{"gene":"SUPT7L","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2007,"finding":"STAF65gamma (SUPT7L) is a structural component of the STAGA complex required for stable association of TRRAP and GCN5 with SPT3 and TAF9 subunits; knockdown of STAF65gamma in human cells disrupts STAGA integrity and impairs transcription of MYC-dependent genes including TERT.","method":"siRNA knockdown in human cells, co-immunoprecipitation, chromatin immunoprecipitation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and ChIP with functional phenotype (gene expression, cell proliferation), multiple orthogonal methods in one focused study","pmids":["17967894"],"is_preprint":false},{"year":2007,"finding":"STAF65gamma (SUPT7L) is required for the interaction of SPT3/STAGA with core Mediator and for MYC recruitment of SPT3, TAF9, and core Mediator to the TERT promoter, but is dispensable for MYC recruitment of TRRAP, GCN5, and p300 and for nucleosome acetylation and loading of TFIID and RNA Pol II.","method":"siRNA knockdown, chromatin immunoprecipitation, co-immunoprecipitation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP with clear positive and negative results distinguishing STAF65gamma-dependent from independent recruitment steps","pmids":["17967894"],"is_preprint":false},{"year":2007,"finding":"SPT7L (SUPT7L) is a component of a small TAF complex (SMAT) containing TAF8, TAF10, and SPT7L, distinct from TFIID and STAGA/TFTC HAT complexes; TAF8 interacts with SPT7L through its C-terminal region and all three proteins form a complex in vitro and in vivo.","method":"Proteomic identification, co-immunoprecipitation, in vitro complex reconstitution","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution plus in vivo Co-IP, single lab but multiple orthogonal methods","pmids":["17375202"],"is_preprint":false},{"year":2005,"finding":"SPT7L (SUPT7L) can transport TAF10 into the nucleus via its nuclear localization signal (NLS); mutation of the SPT7L NLS causes TAF10 to remain cytoplasmic, demonstrating SPT7L acts as a nuclear import chaperone for TAF10.","method":"Fluorescent fusion proteins, NLS mutagenesis, FRAP, importin beta binding assay in vitro","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — NLS mutagenesis combined with live-cell fluorescence imaging and in vitro importin binding assay, single lab but multiple orthogonal methods","pmids":["15870280"],"is_preprint":false},{"year":2005,"finding":"SPT7L (SUPT7L) does not mediate TAF10 binding to importin beta (negative result): TAF10 binding to importin beta in vitro is dependent on co-expression of TAF8 or TAF3, but not SPT7L, indicating SPT7L uses an importin-beta-independent mechanism for nuclear import of TAF10.","method":"In vitro importin beta binding assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro assay, single lab, single method for this specific negative finding","pmids":["15870280"],"is_preprint":false},{"year":2006,"finding":"STAF65gamma (SUPT7L) physically interacts with TRIP-Br family members (TRIP-Br1, TRIP-Br2, TRIP-Br3) and differentially influences their transcriptional activity.","method":"Co-immunoprecipitation, transcriptional reporter assays","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP interaction reported, single lab, limited mechanistic follow-up","pmids":["17141982"],"is_preprint":false},{"year":2014,"finding":"STAF65gamma (SUPT7L) physically associates with transcription factor YY1 and class IIa HDACs to repress the c-Myc oncogene; SUMOylation of STAF65gamma is required to maintain this co-repressor complex at the promoter.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, SUMOylation assays, transcriptional reporter assays","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP with SUMOylation functional validation, single lab, multiple methods","pmids":["24852358"],"is_preprint":false},{"year":2014,"finding":"Physical interaction between STAF65gamma (SUPT7L) and class IIa HDACs facilitates nuclear enrichment of class IIa HDACs and regulates assembly of HDAC complexes.","method":"Co-immunoprecipitation, subcellular fractionation, fluorescence microscopy","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and localization experiments, single lab, two complementary methods","pmids":["24852358"],"is_preprint":false},{"year":2024,"finding":"Loss-of-function variants in SUPT7L lead to complete absence of SUPT7L protein in dermal fibroblasts (compound heterozygous missense causing aberrant splicing plus frameshift), resulting in