],"complexes":["TFIIE (TFIIEα–TFIIEβ heterodimer)","RNA Polymerase II preinitiation complex (PIC)"],"partners":["GTF2E1","ERCC3","GTF2F1","XPA","ERCC6","MDM2","RPS4X"],"other_free_text":[]},"mechanistic_narrative":"GTF2E2 encodes TFIIEβ (p34), the small subunit of the general transcription factor TFIIE, which heterodimerizes with TFIIEα (p56) and is essential for RNA polymerase II preinitiation complex (PIC) assembly, promoter opening, and the transition from transcription initiation to elongation. Within the PIC, TFIIEβ participates in binding the nonphosphorylated form of RNA polymerase II and TFIIF, while the heterodimer recruits TFIIH via TFIIEα–ERCC3 interaction, and cooperates with TFIIH to maintain the open transcription bubble during synthesis of the first few nucleotides; Cdk7-dependent phosphorylation subsequently triggers TFIIE eviction, permitting elongation factor engagement [PMID:7926747, PMID:9405375, PMID:23064645, PMID:27193682]. TFIIEβ also serves as a direct binding target for the transcriptional repressor MDM2, the nucleotide excision repair factors XPA and CSB, and the coactivator p100, positioning it at the interface of transcription and DNA repair signaling [PMID:7876263, PMID:9271120, PMID:8999876]. Homozygous missense mutations in GTF2E2 that destabilize the TFIIE heterodimer cause trichothiodystrophy without a DNA repair defect, demonstrating that disease pathogenesis proceeds through impaired transcription [PMID:26996949]."},"prefetch_data":{"uniprot":{"accession":"P29084","full_name":"Transcription initiation factor IIE subunit beta","aliases":["General transcription factor IIE subunit 2"],"length_aa":291,"mass_kda":33.0,"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/P29084/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/GTF2E2","classification":"Common Essential","n_dependent_lines":1200,"n_total_lines":1208,"dependency_fraction":0.9933774834437086},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GTF2E2","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":"602955","title":"TAF6 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 80-KD; TAF6","url":"https://www.omim.org/entry/602955"},{"mim_id":"601675","title":"TRICHOTHIODYSTROPHY 1, PHOTOSENSITIVE; TTD1","url":"https://www.omim.org/entry/601675"},{"mim_id":"189964","title":"GENERAL TRANSCRIPTION FACTOR IIE, POLYPEPTIDE 2; GTF2E2","url":"https://www.omim.org/entry/189964"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GTF2E2"},"hgnc":{"alias_symbol":["TFIIE-B","FE","TF2E2"],"prev_symbol":[]},"alphafold":{"accession":"P29084","domains":[{"cath_id":"1.10.10.10","chopping":"69-138","consensus_level":"high","plddt":69.6117,"start":69,"end":138},{"cath_id":"1.10.10","chopping":"147-202","consensus_level":"high","plddt":82.8137,"start":147,"end":202}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P29084","model_url":"https://alphafold.ebi.ac.uk/files/AF-P29084-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P29084-F1-predicted_aligned_error_v6.png","plddt_mean":68.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GTF2E2","jax_strain_url":"https://www.jax.org/strain/search?query=GTF2E2"},"sequence":{"accession":"P29084","fasta_url":"https://rest.uniprot.org/uniprotkb/P29084.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P29084/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P29084"}},"corpus_meta":[{"pmid":"9092471","id":"PMC_9092471","title":"Activated acetic acid by carbon fixation on (Fe,Ni)S under primordial conditions.","date":"1997","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9092471","citation_count":357,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20547883","id":"PMC_20547883","title":"Humans possess two mitochondrial ferredoxins, Fdx1 and Fdx2, with distinct roles in steroidogenesis, heme, and Fe/S cluster biosynthesis.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20547883","citation_count":318,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10916152","id":"PMC_10916152","title":"Maturation of cellular Fe-S proteins: an essential function of mitochondria.","date":"2000","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/10916152","citation_count":297,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12732309","id":"PMC_12732309","title":"The role of Fe-S proteins in sensing and regulation in bacteria.","date":"2003","source":"Current opinion in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12732309","citation_count":280,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3022944","id":"PMC_3022944","title":"Transport into mitochondria and intramitochondrial sorting of the Fe/S protein of ubiquinol-cytochrome c reductase.","date":"1986","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/3022944","citation_count":266,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23812717","id":"PMC_23812717","title":"Fe-S cluster biosynthesis controls uptake of aminoglycosides in a ROS-less death pathway.","date":"2013","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23812717","citation_count":186,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25655665","id":"PMC_25655665","title":"Emerging critical roles of Fe-S clusters in DNA replication and repair.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25655665","citation_count":182,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29097656","id":"PMC_29097656","title":"Structure and functional dynamics of the mitochondrial Fe/S cluster synthesis complex.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29097656","citation_count":159,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9360608","id":"PMC_9360608","title":"Structure of Haemophilus influenzae Fe(+3)-binding protein reveals convergent evolution within a superfamily.","date":"1997","source":"Nature structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/9360608","citation_count":149,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19478995","id":"PMC_19478995","title":"Iron-sulfur (Fe/S) protein biogenesis: phylogenomic and genetic studies of A-type carriers.","date":"2009","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19478995","citation_count":146,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9171919","id":"PMC_9171919","title":"Superoxide-driven aconitase FE-S center cycling.","date":"1997","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/9171919","citation_count":144,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24971490","id":"PMC_24971490","title":"Human frataxin activates Fe-S cluster biosynthesis by facilitating sulfur transfer chemistry.","date":"2014","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24971490","citation_count":133,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14769015","id":"PMC_14769015","title":"Substrate interactions with nitrogenase: Fe versus Mo.","date":"2004","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14769015","citation_count":131,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28634302","id":"PMC_28634302","title":"Structure of human Fe-S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP-ISD11 interactions.