{"gene":"THOC7","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2004,"finding":"Drosophila THO complex is composed of THO2, HPR1, THOC5, THOC6, and THOC7 (the latter three having no orthologs in budding yeast). Depletion of THO components showed that export of heat-shock mRNAs under heat stress is strictly dependent on THO function, while <20% of the transcriptome is regulated by THO under normal conditions.","method":"Gene expression profiling (microarray) in Drosophila cells depleted of THO components; RNAi knockdown","journal":"Nature structural & molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi depletion with transcriptome-wide readout in Drosophila, single lab but multiple components tested and replicated across subunits","pmids":["15133499"],"is_preprint":false},{"year":2008,"finding":"THOC7 does not contain a nuclear localization signal and resides mainly in the cytoplasm in the absence of FMIP (THOC5). THOC7 (amino acids 50–137) directly binds the N-terminal portion (aa 1–199) of FMIP, and this interaction is required for THOC7 nuclear localization; a THOC7 mutant lacking the FMIP-binding site fails to co-localize with FMIP in the nucleus.","method":"Co-immunoprecipitation, deletion mapping, fluorescence microscopy (co-localization), direct binding assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding mapped to defined domains, co-localization imaging, and functional mutant validation in a single lab","pmids":["19059247"],"is_preprint":false},{"year":2011,"finding":"THOC7 is a component of the mammalian THO subcomplex (together with THOC1, THOC2, THOC5, THOC6), which is part of the TREX complex required for nuclear export of specific mRNAs. In THOC5-knockout mouse embryo fibroblasts, 10 genes were identified that were spliced but not exported to the cytoplasm; these mRNAs co-purified with THOC5, placing THO at the mRNA export step. Hsp70 mRNA export required THOC5 under heat shock (42°C) but not under normal conditions (37°C).","method":"Conditional knockout (Cre/lox), transcriptome analysis of cytoplasmic RNA, RNA co-immunoprecipitation with THOC5","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with cytoplasmic RNA fractionation and RNA co-IP, single lab, multiple orthogonal methods","pmids":["21525145"],"is_preprint":false},{"year":2018,"finding":"In Drosophila, mutations in thoc7 (and thoc5) disrupt interactions among the remaining THO subunits and reduce UAP56 binding to the core THO subunit Hpr1, thereby disrupting piRNA precursor complex assembly. THOC7 mutations are viable but cause sterility and impair piRNA biogenesis. Furthermore, thoc7 mutations reduce Rhino (HP1 homolog) binding to piRNA clusters and trigger ectopic Rhino binding across the genome, demonstrating that THO complexes restrict Rhino localization to cluster heterochromatin.","method":"Genetic epistasis (viable thoc7 mutations), co-immunoprecipitation (subunit interaction mapping), germline sterility assay, ChIP for Rhino","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mutations, reciprocal co-IP for subunit interactions, ChIP, and functional piRNA/Rhino localization assays, replicated with multiple THO subunit alleles","pmids":["30257203"],"is_preprint":false},{"year":2019,"finding":"THOC7 negatively regulates the cellular antiviral innate immune response by promoting K48-linked polyubiquitination and proteasomal degradation of TBK1. THOC7 overexpression inhibited Sendai virus- or polyI:C-induced IRF3 dimerization/phosphorylation and IFN-β production, while THOC7 knockdown had opposite effects. THOC7 was found to associate with the MAVS signalosome and acts at the TBK1 level of the RLR/MAVS signaling cascade.","method":"Overexpression and knockdown (siRNA), co-immunoprecipitation (MAVS signalosome), ubiquitination assay (K48 polyubiquitination), IRF3 dimerization/phosphorylation assay, IFN-β reporter assay","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, ubiquitination assay, and gain/loss-of-function with defined molecular readouts; single lab","pmids":["30769920"],"is_preprint":false},{"year":2020,"finding":"Human THOC7 occupies repetitive genomic sequences (microsatellite repeats in genic/intergenic regions and telomeric repeats) as determined by ChIP-seq; THOC7 ChIP peaks overlap with those of elongating RNA Pol II and R-loops, indicating accumulation at transcriptionally active repeat regions. Knockdown of THOC5 (an RNA-binding THO subunit) induces γH2AX accumulation at repeat regions and telomere aberrations, linking the THO complex to