increased DNA damage; transient overexpression of wildtype SUPT7L normalizes DNA damage levels, establishing SUPT7L as required for genome stability.","method":"Transcriptome sequencing, genome-edited HeLa cells, DNA damage assays, transient overexpression rescue","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function patient cells plus genome-edited cell line plus rescue experiment, single lab, multiple methods","pmids":["38592547"],"is_preprint":false},{"year":2021,"finding":"Yeast Spt7 (ortholog of human SUPT7L/STAF65gamma) is responsible for the integrity and proper assembly of the SAGA complex; deletion of Spt7 elevates DNA recombination frequency and increases spontaneous Rad52 foci in S phase, linking SAGA complex integrity to DNA recombination control.","method":"Yeast deletion mutants, DNA recombination assays, fluorescence microscopy (Rad52 foci)","journal":"Mechanisms of ageing and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with defined molecular phenotype in orthologous yeast system, multiple assays, single lab","pmids":["33831401"],"is_preprint":false},{"year":2026,"finding":"DARS1 (aspartyl-tRNA synthetase) is found in the nucleus interacting with members of the SAGA transcriptional co-activator complex including SUPT7L; this interaction affects MYC regulation, as DARS1 depletion reduces MYC protein levels and increases MYC phosphorylation.","method":"Quantitative proteomics, co-immunoprecipitation, genetic knockdown","journal":"Hepatology (Baltimore, Md.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP interaction plus functional phenotype but SUPT7L-specific mechanistic contribution not dissected, single lab","pmids":["41790991"],"is_preprint":false}],"current_model":"SUPT7L (STAF65gamma) is a structural scaffolding subunit of the STAGA/TFTC histone acetyltransferase coactivator complexes that maintains complex integrity by bridging TRRAP and GCN5 with SPT3 and TAF9; it also forms a distinct small TAF complex (SMAT) with TAF8 and TAF10, serves as a nuclear import chaperone for TAF10, mediates recruitment of core Mediator to MYC target promoters, can act as a co-repressor through physical association with YY1 and class IIa HDACs in a SUMOylation-dependent manner, and is required for genome stability as its loss causes increased DNA damage that is rescued by wildtype SUPT7L re-expression."},"narrative":{"mechanistic_narrative":"SUPT7L (STAF65gamma) is a structural scaffolding subunit of the STAGA/SAGA histone acetyltransferase coactivator complex that maintains complex integrity by enabling the stable association of TRRAP and GCN5 with the SPT3 and TAF9 modules [PMID:17967894]. Through this scaffolding role it governs a defined subset of coactivator recruitment events: SUPT7L is specifically required to bridge SPT3/STAGA to core Mediator and to recruit SPT3, TAF9, and core Mediator to MYC target promoters such as TERT, while being dispensable for MYC recruitment of TRRAP, GCN5, and p300 and for nucleosome acetylation and TFIID/Pol II loading [PMID:17967894]. Beyond the canonical coactivator complex, SUPT7L participates in a distinct small TAF complex (SMAT) with TAF8 and TAF10 [PMID:17375202] and acts as a nuclear import chaperone for TAF10, carrying it into the nucleus via its own NLS through an importin-beta-independent mechanism [PMID:15870280]. In a separate regulatory mode, SUPT7L functions as a co-repressor, physically associating with YY1 and class IIa HDACs to repress c-Myc in a manner dependent on its SUMOylation, and promoting nuclear enrichment and assembly of class IIa HDAC complexes [PMID:24852358]. SUPT7L is required for genome stability: loss of SUPT7L protein increases DNA damage that is normalized by re-expression of wildtype protein [PMID:38592547], consistent with the elevated DNA recombination seen upon deletion of its yeast ortholog Spt7 [PMID:33831401].","teleology":[{"year":2005,"claim":"Established a non-transcriptional cellular role by showing SUPT7L acts as a dedicated nuclear import chaperone, answering how the TAF10 subunit reaches the nucleus.","evidence":"Fluorescent fusion proteins with NLS mutagenesis, FRAP, and in vitro importin beta binding assays in human cells","pmids":["15870280"],"confidence":"High","gaps":["The importin-beta-independent import mechanism for TAF10 is not molecularly defined","Whether SUPT7L chaperones other subunits is untested"]},{"year":2006,"claim":"Extended SUPT7L's interaction landscape to TRIP-Br transcriptional regulators, hinting at functions