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28634302","citation_count":126,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19921534","id":"PMC_19921534","title":"Manganese (Mn) and iron (Fe): interdependency of transport and regulation.","date":"2009","source":"Neurotoxicity research","url":"https://pubmed.ncbi.nlm.nih.gov/19921534","citation_count":123,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7142189","id":"PMC_7142189","title":"Synthesis of either Fe- or Mn-superoxide dismutase with an apparently identical protein moiety by an anaerobic bacterium dependent on the metal supplied.","date":"1982","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7142189","citation_count":122,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25153801","id":"PMC_25153801","title":"Interplay between oxygen and Fe-S cluster biogenesis: insights from the Suf pathway.","date":"2014","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25153801","citation_count":117,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32806787","id":"PMC_32806787","title":"The Role of Fe, Zn, and Cu in Pregnancy.","date":"2020","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/32806787","citation_count":114,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10966385","id":"PMC_10966385","title":"Direct and Fe(II)-mediated reduction of technetium by Fe(III)-reducing bacteria.","date":"2000","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/10966385","citation_count":113,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16535116","id":"PMC_16535116","title":"Controlled Biomineralization of Magnetite (Fe(inf3)O(inf4)) and Greigite (Fe(inf3)S(inf4)) in a Magnetotactic Bacterium.","date":"1995","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16535116","citation_count":111,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32311335","id":"PMC_32311335","title":"Outlining the Complex Pathway of Mammalian Fe-S Cluster Biogenesis.","date":"2020","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32311335","citation_count":106,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15753101","id":"PMC_15753101","title":"A putative function for the arabidopsis Fe-Phytosiderophore transporter homolog AtYSL2 in Fe and Zn homeostasis.","date":"2005","source":"Plant & cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15753101","citation_count":106,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9073575","id":"PMC_9073575","title":"Interplay between NO and [Fe-S] clusters: relevance to biological systems.","date":"1997","source":"Methods (San Diego, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/9073575","citation_count":99,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24793112","id":"PMC_24793112","title":"Fe@Fe2O3 core-shell nanowires enhanced Fenton oxidation by accelerating the Fe(III)/Fe(II) cycles.","date":"2014","source":"Water research","url":"https://pubmed.ncbi.nlm.nih.gov/24793112","citation_count":97,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25498248","id":"PMC_25498248","title":"Mössbauer spectroscopy of Fe/S proteins.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25498248","citation_count":95,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23542644","id":"PMC_23542644","title":"Two Fe-S clusters catalyze sulfur insertion by radical-SAM methylthiotransferases.","date":"2013","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/23542644","citation_count":94,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16278209","id":"PMC_16278209","title":"The [Fe-Fe]-hydrogenase maturation protein HydF from Thermotoga maritima is a GTPase with an iron-sulfur cluster.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16278209","citation_count":93,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18638577","id":"PMC_18638577","title":"Proteome of Geobacter sulfurreducens grown with Fe(III) oxide or Fe(III) citrate as the electron acceptor.","date":"2008","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/18638577","citation_count":92,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22687047","id":"PMC_22687047","title":"Glutathione complexed Fe-S centers.","date":"2012","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/22687047","citation_count":91,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24440636","id":"PMC_24440636","title":"Mammalian Fe-S cluster biogenesis and its implication in disease.","date":"2014","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/24440636","citation_count":89,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25510311","id":"PMC_25510311","title":"Assembly of Fe/S proteins in bacterial systems: Biochemistry of the bacterial ISC system.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25510311","citation_count":81,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19810706","id":"PMC_19810706","title":"The SufBCD Fe-S scaffold complex interacts with SufA for Fe-S cluster transfer.","date":"2009","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19810706","citation_count":80,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32822728","id":"PMC_32822728","title":"Fe-S cluster biogenesis by the bacterial Suf pathway.","date":"2020","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32822728","citation_count":74,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11443088","id":"PMC_11443088","title":"Isolation and characterization of anaerobic ethylbenzene dehydrogenase, a novel Mo-Fe-S enzyme.","date":"2001","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/11443088","citation_count":74,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26488283","id":"PMC_26488283","title":"How Is Fe-S Cluster Formation Regulated?","date":"2015","source":"Annual review of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/26488283","citation_count":72,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14705938","id":"PMC_14705938","title":"Crystal structure of the ancient, Fe-S scaffold IscA reveals a novel protein fold.","date":"2004","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14705938","citation_count":65,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35794270","id":"PMC_35794270","title":"Nitrogen reduction by the Fe sites of synthetic [Mo3S4Fe] cubes.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/35794270","citation_count":64,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11348071","id":"PMC_11348071","title":"Microbial reduction of Fe(III) and sorption/precipitation of Fe(II) on Shewanella putrefaciens strain CN32.","date":"2001","source":"Environmental science & technology","url":"https://pubmed.ncbi.nlm.nih.gov/11348071","citation_count":64,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22685165","id":"PMC_22685165","title":"Fe sparing and Fe recycling contribute to increased superoxide dismutase capacity in iron-starved Chlamydomonas reinhardtii.","date":"2012","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/22685165","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27208259","id":"PMC_27208259","title":"A WRKY Transcription Factor Regulates Fe Translocation under Fe Deficiency.","date":"2016","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27208259","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29243944","id":"PMC_29243944","title":"Mitochondrial complex III Rieske Fe-S protein processing and assembly.","date":"2018","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/29243944","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25447545","id":"PMC_25447545","title":"Recent advances in the Suf Fe-S cluster biogenesis pathway: Beyond the Proteobacteria.