maintenance of genome stability at repetitive sequences.","method":"Chromatin immunoprecipitation sequencing (ChIP-seq) of THOC7, siRNA knockdown of THOC5, γH2AX immunofluorescence, R-loop co-localization","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq for direct genomic localization of THOC7 protein, functional consequence shown by γH2AX after THOC5 KD; single lab","pmids":["32065701"],"is_preprint":false},{"year":2014,"finding":"Depletion of THOC7 (along with THOC5) selectively reduced the level of unspliced (but not spliced) murine leukemia virus (MLV) transcripts in the cytoplasm, and THOC5 RNA immunoprecipitation showed association specifically with the unspliced viral transcript, placing THOC7/THOC5 in the nuclear export pathway for unspliced viral RNAs via the NXF1 pathway.","method":"siRNA knockdown of THOC7/THOC5, cytoplasmic RNA quantification, RNA immunoprecipitation (THOC5)","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — selective knockdown with transcript fractionation and RNA-protein interaction (RIP), single lab, two orthogonal methods","pmids":["24618812"],"is_preprint":false},{"year":2021,"finding":"In Drosophila, null thoc7 mutations displace Thoc5 and Thoc6 from a Tho2-Hpr1 subcomplex. Despite reducing expression of a subset of germline piRNAs and increasing transposon transcription, thoc7-null mutations do not reduce anti-sense piRNAs targeting half of the activated transposon families, do not reduce piRNA-guided H3K9me3, and do not block Panoramix-dependent silencing of a reporter. Unspliced transposon transcripts co-precipitate with THO through a Piwi- and Panoramix-independent mechanism. Piwi mutations dominantly enhance germline defects in thoc7-null alleles, establishing that THO acts in a piRNA-independent transposon-silencing pathway cooperatively with Piwi.","method":"Genetic epistasis (null thoc7 alleles, piwi mutations, double mutants), RNA co-immunoprecipitation (transposon transcript-THO), H3K9me3 ChIP, piRNA sequencing, reporter transgene assay","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (genetic epistasis, RNA co-IP, ChIP, piRNA-seq, reporter assay) in a single rigorous study establishing a piRNA-independent mechanism","pmids":["34547226"],"is_preprint":false},{"year":2022,"finding":"THOC7 directly binds lncRNA Pnky as confirmed by colocalization and RNA immunoprecipitation (RIP) assays, and this interaction is proposed to couple mRNA splicing and nuclear export of NSC migration-related mRNAs.","method":"RNA immunoprecipitation (RIP), colocalization assay","journal":"Cellular and molecular neurobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RIP assay and colocalization for THOC7-Pnky binding; functional consequence attributed to the lncRNA pathway, not directly to THOC7 alone; single lab","pmids":["35748966"],"is_preprint":false},{"year":2026,"finding":"In Drosophila, thoc7 mutations (which disrupt piRNA precursor binding to the THO complex) delay RDC (Rhino-Deadlock-Cuff) relocalization to piRNA clusters after acute heat shock, while piwi mutations accelerate it. This places THOC7-dependent THO complex assembly upstream of RDC cluster reassembly after stress, and demonstrates that maternally deposited piRNAs are dispensable for RDC localization to the major 42AB cluster.","method":"Genetic epistasis (thoc7 mutants, piwi mutants), live imaging of RDC localization, fluorescence microscopy after heat shock recovery","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with defined alleles and imaging-based functional readout; single lab, single study","pmids":["41397876"],"is_preprint":false}],"current_model":"THOC7 is a structural subunit of the evolutionarily conserved THO/TREX complex that, through direct interaction with THOC5/FMIP (required for its own nuclear import), participates in co-transcriptional mRNA processing and selective nuclear export of specific transcripts (including heat-shock mRNAs and unspliced viral RNAs); in the Drosophila germline, THOC7 is required for THO complex integrity (its absence displaces THOC5/6 from the Tho2-Hpr1 core), promotes piRNA precursor association with the THO complex to restrict Rhino heterochromatin to cluster loci, and supports a piRNA-independent transposon-silencing pathway acting cooperatively with Piwi; in addition, human THOC7 localizes to transcriptionally active repetitive genomic regions (microsatellites, telomeres) where it helps maintain genome stability, and in the innate immune context THOC7 negatively regulates antiviral signaling by promoting K48-polyubiquitination and proteasomal degradation of TBK1."