beyond the core coactivator complex.","evidence":"Co-immunoprecipitation and transcriptional reporter assays","pmids":["17141982"],"confidence":"Low","gaps":["Single Co-IP without reciprocal or structural validation","Functional consequence at native promoters not established"]},{"year":2007,"claim":"Defined SUPT7L as the structural linchpin of STAGA, answering whether it is a passive subunit or required for complex assembly and which recruitment steps depend on it.","evidence":"siRNA knockdown, reciprocal Co-IP, and ChIP at MYC target promoters in human cells","pmids":["17967894"],"confidence":"High","gaps":["Structural basis for bridging TRRAP/GCN5 to SPT3/TAF9 not resolved","Direct binding interfaces within STAGA not mapped"]},{"year":2007,"claim":"Identified a SUPT7L-containing assembly distinct from TFIID and STAGA (SMAT), showing the protein partitions into multiple complexes.","evidence":"Proteomic identification, Co-IP, and in vitro reconstitution with TAF8 and TAF10","pmids":["17375202"],"confidence":"High","gaps":["Cellular function of SMAT relative to STAGA undefined","Stoichiometry and regulation of partitioning between complexes unknown"]},{"year":2014,"claim":"Revealed a repressive, SUMOylation-gated function of SUPT7L, answering whether it acts solely as a coactivator subunit or can also organize repressor complexes.","evidence":"Co-IP, ChIP, SUMOylation assays, and reporter assays examining YY1 and class IIa HDAC association at c-Myc","pmids":["24852358"],"confidence":"Medium","gaps":["SUMO sites on SUPT7L not mapped","How activator versus repressor modes are switched in vivo unclear"]},{"year":2021,"claim":"Used the yeast ortholog to causally link SUPT7L/Spt7-dependent complex integrity to DNA recombination control, framing a genome-stability role.","evidence":"Yeast Spt7 deletion mutants with recombination assays and Rad52 foci imaging in S phase","pmids":["33831401"],"confidence":"Medium","gaps":["Whether the human protein controls recombination by the same route is not shown","Molecular connection between SAGA integrity and recombination undefined"]},{"year":2024,"claim":"Demonstrated in human cells that loss of SUPT7L causes DNA damage rescuable by wildtype re-expression, establishing a direct requirement for genome stability.","evidence":"Patient fibroblasts with biallelic loss-of-function variants, genome-edited HeLa cells, DNA damage assays, and transient overexpression rescue","pmids":["38592547"],"confidence":"Medium","gaps":["Whether DNA damage arises from transcriptional defects or a direct repair role is unresolved","Associated clinical phenotype not mechanistically connected to genome instability"]},{"year":2026,"claim":"Placed SUPT7L within a nuclear DARS1–SAGA interaction modulating MYC, expanding the set of factors converging on SUPT7L-associated MYC regulation.","evidence":"Quantitative proteomics, Co-IP, and knockdown with MYC protein/phosphorylation readouts","pmids":["41790991"],"confidence":"Low","gaps":["SUPT7L-specific contribution to the DARS1 effect not dissected","Direct versus indirect interaction not established"]},{"year":null,"claim":"How SUPT7L's distinct activities — STAGA scaffolding, SMAT/TAF10 chaperoning, HDAC co-repression, and genome stability — are coordinated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of SUPT7L across its complexes","Mechanism coupling SUPT7L loss to DNA damage in humans unknown","Regulation switching between activator and repressor roles undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,7]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,6]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,9]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3]}],"complexes":["STAGA/SAGA HAT complex","SMAT (TAF8-TAF10-SPT7L) complex","YY1/class IIa HDAC co-repressor complex"],"partners":["TRRAP","GCN5","SPT3","TAF9","TAF8","TAF10","YY1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94864","full_name":"STAGA complex 65 subunit gamma","aliases":["Adenocarcinoma antigen ART1","SPTF-associated factor 65 gamma","STAF65gamma","Suppressor of Ty 7-like"],"length_aa":414,"mass_kda":46.2,"function":"","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O94864/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SUPT7L","classification":"Not