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25447545","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24914049","id":"PMC_24914049","title":"TtcA a new tRNA-thioltransferase with an Fe-S cluster.","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/24914049","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27061491","id":"PMC_27061491","title":"Roles of Fe-S proteins: from cofactor synthesis to iron homeostasis to protein synthesis.","date":"2016","source":"Current opinion in genetics & development","url":"https://pubmed.ncbi.nlm.nih.gov/27061491","citation_count":54,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23786413","id":"PMC_23786413","title":"Potential anticancer heterometallic Fe-Au and Fe-Pd agents: initial mechanistic insights.","date":"2013","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23786413","citation_count":54,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21288764","id":"PMC_21288764","title":"Fe-S clusters, fragile sentinels of the cell.","date":"2011","source":"Current opinion in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/21288764","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26996949","id":"PMC_26996949","title":"GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26996949","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2500438","id":"PMC_2500438","title":"Fe:S cluster ligands are the only cysteines required for nitrogenase Fe-protein activities.","date":"1989","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2500438","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34890460","id":"PMC_34890460","title":"Two stripe rust effectors impair wheat resistance by suppressing import of host Fe-S protein into chloroplasts.","date":"2021","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/34890460","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35188748","id":"PMC_35188748","title":"Understanding the Importance of Labile Fe(III) during Fe(II)-Catalyzed Transformation of Metastable Iron Oxyhydroxides.","date":"2022","source":"Environmental science & technology","url":"https://pubmed.ncbi.nlm.nih.gov/35188748","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6327620","id":"PMC_6327620","title":"Rhizobium japonicum nitrogenase Fe protein gene (nifH).","date":"1984","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/6327620","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20217243","id":"PMC_20217243","title":"Identification of Fe-excess-induced genes in rice shoots reveals a WRKY transcription factor responsive to Fe, drought and senescence.","date":"2010","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/20217243","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31338452","id":"PMC_31338452","title":"Crop biofortification for iron (Fe), zinc (Zn) and vitamin A with transgenic approaches.","date":"2019","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/31338452","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25711703","id":"PMC_25711703","title":"Ethylene is critical to the maintenance of primary root growth and Fe homeostasis under Fe stress in Arabidopsis.","date":"2015","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/25711703","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20507538","id":"PMC_20507538","title":"A potyvirus P1 protein interacts with the Rieske Fe/S protein of its host.","date":"2007","source":"Molecular plant pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20507538","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21936771","id":"PMC_21936771","title":"Mutation in the Fe-S scaffold protein Isu bypasses frataxin deletion.","date":"2012","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/21936771","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34014661","id":"PMC_34014661","title":"Anaerobic Ammonium Removal Pathway Driven by the Fe(II)/Fe(III) Cycle through Intermittent Aeration.","date":"2021","source":"Environmental science & technology","url":"https://pubmed.ncbi.nlm.nih.gov/34014661","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38199006","id":"PMC_38199006","title":"METTL17 is an Fe-S cluster checkpoint for mitochondrial translation.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/38199006","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26135358","id":"PMC_26135358","title":"Bacillithiol has a role in Fe-S cluster biogenesis in Staphylococcus aureus.","date":"2015","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/26135358","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33296795","id":"PMC_33296795","title":"Porous yolk-shell Fe/Fe3O4 nanoparticles with controlled exposure of highly active Fe(0) for cancer therapy.","date":"2020","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/33296795","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30292110","id":"PMC_30292110","title":"Effect of Fe(II) on reactivity of heterotrophic denitrifiers in the remediation of nitrate- and Fe(II)-contaminated groundwater.","date":"2018","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/30292110","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36893757","id":"PMC_36893757","title":"Oxygen toxicity causes cyclic damage by destabilizing specific Fe-S cluster-containing protein complexes.","date":"2023","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/36893757","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26073914","id":"PMC_26073914","title":"Elevation of NO production increases Fe immobilization in the Fe-deficiency roots apoplast by decreasing pectin methylation of cell wall.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26073914","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23758282","id":"PMC_23758282","title":"Conserved hydrogen bonding networks of MitoNEET tune Fe-S cluster binding and structural stability.","date":"2013","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23758282","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29626095","id":"PMC_29626095","title":"The ErpA/NfuA complex builds an oxidation-resistant Fe-S cluster delivery pathway.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29626095","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9222517","id":"PMC_9222517","title":"On the chemistry of RNA degradation by Fe.bleomycin.","date":"1997","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9222517","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32632277","id":"PMC_32632277","title":"Structural insights into Fe-S protein biogenesis by the CIA targeting complex.","date":"2020","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/32632277","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36480258","id":"PMC_36480258","title":"Structure of the mitoribosomal small subunit with streptomycin reveals Fe-S clusters and physiological molecules.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36480258","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28695709","id":"PMC_28695709","title":"[Fe-S] cluster assembly in the apicoplast and its indispensability in mosquito stages of the malaria parasite.","date":"2017","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/28695709","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10788513","id":"PMC_10788513","title":"Identification of the [Fe-S] cluster-binding residues of Escherichia coli biotin synthase.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10788513","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20442400","id":"PMC_20442400","title":"The Fe/S cluster assembly protein Isd11 is essential for tRNA thiolation in Trypanosoma brucei.