},"narrative":{"mechanistic_narrative":"THOC7 is a structural subunit of the evolutionarily conserved THO/TREX complex that participates in co-transcriptional mRNA processing and selective nuclear export of specific transcripts, including heat-shock mRNAs and unspliced viral RNAs [PMID:15133499, PMID:21525145, PMID:24618812]. THOC7 lacks a nuclear localization signal and depends on a direct interaction between its central region (aa 50–137) and the N-terminus of THOC5/FMIP for its own nuclear import [PMID:19059247]. In the Drosophila germline, THOC7 is essential for THO complex integrity: its loss displaces THOC5 and THOC6 from the Tho2–Hpr1 core and weakens UAP56 binding, disrupting piRNA precursor complex assembly and causing sterility, while restricting Rhino (RDC) heterochromatin to piRNA cluster loci [PMID:30257203, PMID:34547226, PMID:41397876]. THO/THOC7 additionally supports a piRNA-independent transposon-silencing pathway that acts cooperatively with Piwi, capturing unspliced transposon transcripts independently of Panoramix [PMID:34547226]. In human cells THOC7 occupies transcriptionally active repetitive genomic regions (microsatellites and telomeres) coincident with elongating RNA Pol II and R-loops, contributing to genome stability at these sequences [PMID:32065701]. Beyond its RNA-handling roles, THOC7 negatively regulates antiviral innate immunity by associating with the MAVS signalosome and promoting K48-linked polyubiquitination and proteasomal degradation of TBK1, dampening IRF3 activation and IFN-β production [PMID:30769920].","teleology":[{"year":2004,"claim":"Established THOC7 as a metazoan-specific subunit of the THO complex and defined the complex's selective role in stress-induced mRNA export, answering whether THO acts globally or on specific transcripts.","evidence":"Microarray expression profiling after RNAi depletion of THO subunits in Drosophila cells","pmids":["15133499"],"confidence":"Medium","gaps":["Did not map THOC7's contribution distinct from other subunits","No mechanism for transcript selectivity","No structural placement of THOC7 within the complex"]},{"year":2008,"claim":"Resolved how THOC7 enters the nucleus, showing that it has no intrinsic NLS and is imported via direct binding to THOC5/FMIP, defining a subunit dependency for assembly.","evidence":"Co-immunoprecipitation, deletion mapping (THOC7 aa 50–137 to FMIP aa 1–199), and co-localization microscopy with a binding-deficient mutant","pmids":["19059247"],"confidence":"Medium","gaps":["Binding interface not validated by structure","Did not test whether import is required for THO function","Single-lab mapping"]},{"year":2011,"claim":"Confirmed THOC7 as a mammalian THO subunit and placed the complex at the post-splicing mRNA export step, distinguishing export from splicing defects.","evidence":"Conditional THOC5 knockout MEFs, cytoplasmic RNA transcriptome analysis, and RNA co-IP with THOC5","pmids":["21525145"],"confidence":"Medium","gaps":["THOC7-specific contribution inferred from THOC5 knockout","Only 10 export-dependent genes identified","No reconstitution of the export step"]},{"year":2014,"claim":"Extended THO/THOC7 function to viral RNA biology, showing selective export of unspliced retroviral transcripts via the NXF1 pathway.","evidence":"siRNA knockdown of THOC7/THOC5, cytoplasmic RNA quantification, and THOC5 RNA immunoprecipitation of unspliced MLV transcripts","pmids":["24618812"],"confidence":"Medium","gaps":["Direct THOC7-RNA contact not demonstrated","Mechanism distinguishing spliced from unspliced transcripts unresolved","Single virus model"]},{"year":2018,"claim":"Defined THOC7 as required for THO complex integrity in the germline and for restricting Rhino heterochromatin to piRNA clusters, linking complex assembly to piRNA biogenesis.","evidence":"Viable thoc7 mutations, reciprocal co-IP subunit mapping, sterility assays, and Rhino ChIP in Drosophila","pmids":["30257203"],"confidence":"High","gaps":["Molecular basis of UAP56 recruitment loss not detailed","How THO restricts Rhino spreading mechanistically unclear"]},{"year":2019,"claim":"Uncovered a non-RNA-export role for THOC7 as a negative regulator of antiviral signaling, identifying TBK1 as a degradation target.","evidence":"Gain/loss-of-function (overexpression/siRNA), MAVS signalosome co-IP, K48 ubiquitination assay, IRF3 dimerization, and IFN-β reporter assays","pmids":["30769920"],"confidence":"Medium","gaps":["E3 ligase mediating TBK1 