Classified","n_dependent_lines":140,"n_total_lines":1208,"dependency_fraction":0.11589403973509933},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SF3B3","stoichiometry":10.0},{"gene":"SF3B5","stoichiometry":10.0},{"gene":"TAF12","stoichiometry":10.0},{"gene":"TRRAP","stoichiometry":10.0},{"gene":"USP22","stoichiometry":10.0},{"gene":"ENY2","stoichiometry":0.2},{"gene":"TBP","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SUPT7L","total_profiled":1310},"omim":[{"mim_id":"621130","title":"FISCHER-ZIRNSAK PROGEROID SYNDROME; FZPS","url":"https://www.omim.org/entry/621130"},{"mim_id":"612762","title":"SPTY7-LIKE, STAGA COMPLEX SUBUNIT GAMMA; SUPT7L","url":"https://www.omim.org/entry/612762"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SUPT7L"},"hgnc":{"alias_symbol":["STAF65gamma","KIAA0764","SPT7L","STAF65"],"prev_symbol":[]},"alphafold":{"accession":"O94864","domains":[{"cath_id":"-","chopping":"60-92_147-265","consensus_level":"medium","plddt":92.7446,"start":60,"end":265}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94864","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94864-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94864-F1-predicted_aligned_error_v6.png","plddt_mean":64.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SUPT7L","jax_strain_url":"https://www.jax.org/strain/search?query=SUPT7L"},"sequence":{"accession":"O94864","fasta_url":"https://rest.uniprot.org/uniprotkb/O94864.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94864/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94864"}},"corpus_meta":[{"pmid":"17967894","id":"PMC_17967894","title":"STAGA recruits Mediator to the MYC oncoprotein to stimulate transcription and cell proliferation.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17967894","citation_count":60,"is_preprint":false},{"pmid":"17375202","id":"PMC_17375202","title":"Identification of a small TAF complex and its role in the assembly of TAF-containing complexes.","date":"2007","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/17375202","citation_count":47,"is_preprint":false},{"pmid":"15870280","id":"PMC_15870280","title":"The nuclear import of TAF10 is regulated by one of its three histone fold domain-containing interaction partners.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15870280","citation_count":45,"is_preprint":false},{"pmid":"17141982","id":"PMC_17141982","title":"Transcriptional and subcellular regulation of the TRIP-Br family.","date":"2006","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/17141982","citation_count":26,"is_preprint":false},{"pmid":"33831401","id":"PMC_33831401","title":"The Spt7 subunit of the SAGA complex is required for the regulation of lifespan in both dividing and nondividing yeast cells.","date":"2021","source":"Mechanisms of ageing and development","url":"https://pubmed.ncbi.nlm.nih.gov/33831401","citation_count":11,"is_preprint":false},{"pmid":"29794791","id":"PMC_29794791","title":"Oncogenomic analysis identifies novel biomarkers for tumor stage mycosis fungoides.","date":"2018","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29794791","citation_count":9,"is_preprint":false},{"pmid":"24852358","id":"PMC_24852358","title":"The transcriptional repression activity of STAF65γ is facilitated by promoter tethering and nuclear import of class IIa histone deacetylases.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/24852358","citation_count":5,"is_preprint":false},{"pmid":"38592547","id":"PMC_38592547","title":"Loss-of-function variants affecting the STAGA complex component SUPT7L cause a developmental disorder with generalized lipodystrophy.","date":"2024","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38592547","citation_count":3,"is_preprint":false},{"pmid":"41791496","id":"PMC_41791496","title":"Neuroinflammatory and functional outcomes after TBI are sex-dependent: Lessons from estrous-phase stratified female mice.","date":"2026","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/41791496","citation_count":2,"is_preprint":false},{"pmid":"41554700","id":"PMC_41554700","title":"The role of histone demethylase PHF2 as a tumour suppressor in hepatocellular carcinoma by regulating SRXN1.","date":"2026","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/41554700","citation_count":0,"is_preprint":false},{"pmid":"41790991","id":"PMC_41790991","title":"Aspartyl-tRNA synthetase 1 (DARS1) reshapes hepatocellular carcinoma proteome and promotes aggressiveness through non-canonical SAGA-MYC signalling modulation.","date":"2026","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/41790991","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7677,"output_tokens":2503,"usd":0.030288,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9645,"output_tokens":2961,"usd":0.061125,"stage2_stop_reason":"end_turn"},"total_usd":0.091413,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"STAF65gamma (SUPT7L) is a structural component of the STAGA complex required for stable association of TRRAP and GCN5 with SPT3 and TAF9 subunits; knockdown of STAF65gamma in human cells disrupts STAGA integrity and impairs transcription of MYC-dependent genes including TERT.