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20442400","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29569085","id":"PMC_29569085","title":"The NMR contribution to protein-protein networking in Fe-S protein maturation.","date":"2018","source":"Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29569085","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34123177","id":"PMC_34123177","title":"Biosynthesis of the catalytic H-cluster of [FeFe] hydrogenase: the roles of the Fe-S maturase proteins HydE, HydF, and HydG.","date":"2020","source":"Chemical science","url":"https://pubmed.ncbi.nlm.nih.gov/34123177","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21288761","id":"PMC_21288761","title":"Iron chaperones for mitochondrial Fe-S cluster biosynthesis and ferritin iron storage.","date":"2011","source":"Current opinion in chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/21288761","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31951953","id":"PMC_31951953","title":"Nafcillin degradation by heterogeneous electro-Fenton process using Fe, Cu and Fe/Cu nanoparticles.","date":"2020","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/31951953","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25988368","id":"PMC_25988368","title":"Protective role of bacillithiol in superoxide stress and Fe-S metabolism in Bacillus subtilis.","date":"2015","source":"MicrobiologyOpen","url":"https://pubmed.ncbi.nlm.nih.gov/25988368","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30184127","id":"PMC_30184127","title":"Fe-S Cluster Assembly in Oxymonads and Related Protists.","date":"2018","source":"Molecular biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/30184127","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30204426","id":"PMC_30204426","title":"The H2O2-Resistant Fe-S Redox Switch MitoNEET Acts as a pH Sensor To Repair Stress-Damaged Fe-S Protein.","date":"2018","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30204426","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34829609","id":"PMC_34829609","title":"Sulfur Administration in Fe-S Cluster Homeostasis.","date":"2021","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34829609","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21492791","id":"PMC_21492791","title":"Microfluidic preparation of [18F]FE@SUPPY and [18F]FE@SUPPY:2--comparison with conventional radiosyntheses.","date":"2010","source":"Nuclear medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/21492791","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27651365","id":"PMC_27651365","title":"A Regulatory Circuit Composed of a Transcription Factor, IscR, and a Regulatory RNA, RyhB, Controls Fe-S Cluster Delivery.","date":"2016","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/27651365","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16026168","id":"PMC_16026168","title":"Resolution and reconstitution of a bound Fe-S protein from the photosynthetic reaction center of Heliobacterium modesticaldum.","date":"2005","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16026168","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25197096","id":"PMC_25197096","title":"Epigenetic role for the conserved Fe-S cluster biogenesis protein AtDRE2 in Arabidopsis thaliana.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25197096","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27473689","id":"PMC_27473689","title":"Alpha proteobacterial ancestry of the [Fe-Fe]-hydrogenases in anaerobic eukaryotes.","date":"2016","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/27473689","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25044349","id":"PMC_25044349","title":"The scaffold protein IscU retains a structured conformation in the Fe-S cluster assembly complex.","date":"2014","source":"Chembiochem : a European journal of chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/25044349","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31876088","id":"PMC_31876088","title":"Redox cycling of Fe(II) and Fe(III) in magnetite accelerates aceticlastic methanogenesis by Methanosarcina mazei.","date":"2020","source":"Environmental microbiology reports","url":"https://pubmed.ncbi.nlm.nih.gov/31876088","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32853807","id":"PMC_32853807","title":"Biodegradable ternary Zn-3Ge-0.5X (X=Cu, Mg, and Fe) alloys for orthopedic applications.","date":"2020","source":"Acta biomaterialia","url":"https://pubmed.ncbi.nlm.nih.gov/32853807","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30064903","id":"PMC_30064903","title":"Recent Advances in the [Fe-S] Cluster Biogenesis (SUF) Pathway Functional in the Apicoplast of Plasmodium.","date":"2018","source":"Trends in parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/30064903","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29425096","id":"PMC_29425096","title":"Function and maturation of the Fe-S center in dihydroxyacid dehydratase from Arabidopsis.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29425096","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23712964","id":"PMC_23712964","title":"Protein profile of Lupinus texensis phloem sap exudates: searching for Fe- and Zn-containing proteins.","date":"2013","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/23712964","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28882200","id":"PMC_28882200","title":"Fe-S Cluster Hsp70 Chaperones: The ATPase Cycle and Protein Interactions.","date":"2017","source":"Methods in enzymology","url":"https://pubmed.ncbi.nlm.nih.gov/28882200","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35427399","id":"PMC_35427399","title":"Mycobacterium tuberculosis requires SufT for Fe-S cluster maturation, metabolism, and survival in vivo.","date":"2022","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/35427399","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29746243","id":"PMC_29746243","title":"Steps Toward Understanding Mitochondrial Fe/S Cluster Biogenesis.","date":"2017","source":"Methods in enzymology","url":"https://pubmed.ncbi.nlm.nih.gov/29746243","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26396185","id":"PMC_26396185","title":"Cytosolic Fe-S Cluster Protein Maturation and Iron Regulation Are Independent of the Mitochondrial Erv1/Mia40 Import System.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26396185","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28449254","id":"PMC_28449254","title":"Bioresorbable Fe-Mn and Fe-Mn-HA Materials for Orthopedic Implantation: Enhancing Degradation through Porosity Control.","date":"2017","source":"Advanced healthcare materials","url":"https://pubmed.ncbi.nlm.nih.gov/28449254","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23138661","id":"PMC_23138661","title":"Bacterial sensor kinases using Fe-S cluster binding PAS or GAF domains for O2 sensing.","date":"2012","source":"Dalton transactions (Cambridge, England : 2003)","url":"https://pubmed.ncbi.nlm.nih.gov/23138661","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33757492","id":"PMC_33757492","title":"Knockdown of GTF2E2 inhibits the growth and progression of lung adenocarcinoma via RPS4X in vitro and in vivo.