ubiquitination not identified","Whether THOC7 acts as part of THO complex here is unknown","Single-lab study"]},{"year":2020,"claim":"Localized human THOC7 directly to transcriptionally active repetitive sequences and tied the THO complex to genome stability at these loci.","evidence":"THOC7 ChIP-seq overlapping elongating Pol II and R-loops, plus γH2AX immunofluorescence and telomere aberration scoring after THOC5 knockdown","pmids":["32065701"],"confidence":"Medium","gaps":["Genome-instability phenotype shown via THOC5, not THOC7, knockdown","Mechanism linking THOC7 occupancy to R-loop resolution unresolved"]},{"year":2021,"claim":"Established that THO acts in a piRNA- and Panoramix-independent transposon-silencing pathway cooperatively with Piwi, separating THO's silencing role from canonical piRNA-guided heterochromatin.","evidence":"Null thoc7 and piwi alleles and double mutants, RNA co-IP of transposon transcripts, H3K9me3 ChIP, piRNA-seq, and reporter assays","pmids":["34547226"],"confidence":"High","gaps":["Effector of the piRNA-independent silencing not identified","How THO selects unspliced transposon transcripts unclear"]},{"year":2022,"claim":"Proposed a direct THOC7–lncRNA Pnky interaction coupling splicing and export of NSC migration mRNAs.","evidence":"RNA immunoprecipitation and colocalization assays","pmids":["35748966"],"confidence":"Low","gaps":["Single RIP without reciprocal or functional validation of THOC7 alone","Functional outcome attributed to the lncRNA pathway, not THOC7 directly","No binding interface mapped"]},{"year":2026,"claim":"Placed THOC7-dependent THO assembly upstream of RDC cluster reassembly after heat stress and showed maternal piRNAs are dispensable for RDC localization at the major cluster.","evidence":"Genetic epistasis (thoc7, piwi mutants) with live imaging of RDC relocalization after heat shock recovery in Drosophila","pmids":["41397876"],"confidence":"Medium","gaps":["Molecular link between THO assembly and RDC kinetics undefined","Generality beyond the 42AB cluster untested"]},{"year":null,"claim":"How a single subunit reconciles THOC7's roles in mRNA export, repeat genome stability, piRNA-cluster heterochromatin, and TBK1 degradation remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of THOC7 within the THO/TREX complex","E3 ligase and complex context for TBK1 degradation unknown","Whether the immune and RNA-export functions share a mechanism is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2,6]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3,7]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,6]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,7]}],"complexes":["THO complex","TREX complex"],"partners":["THOC5","THOC6","THOC2","THOC1","UAP56","TBK1","MAVS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6I9Y2","full_name":"THO complex subunit 7","aliases":["Functional spliceosome-associated protein 24","fSAP24","Ngg1-interacting factor 3-like protein 1-binding protein 1","NIF3L1-binding protein 1","hTREX30"],"length_aa":204,"mass_kda":23.7,"function":"Component of the THO subcomplex of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and which specifically associates with spliced mRNA and not with unspliced pre-mRNA (PubMed:15833825, PubMed:15998806, PubMed:17190602). Required for efficient export of polyadenylated RNA (PubMed:23222130). Plays a key structural role in the oligomerization of the THO-DDX39B complex (PubMed:33191911). TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NXF1 pathway (PubMed:15833825, PubMed:15998806, PubMed:17190602) (Microbial infection) The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production","subcellular_location":"Cytoplasm; Nucleus; Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/Q6I9Y2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/THOC7","classification":"Common Essential","n_dependent_lines":1194,"n_total_lines":1208,"dependency_fraction":0.9884105960264901},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/THOC7","total_profiled":1310},"omim":[{"mim_id":"615403","title":"THO COMPLEX, SUBUNIT 6; THOC6","url":"https://www.omim.org/entry/615403"},{"mim_id":"612733","title":"THO COMPLEX, SUBUNIT 5; THOC5","url":"https://www.omim.org/entry/612733"},{"mim_id":"611965","title":"THO COMPLEX, SUBUNIT 7; THOC7","url":"https://www.omim.org/entry/611965"},{"mim_id":"606930","title":"THO COMPLEX, SUBUNIT 1; THOC1","url":"https://www.omim.org/entry/606930"},{"mim_id":"606929","title":"THO COMPLEX, SUBUNIT 3; THOC3","url":"https://www.omim.org/entry/606929"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/THOC7"},"hgnc":{"alias_symbol":["NIF3L1BP1","FLJ23445","fSAP24"],"prev_symbol":[]},"alphafold":{"accession":"Q6I9Y2","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6I9Y2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6I9Y2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6I9Y2-F1-predicted_aligned_error_v6.png","plddt_mean":87.