\",\n      \"method\": \"siRNA knockdown in human cells, co-immunoprecipitation, chromatin immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and ChIP with functional phenotype (gene expression, cell proliferation), multiple orthogonal methods in one focused study\",\n      \"pmids\": [\"17967894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"STAF65gamma (SUPT7L) is required for the interaction of SPT3/STAGA with core Mediator and for MYC recruitment of SPT3, TAF9, and core Mediator to the TERT promoter, but is dispensable for MYC recruitment of TRRAP, GCN5, and p300 and for nucleosome acetylation and loading of TFIID and RNA Pol II.\",\n      \"method\": \"siRNA knockdown, chromatin immunoprecipitation, co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP with clear positive and negative results distinguishing STAF65gamma-dependent from independent recruitment steps\",\n      \"pmids\": [\"17967894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SPT7L (SUPT7L) is a component of a small TAF complex (SMAT) containing TAF8, TAF10, and SPT7L, distinct from TFIID and STAGA/TFTC HAT complexes; TAF8 interacts with SPT7L through its C-terminal region and all three proteins form a complex in vitro and in vivo.\",\n      \"method\": \"Proteomic identification, co-immunoprecipitation, in vitro complex reconstitution\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution plus in vivo Co-IP, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17375202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SPT7L (SUPT7L) can transport TAF10 into the nucleus via its nuclear localization signal (NLS); mutation of the SPT7L NLS causes TAF10 to remain cytoplasmic, demonstrating SPT7L acts as a nuclear import chaperone for TAF10.\",\n      \"method\": \"Fluorescent fusion proteins, NLS mutagenesis, FRAP, importin beta binding assay in vitro\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — NLS mutagenesis combined with live-cell fluorescence imaging and in vitro importin binding assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15870280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SPT7L (SUPT7L) does not mediate TAF10 binding to importin beta (negative result): TAF10 binding to importin beta in vitro is dependent on co-expression of TAF8 or TAF3, but not SPT7L, indicating SPT7L uses an importin-beta-independent mechanism for nuclear import of TAF10.\",\n      \"method\": \"In vitro importin beta binding assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro assay, single lab, single method for this specific negative finding\",\n      \"pmids\": [\"15870280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"STAF65gamma (SUPT7L) physically interacts with TRIP-Br family members (TRIP-Br1, TRIP-Br2, TRIP-Br3) and differentially influences their transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assays\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP interaction reported, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"17141982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STAF65gamma (SUPT7L) physically associates with transcription factor YY1 and class IIa HDACs to repress the c-Myc oncogene; SUMOylation of STAF65gamma is required to maintain this co-repressor complex at the promoter.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, SUMOylation assays, transcriptional reporter assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP with SUMOylation functional validation, single lab, multiple methods\",\n      \"pmids\": [\"24852358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Physical interaction between STAF65gamma (SUPT7L) and class IIa HDACs facilitates nuclear enrichment of class IIa HDACs and regulates assembly of HDAC complexes.