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33757492","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32466579","id":"PMC_32466579","title":"Hereditary Ataxia: A Focus on Heme Metabolism and Fe-S Cluster Biogenesis.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32466579","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37488138","id":"PMC_37488138","title":"The Fe-S cluster assembly protein IscU2 increases α-ketoglutarate catabolism and DNA 5mC to promote tumor growth.","date":"2023","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37488138","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32184258","id":"PMC_32184258","title":"Feedback Control of a Two-Component Signaling System by an Fe-S-Binding Receiver Domain.","date":"2020","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/32184258","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22658674","id":"PMC_22658674","title":"Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22658674","citation_count":1718,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8946909","id":"PMC_8946909","title":"The general transcription factors of RNA polymerase II.","date":"1996","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/8946909","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8152490","id":"PMC_8152490","title":"Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II.","date":"1994","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/8152490","citation_count":436,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"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":"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":"9271120","id":"PMC_9271120","title":"Repression of p53-mediated transcription by MDM2: a dual mechanism.","date":"1997","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/9271120","citation_count":239,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22678362","id":"PMC_22678362","title":"MMS19 assembles iron-sulfur proteins required for DNA metabolism and genomic integrity.","date":"2012","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22678362","citation_count":230,"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":"8999876","id":"PMC_8999876","title":"Human transcription-repair coupling factor CSB/ERCC6 is a DNA-stimulated ATPase but is not a helicase and does not disrupt the ternary transcription complex of stalled RNA polymerase II.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8999876","citation_count":220,"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":"21988832","id":"PMC_21988832","title":"Toward an understanding of the protein interaction network of the human liver.","date":"2011","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/21988832","citation_count":207,"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":"7876263","id":"PMC_7876263","title":"The general transcription-repair factor TFIIH is recruited to the excision repair complex by the XPA protein independent of the TFIIE transcription factor.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7876263","citation_count":180,"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"},{"pmid":"7926747","id":"PMC_7926747","title":"Transcription factor IIE binds preferentially to RNA polymerase IIa and recruits TFIIH: a model for promoter clearance.","date":"1994","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/7926747","citation_count":151,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43973,"output_tokens":765,"usd":0.071697},"stage2":{"model":"claude-opus-4-6","input_tokens":3954,"output_tokens":1110,"usd":0.07128},"total_usd":0.408879,"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":54758,"output_tokens":3818,"usd":0.110772},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6904,"output_tokens":2756,"usd":0.15513}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"Homozygous missense mutations in GTF2E2 (encoding TFIIEβ, the beta subunit of transcription factor IIE) cause trichothiodystrophy (TTD) with normal nucleotide excision repair (NER), establishing that TFIIE is not involved in NER. Mutant cells show decreased protein levels of both TFIIEα and TFIIEβ subunits and decreased phosphorylation of TFIIEα, demonstrating that GTF2E2 mutations destabilize the TFIIE complex and impair transcription-related phosphorylation events.\",\n      \"method\": \"Patient-derived cell studies with protein-level analysis (Western blot for TFIIEα and TFIIEβ levels and phosphorylation), UV-damage repair assays, homozygous missense mutation identification (c.448G>C [p.Ala150Pro] and c.559G>T [p.Asp187Tyr])\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — patient mutations with direct protein-level functional consequences, multiple orthogonal readouts (protein stability, phosphorylation, repair assays), replicated across two unrelated families\",\n      \"pmids\": [\"26996949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GTF2E2 knockdown inhibits lung adenocarcinoma cell proliferation, migration, and invasion in vitro and attenuates tumor growth in vivo. LC-MS/MS proteomics identified RPS4X as a physical interacting partner of GTF2E2, and GTF2E2 mediates its regulatory effects on tumor development through the mTOR pathway via RPS4X.\",\n      \"method\": \"shRNA knockdown, in vitro proliferation/migration/invasion assays, in vivo xenograft, shotgun LC-MS/MS interactomics\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — KD with defined cellular phenotype and MS-identified interactor, but mechanistic link to mTOR pathway is not fully reconstituted and is from a single lab\",\n      \"pmids\": [\"33757492\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GTF2E2 encodes TFIIEβ, the beta subunit of the general transcription factor TFIIE, which is essential for RNA polymerase II transcription initiation through direct interaction with TFIIH; pathogenic GTF2E2 mutations destabilize the TFIIE heterodimer and reduce TFIIEα phosphorylation, causing transcriptional impairment (without NER defects) that underlies trichothiodystrophy, while GTF2E2 also physically interacts with the ribosomal protein RPS4X to influence cell growth signaling.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to identify papers about GTF2E2 (the β subunit of general transcription factor IIE, TFIIEβ, involved in RNA polymerase II transcription initiation).\n\n**Classification:**\n- Papers [1]-[46], [48]-[100] in the main corpus (except [47] and [97]): These are overwhelmingly about Fe-S clusters, iron chemistry, and unrelated biology — EXCLUDE (alias collision with \"Fe\" chemistry or completely unrelated topics)\n- Paper [47]: \"GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE\" — KEEP\n- Paper [97]: \"Knockdown of GTF2E2 inhibits the growth and progression of lung adenocarcinoma via RPS4X\" — KEEP (describes GTF2E2 protein function/interactions)\n\n**Additional curated papers:**\n- [5] General transcription factors of RNA pol II — KEEP (foundational context)\n- [10] Dual role of TFIIH — KEEP (direct TFIIE interaction described)\n- [14] CDK control of initiation-to-elongation — KEEP (TFIIE retention shown)\n- [16] Purification and functional analysis of TFIIB and TFIIE — KEEP\n- [17] Enhanced processivity via Tat — KEEP (TFIIH/TFIIE interaction)\n- [18] Near-atomic resolution PIC structure — KEEP (TFIIE structure)\n- [19] MDM2 repression — KEEP (TFIIEβ/small subunit binding)\n- [22] CSB/ERCC6 — KEEP (p34 subunit of TFIIE binding)\n- [23] EBNA2 coactivator p100 — KEEP (TFIIE interaction)\n- [26] Structure and functional properties of human TFIIE — KEEP (direct characterization of both subunits including TFIIEβ)\n- [27] TFIIH recruited by XPA — KEEP (XPA binds p34 of TFIIE)\n- [28] Three transitions in RNA pol II transcription — KEEP (TFIIH/TFIIE roles)\n- [30] TFIIE binds RNA pol IIa and recruits TFIIH — KEEP\n\nOthers in curated list are interactome/proteomics surveys without specific GTF2E2 mechanistic findings — these are EXCLUDE for mechanistic discoveries.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1987,\n      \"finding\": \"TFIIE (containing the TFIIEβ/p34 subunit) was purified from HeLa nuclear extracts and shown to be absolutely required, together with TFIIA, TFIID, TFIIB, and RNA polymerase II, for specific transcription initiation at class II promoters. TFIIE was found to interact independently with TFIIB and with purified RNA polymerase II, but not RNA polymerase III, establishing its role as a basal initiation factor.\",\n      \"method\": \"Biochemical purification, glycerol gradient sedimentation, in vitro transcription reconstitution\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with purified components, multiple functional assays\",\n      \"pmids\": [\"3029109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Human TFIIE is a heterodimer composed of two subunits (TFIIEα/p56 and TFIIEβ/p34, the latter encoded by GTF2E2). Both subunits are essential to form a stable preinitiation complex and to reconstitute basal-level and Sp1-activated transcription in vitro. Sequence analysis revealed structural motifs relevant to transcription initiation.\",\n      \"method\": \"cDNA cloning, recombinant protein expression, in vitro transcription reconstitution, preinitiation complex assembly assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted transcription with purified recombinant subunits, both subunits individually tested\",\n      \"pmids\": [\"1956398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"TFIIE (via its 56-kD subunit TFIIEα) binds selectively to the nonphosphorylated form of RNA polymerase II (IIa), interacts with TBP/TFIID and TFIIF subunits, and recruits TFIIH to the transcription complex through a direct interaction with ERCC3 (XPB subunit of TFIIH). The small subunit of TFIIE (TFIIEβ/p34, encoded by GTF2E2) also participates in TFIIF interaction. This supports a model in which TFIIE plays a role in promoter clearance and recruitment of TFIIH.\",\n      \"method\": \"Protein affinity binding assays, affinity resin pulldowns, in vitro transcription\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding assays with purified proteins, functional transcription reconstitution\",\n      \"pmids\": [\"7926747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"TFIIE negatively modulates the helicase activity of TFIIH through a direct interaction between TFIIE and the ERCC3 (XPB) subunit of TFIIH, as demonstrated in transcription and DNA repair reconstitution assays.\",\n      \"method\": \"In vitro transcription/repair reconstitution, direct protein interaction assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with purified components showing functional consequence\",\n      \"pmids\": [\"8152490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The p34 subunit of TFIIE (TFIIEβ, encoded by GTF2E2) was found to bind specifically to the DNA repair/transcription coupling protein XPA, in competition with the p56 subunit of TFIIE. Separately, the coactivator p100 bound both subunits (p56 and p34) of TFIIE independently in vitro, suggesting TFIIEβ is accessible for protein interactions relevant to transcription activation.\",\n      \"method\": \"Protein binding/affinity assays, co-immunoprecipitation, in vitro binding with translated subunits\",\n      \"journal\": \"The Journal of biological chemistry / Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct binding assays, single-lab studies each with one main method\",\n      \"pmids\": [\"7876263\", \"7651391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"MDM2 directly binds the small subunit of TFIIE (TFIIEβ/p34, encoded by GTF2E2) through its inhibitory domain (amino acids 50–222). This interaction, along with MDM2 binding to monomeric TBP, contributes to direct repression of basal transcription, suggesting MDM2 interferes with preinitiation complex function via TFIIEβ.\",\n      \"method\": \"Protein affinity binding, GST pulldown, in vitro transcription with MDM2 domain fusions\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding mapped to specific domain with functional transcription repression readout, single lab\",\n      \"pmids\": [\"9271120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CSB (ERCC6), the transcription-repair coupling factor, binds the p34 subunit of TFIIE (TFIIEβ, encoded by GTF2E2) as well as XPA and TFIIH, suggesting TFIIEβ participates in protein interaction networks linking transcription initiation and DNA repair.\",\n      \"method\": \"Direct protein binding assays with purified recombinant CSB and TFIIE subunits\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct biochemical binding demonstrated with purified proteins, single lab\",\n      \"pmids\": [\"8999876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"During transcription initiation, TFIIH requires TFIIE to maintain the open transcription bubble only during formation of the first three phosphodiester bonds (up to a 4-nt RNA). After this second transition, the open complex is no longer sensitive to ATPγS, indicating TFIIE and TFIIH cooperate specifically during early stages of transcript synthesis.\",\n      \"method\": \"In vitro transcription with stalled complexes, ATPγS sensitivity assays, defined-position stalling on adenovirus major late promoter\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with purified homogeneous proteins, mechanistic transitions precisely mapped\",\n      \"pmids\": [\"9405375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TFIIH's ERCC3 (XPB) subunit, which mediates ATP-dependent promoter melting, interacts with DNA downstream of the melting region (not the region undergoing melting itself). TFIIE is positioned upstream and its fixed protein-DNA interactions provide the fulcrum for TFIIH's proposed molecular wrench mechanism for promoter opening.\",\n      \"method\": \"DNA footprinting, protein-DNA crosslinking, in vitro transcription with mutant templates\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mechanistic dissection by multiple orthogonal methods in vitro\",\n      \"pmids\": [\"10827951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Selective inhibition of Cdk7 (part of TFIIH) increases TFIIE retention at promoters and prevents DRB sensitivity-inducing factor (DSIF) recruitment, attenuating pausing in human cells. This places TFIIE (including TFIIEβ) downstream of Cdk7 phosphorylation in the initiation-to-elongation switch, where TFIIE must be evicted before elongation factors can engage.\",\n      \"method\": \"Selective Cdk7 inhibition (analog-sensitive kinase), ChIP, in vivo functional assays in human cells\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean chemical-genetic inhibition with ChIP readout, mechanistic pathway placement in human cells\",\n      \"pmids\": [\"23064645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cryo-EM structures of the human pre-initiation complex (PIC) in closed, open, and initially transcribing states provided near-atomic resolution views of TFIIE (both subunits, including TFIIEβ/GTF2E2) within the PIC. TFIIE is shown to stabilize the transcription bubble and undergoes conformational changes during the transition from closed to open complex, with TFIIB playing a key role in bubble stabilization.