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, fluorescence microscopy\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and localization experiments, single lab, two complementary methods\",\n      \"pmids\": [\"24852358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss-of-function variants in SUPT7L lead to complete absence of SUPT7L protein in dermal fibroblasts (compound heterozygous missense causing aberrant splicing plus frameshift), resulting in increased DNA damage; transient overexpression of wildtype SUPT7L normalizes DNA damage levels, establishing SUPT7L as required for genome stability.\",\n      \"method\": \"Transcriptome sequencing, genome-edited HeLa cells, DNA damage assays, transient overexpression rescue\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function patient cells plus genome-edited cell line plus rescue experiment, single lab, multiple methods\",\n      \"pmids\": [\"38592547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Yeast Spt7 (ortholog of human SUPT7L/STAF65gamma) is responsible for the integrity and proper assembly of the SAGA complex; deletion of Spt7 elevates DNA recombination frequency and increases spontaneous Rad52 foci in S phase, linking SAGA complex integrity to DNA recombination control.\",\n      \"method\": \"Yeast deletion mutants, DNA recombination assays, fluorescence microscopy (Rad52 foci)\",\n      \"journal\": \"Mechanisms of ageing and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with defined molecular phenotype in orthologous yeast system, multiple assays, single lab\",\n      \"pmids\": [\"33831401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DARS1 (aspartyl-tRNA synthetase) is found in the nucleus interacting with members of the SAGA transcriptional co-activator complex including SUPT7L; this interaction affects MYC regulation, as DARS1 depletion reduces MYC protein levels and increases MYC phosphorylation.\",\n      \"method\": \"Quantitative proteomics, co-immunoprecipitation, genetic knockdown\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP interaction plus functional phenotype but SUPT7L-specific mechanistic contribution not dissected, single lab\",\n      \"pmids\": [\"41790991\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SUPT7L (STAF65gamma) is a structural scaffolding subunit of the STAGA/TFTC histone acetyltransferase coactivator complexes that maintains complex integrity by bridging TRRAP and GCN5 with SPT3 and TAF9; it also forms a distinct small TAF complex (SMAT) with TAF8 and TAF10, serves as a nuclear import chaperone for TAF10, mediates recruitment of core Mediator to MYC target promoters, can act as a co-repressor through physical association with YY1 and class IIa HDACs in a SUMOylation-dependent manner, and is required for genome stability as its loss causes increased DNA damage that is rescued by wildtype SUPT7L re-expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SUPT7L (STAF65gamma) is a structural scaffolding subunit of the STAGA/SAGA histone acetyltransferase coactivator complex that maintains complex integrity by enabling the stable association of TRRAP and GCN5 with the SPT3 and TAF9 modules [#0]. Through this scaffolding role it governs a defined subset of coactivator recruitment events: SUPT7L is specifically required to bridge SPT3/STAGA to core Mediator and to recruit SPT3, TAF9, and core Mediator to MYC target promoters such as TERT, while being dispensable for MYC recruitment of TRRAP, GCN5, and p300 and for nucleosome acetylation and TFIID/Pol II loading [#1]. Beyond the canonical coactivator complex, SUPT7L participates in a distinct small TAF complex (SMAT) with TAF8 and TAF10 [#2] and acts as a nuclear import chaperone for TAF10, carrying it into the nucleus via its own NLS through an importin-beta-independent mechanism [#3, #4]. In a separate regulatory mode, SUPT7L functions as a co-repressor, physically associating with YY1 and class IIa HDACs to repress c-Myc in a manner dependent on its SUMOylation, and promoting nuclear enrichment and assembly of class IIa HDAC complexes [#6, #7]. SUPT7L is required for genome stability: loss of SUPT7L protein increases DNA damage that is normalized by re-expression of wildtype protein [#8], consistent with the elevated DNA recombination seen upon deletion of its yeast ortholog Spt7 [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established a non-transcriptional cellular role by showing SUPT7L acts as a dedicated nuclear import chaperone, answering how the TAF10 subunit reaches the nucleus.\",\n      \"evidence\": \"Fluorescent fusion proteins with NLS mutagenesis, FRAP, and in vitro importin beta binding assays in human cells\",\n      \"pmids\": [\"15870280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The importin-beta-independent import mechanism for TAF10 is not molecularly defined\", \"Whether SUPT7L chaperones other subunits is untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended SUPT7L's interaction landscape to TRIP-Br transcriptional regulators, hinting at functions beyond the core coactivator complex.\",\n      \"evidence\": \"Co-immunoprecipitation and transcriptional reporter assays\",\n      \"pmids\": [\"17141982\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal or structural validation\", \"Functional consequence at native promoters not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined SUPT7L as the structural linchpin of STAGA, answering whether it is a passive subunit or required for complex assembly and which recruitment steps depend on it.\",\n      \"evidence\": \"siRNA knockdown, reciprocal Co-IP, and ChIP at MYC target promoters in human cells\",\n      \"pmids\": [\"17967894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for bridging TRRAP/GCN5 to SPT3/TAF9 not resolved\", \"Direct binding interfaces within STAGA not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified a SUPT7L-containing assembly distinct from TFIID and STAGA (SMAT), showing the protein partitions into multiple complexes.\",\n      \"evidence\": \"Proteomic identification, Co-IP, and in vitro reconstitution with TAF8 and TAF10\",\n      \"pmids\": [\"17375202\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular function of SMAT relative to STAGA undefined\", \"Stoichiometry and regulation of partitioning between complexes unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a repressive, SUMOylation-gated function of SUPT7L, answering whether it acts solely as a coactivator subunit or can also organize repressor complexes.\",\n      \"evidence\": \"Co-IP, ChIP, SUMOylation assays, and reporter assays examining YY1 and class IIa HDAC association at c-Myc\",\n      \"pmids\": [\"24852358\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO sites on SUPT7L not mapped\", \"How activator versus repressor modes are switched in vivo unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Used the yeast ortholog to causally link SUPT7L/Spt7-dependent complex integrity to DNA recombination control, framing a genome-stability role.\",\n      \"evidence\": \"Yeast Spt7 deletion mutants with recombination assays and Rad52 foci imaging in S phase\",\n      \"pmids\": [\"33831401\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the human protein controls recombination by the same route is not shown\", \"Molecular connection between SAGA integrity and recombination undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated in human cells that loss of SUPT7L causes DNA damage rescuable by wildtype re-expression, establishing a direct requirement for genome stability.\",\n      \"evidence\": \"Patient fibroblasts with biallelic loss-of-function variants, genome-edited HeLa cells, DNA damage assays, and transient overexpression rescue\",\n      \"pmids\": [\"38592547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DNA damage arises from transcriptional defects or a direct repair role is unresolved\", \"Associated clinical phenotype not mechanistically connected to genome instability\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed SUPT7L within a nuclear DARS1–SAGA interaction modulating MYC, expanding the set of factors converging on SUPT7L-associated MYC regulation.\",\n      \"evidence\": \"Quantitative proteomics, Co-IP, and knockdown with MYC protein/phosphorylation readouts\",\n      \"pmids\": [\"41790991\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"SUPT7L-specific contribution to the DARS1 effect not dissected\", \"Direct versus indirect interaction not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SUPT7L's distinct activities — STAGA scaffolding, SMAT/TAF10 chaperoning, HDAC co-repression, and genome stability — are coordinated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of SUPT7L across its complexes\", \"Mechanism coupling SUPT7L loss to DNA damage in humans unknown\", \"Regulation switching between activator and repressor roles undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"STAGA/SAGA HAT complex\",\n      \"SMAT (TAF8-TAF10-SPT7L) complex\",\n      \"YY1/class IIa HDAC co-repressor complex\"\n    ],\n    \"partners\": [\n      \"TRRAP\",\n      \"GCN5\",\n      \"SPT3\",\n      \"TAF9\",\n      \"TAF8\",\n      \"TAF10\",\n      \"YY1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}