\",\n      \"method\": \"Cryo-electron microscopy at near-atomic resolution, comparison of three PIC states\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures of multiple PIC states with functional interpretation\",\n      \"pmids\": [\"27193682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Homozygous missense mutations in GTF2E2 (p.Ala150Pro and p.Asp187Tyr in TFIIEβ) cause trichothiodystrophy (TTD) without a DNA repair defect (normal NER). These mutations decrease protein levels of both TFIIE subunits (TFIIEα and TFIIEβ), reduce phosphorylation of TFIIEα, and destabilize the TFIIE complex, establishing that TFIIE mutations cause TTD through impaired transcription rather than NER.\",\n      \"method\": \"Patient cell studies, immunoblotting, UV damage repair assays (NER normal), phosphorylation analysis, clinical genetics\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — disease-causing mutations characterized with multiple cellular assays, NER exclusion, two independent patients\",\n      \"pmids\": [\"26996949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Knockdown of GTF2E2 in lung adenocarcinoma cells inhibits proliferation, migration, invasion, and promotes apoptosis in vitro, and attenuates tumor growth in vivo. LC-MS/MS identified RPS4X as a physical interaction partner of GTF2E2, and GTF2E2 was found to promote tumor development by activating RPS4X-mediated mTOR pathway signaling.\",\n      \"method\": \"shRNA knockdown, in vitro proliferation/migration/invasion/apoptosis assays, xenograft mouse model, LC-MS/MS interactome, mTOR pathway analysis\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss-of-function with defined cellular phenotypes and MS-identified interaction, single lab, pathway placement partially indirect\",\n      \"pmids\": [\"33757492\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GTF2E2 encodes TFIIEβ (p34), the small subunit of the general transcription factor TFIIE, which heterodimerizes with TFIIEα (p56) and is essential for RNA polymerase II preinitiation complex assembly, promoter opening, and the transition from initiation to elongation: TFIIEβ participates in binding RNA pol IIa and in recruiting TFIIH to the promoter (via TFIIEα–ERCC3 interaction), cooperates with TFIIH to maintain the open transcription bubble during early transcript synthesis, must be evicted (via Cdk7-dependent phosphorylation) for productive elongation to proceed, and its destabilization by missense mutations causes the multisystem developmental disorder trichothiodystrophy through impaired transcription rather than DNA repair defects.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GTF2E2 encodes TFIIEβ, the beta subunit of general transcription factor IIE, which functions in RNA polymerase II transcription initiation. Homozygous missense mutations in GTF2E2 destabilize the TFIIEα–TFIIEβ heterodimer, reduce TFIIEα phosphorylation, and cause trichothiodystrophy without nucleotide excision repair defects, demonstrating that TFIIE operates in transcription but is dispensable for NER [PMID:26996949]. GTF2E2 physically interacts with RPS4X, and its depletion suppresses cell proliferation, migration, and invasion in lung adenocarcinoma cells through attenuation of mTOR signaling [PMID:33757492].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing that GTF2E2 mutations cause trichothiodystrophy resolved whether TFIIE participates in NER (it does not) and showed that TFIIEβ integrity is required for TFIIEα stability and phosphorylation, linking transcription initiation defects to human disease.\",\n      \"evidence\": \"Patient-derived fibroblasts from two unrelated families carrying homozygous missense mutations, assessed by Western blot for TFIIE subunit levels and phosphorylation, plus UV-repair assays\",\n      \"pmids\": [\"26996949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis by which missense mutations (Ala150Pro, Asp187Tyr) destabilize the heterodimer is not determined\",\n        \"Downstream transcriptional targets affected by reduced TFIIEα phosphorylation are not identified\",\n        \"Whether TFIIE instability affects TFIIH recruitment quantitatively has not been measured\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of RPS4X as a physical partner of GTF2E2 and demonstration that GTF2E2 depletion impairs tumor cell growth via mTOR signaling expanded the functional scope of TFIIEβ beyond canonical transcription initiation.\",\n      \"evidence\": \"shRNA knockdown in lung adenocarcinoma cells with in vitro and xenograft assays; interactor identified by LC-MS/MS proteomics\",\n      \"pmids\": [\"33757492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"GTF2E2–RPS4X interaction has not been validated by reciprocal co-immunoprecipitation or endogenous-level methods\",\n        \"Whether the mTOR effect is transcription-dependent or reflects a non-canonical function of TFIIEβ is unresolved\",\n        \"Findings are from a single laboratory and a single cancer type\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TFIIEβ integrates its canonical role in PIC assembly with its interaction with RPS4X and mTOR signaling, and whether these functions are relevant across tissues affected in trichothiodystrophy, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No reconstituted in vitro transcription experiments with mutant TFIIEβ have been reported\",\n        \"Tissue-specific transcriptional consequences of GTF2E2 mutations are uncharacterized\",\n        \"No structural model of the TFIIEα–TFIIEβ heterodimer with disease-associated mutations exists\"\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      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"TFIIE\"\n    ],\n    \"partners\": [\n      \"GTF2E1\",\n      \"RPS4X\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"GTF2E2 encodes TFIIE\\u03b2 (p34), the small subunit of the general transcription factor TFIIE, which heterodimerizes with TFIIE\\u03b1 (p56) and is essential for RNA polymerase II preinitiation complex (PIC) assembly, promoter opening, and the transition from transcription initiation to elongation. Within the PIC, TFIIE\\u03b2 participates in binding the nonphosphorylated form of RNA polymerase II and TFIIF, while the heterodimer recruits TFIIH via TFIIE\\u03b1\\u2013ERCC3 interaction, and cooperates with TFIIH to maintain the open transcription bubble during synthesis of the first few nucleotides; Cdk7-dependent phosphorylation subsequently triggers TFIIE eviction, permitting elongation factor engagement [PMID:7926747, PMID:9405375, PMID:23064645, PMID:27193682]. TFIIE\\u03b2 also serves as a direct binding target for the transcriptional repressor MDM2, the nucleotide excision repair factors XPA and CSB, and the coactivator p100, positioning it at the interface of transcription and DNA repair signaling [PMID:7876263, PMID:9271120, PMID:8999876]. Homozygous missense mutations in GTF2E2 that destabilize the TFIIE heterodimer cause trichothiodystrophy without a DNA repair defect, demonstrating that disease pathogenesis proceeds through impaired transcription [PMID:26996949].\",\n  \"teleology\": [\n    {\n      \"year\": 1987,\n      \"claim\": \"Establishing that TFIIE (containing the future-named TFIIE\\u03b2 subunit) is an indispensable basal transcription factor for RNA polymerase II resolved its requirement alongside TFIIA, TFIIB, TFIID, and Pol II for specific promoter-directed initiation.\",\n      \"evidence\": \"Biochemical purification from HeLa nuclear extracts and reconstituted in vitro transcription\",\n      \"pmids\": [\"3029109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual subunit contributions not yet separated\", \"Mechanism of TFIIE action within the PIC unknown\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Identification and cloning of the two TFIIE subunits (\\u03b1/p56 and \\u03b2/p34) demonstrated that both are individually required for preinitiation complex assembly and basal transcription, defining the heterodimeric architecture of the factor.\",\n      \"evidence\": \"cDNA cloning, recombinant protein expression, reconstituted transcription assays\",\n      \"pmids\": [\"1956398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protein\\u2013protein interactions within the PIC not mapped\", \"Structural basis of heterodimerization unknown\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Mapping interaction partners showed that TFIIE\\u03b1 selectively binds nonphosphorylated Pol II and recruits TFIIH via ERCC3, while TFIIE\\u03b2 contacts TFIIF; additionally, TFIIE negatively modulates TFIIH helicase activity, placing TFIIE as a regulatory bridge between Pol II binding and TFIIH function.\",\n      \"evidence\": \"Affinity pulldown assays with purified proteins, in vitro transcription and DNA repair reconstitution\",\n      \"pmids\": [\"7926747\", \"8152490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TFIIE\\u03b2 directly contacts TFIIH remained unclear\", \"Structural topology of TFIIE within the PIC not resolved\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Discovery that TFIIE\\u03b2 directly binds the NER factor XPA and the coactivator p100 expanded its interaction network beyond core PIC components, suggesting roles at the transcription\\u2013repair interface.\",\n      \"evidence\": \"In vitro protein binding and co-immunoprecipitation assays\",\n      \"pmids\": [\"7876263\", \"7651391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences of XPA\\u2013TFIIE\\u03b2 binding on transcription or repair not demonstrated\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Binding of MDM2 and CSB to TFIIE\\u03b2 identified it as a convergence point for transcriptional repression and transcription-coupled repair, while reconstitution experiments pinpointed that TFIIE\\u2013TFIIH cooperation maintains the open bubble only during synthesis of the first 3\\u20134 nucleotides, precisely defining the temporal window of TFIIE function.\",\n      \"evidence\": \"GST pulldown with MDM2 domain fusions and in vitro transcription repression; purified protein binding for CSB; stalled-complex transcription assays with ATP\\u03b3S sensitivity\",\n      \"pmids\": [\"9271120\", \"8999876\", \"9405375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MDM2\\u2013TFIIE\\u03b2 interaction occurs at endogenous promoters in vivo unknown\", \"Mechanism by which TFIIE is released after the transition not identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"DNA footprinting and crosslinking revealed that TFIIE is positioned upstream of the melting region and provides a fixed anchor (fulcrum) for TFIIH\\u2019s molecular-wrench mechanism of promoter opening, explaining how TFIIE\\u2019s protein\\u2013DNA contacts contribute to strand separation.\",\n      \"evidence\": \"DNA footprinting, protein\\u2013DNA crosslinking, mutant template analysis in vitro\",\n      \"pmids\": [\"10827951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact residues of TFIIE\\u03b2 contacting DNA not identified\", \"Model inferred from footprinting, not atomic structure\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Chemical-genetic inhibition of Cdk7 in human cells showed that TFIIE retention at promoters blocks elongation factor (DSIF) recruitment, establishing that Cdk7-dependent phosphorylation drives TFIIE eviction as a prerequisite for the initiation-to-elongation transition in vivo.\",\n      \"evidence\": \"Analog-sensitive Cdk7 inhibition, ChIP in human cells\",\n      \"pmids\": [\"23064645\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Cdk7 directly phosphorylates TFIIE\\u03b2 or acts indirectly (e.g., through Pol II CTD) not resolved\", \"Genome-wide generality of TFIIE eviction requirement not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Cryo-EM structures of the human PIC in closed, open, and initially transcribing states provided near-atomic views of TFIIE\\u03b2 within the complex, showing conformational rearrangements during bubble opening, while independent genetic studies demonstrated that homozygous missense mutations in GTF2E2 destabilize the TFIIE heterodimer and cause trichothiodystrophy through impaired transcription (not NER).\",\n      \"evidence\": \"Cryo-EM at near-atomic resolution of three PIC states; patient cell analysis with immunoblotting, UV-repair assays, and phosphorylation studies in two unrelated families\",\n      \"pmids\": [\"27193682\", \"26996949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of TFIIE\\u03b2 disease mutants within the PIC not available\", \"Specific transcriptional targets affected in TTD patient cells not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Knockdown of GTF2E2 in lung adenocarcinoma cells implicated it in promoting proliferation and mTOR pathway activation through interaction with RPS4X, extending its functional relevance beyond basal transcription to cancer cell biology.\",\n      \"evidence\": \"shRNA knockdown, proliferation/migration/invasion assays, xenograft model, LC-MS/MS interactome\",\n      \"pmids\": [\"33757492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RPS4X interaction not confirmed by reciprocal pulldown or structural data\", \"Whether mTOR activation is a direct consequence of GTF2E2\\u2013RPS4X interaction or indirect transcriptional effect is unclear\", \"Single-lab finding without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the direct phosphorylation event(s) that trigger TFIIE eviction during promoter escape, the structural basis of disease-causing GTF2E2 mutations within the PIC, and the specific transcriptional programs impaired in trichothiodystrophy caused by TFIIE\\u03b2 deficiency.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Cdk7 substrate site(s) on TFIIE subunits not mapped\", \"Atomic-resolution structure of mutant TFIIE in the PIC unavailable\", \"Genome-wide transcriptional consequences of GTF2E2 mutations not profiled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140223\", \"supporting_discovery_ids\": [0, 1, 7, 10]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 7, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3, 4, 6]}\n    ],\n    \"complexes\": [\n      \"TFIIE (TFIIE\\u03b1\\u2013TFIIE\\u03b2 heterodimer)\",\n      \"RNA Polymerase II preinitiation complex (PIC)\"\n    ],\n    \"partners\": [\n      \"GTF2E1\",\n      \"ERCC3\",\n      \"GTF2F1\",\n      \"XPA\",\n      \"ERCC6\",\n      \"MDM2\",\n      \"RPS4X\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}