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=THOC7","jax_strain_url":"https://www.jax.org/strain/search?query=THOC7"},"sequence":{"accession":"Q6I9Y2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6I9Y2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6I9Y2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6I9Y2"}},"corpus_meta":[{"pmid":"15133499","id":"PMC_15133499","title":"Genome-wide analysis of mRNAs regulated by the THO complex in Drosophila melanogaster.","date":"2004","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15133499","citation_count":178,"is_preprint":false},{"pmid":"28416970","id":"PMC_28416970","title":"DNA methylation profiling in peripheral lung tissues of smokers and patients with COPD.","date":"2017","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/28416970","citation_count":74,"is_preprint":false},{"pmid":"21525145","id":"PMC_21525145","title":"Identification of mRNAs that are spliced but not exported to the cytoplasm in the absence of THOC5 in mouse embryo fibroblasts.","date":"2011","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/21525145","citation_count":56,"is_preprint":false},{"pmid":"26291246","id":"PMC_26291246","title":"Interplay between promoter methylation and chromosomal loss in gene silencing at 3p11-p14 in cervical cancer.","date":"2015","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/26291246","citation_count":43,"is_preprint":false},{"pmid":"23335387","id":"PMC_23335387","title":"Identification of eight candidate target genes of the recurrent 3p12-p14 loss in cervical cancer by integrative genomic profiling.","date":"2013","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23335387","citation_count":40,"is_preprint":false},{"pmid":"30257203","id":"PMC_30257203","title":"Co-dependent Assembly of Drosophila piRNA Precursor Complexes and piRNA Cluster Heterochromatin.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30257203","citation_count":27,"is_preprint":false},{"pmid":"19059247","id":"PMC_19059247","title":"Nuclear localization of the pre-mRNA associating protein THOC7 depends upon its direct interaction with Fms tyrosine kinase interacting protein (FMIP).","date":"2008","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/19059247","citation_count":17,"is_preprint":false},{"pmid":"32116545","id":"PMC_32116545","title":"Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor.","date":"2020","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32116545","citation_count":16,"is_preprint":false},{"pmid":"35748966","id":"PMC_35748966","title":"LncRNA Pnky Positively Regulates Neural Stem Cell Migration by Modulating mRNA Splicing and Export of Target Genes.","date":"2022","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/35748966","citation_count":15,"is_preprint":false},{"pmid":"34547226","id":"PMC_34547226","title":"piRNA-independent transposon silencing by the Drosophila THO complex.","date":"2021","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/34547226","citation_count":14,"is_preprint":false},{"pmid":"30769920","id":"PMC_30769920","title":"THO Complex Subunit 7 Homolog Negatively Regulates Cellular Antiviral Response against RNA Viruses by Targeting TBK1.","date":"2019","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/30769920","citation_count":12,"is_preprint":false},{"pmid":"37092861","id":"PMC_37092861","title":"Brain transcriptome-wide association study implicates novel risk genes underlying schizophrenia risk.","date":"2023","source":"Psychological medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37092861","citation_count":11,"is_preprint":false},{"pmid":"24618812","id":"PMC_24618812","title":"Murine leukemia virus uses TREX components for efficient nuclear export of unspliced viral transcripts.","date":"2014","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/24618812","citation_count":8,"is_preprint":false},{"pmid":"38605354","id":"PMC_38605354","title":"THOC7-AS1/OCT1/FSTL1 axis promotes EMT and serves as a therapeutic target in cutaneous squamous cell carcinoma.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38605354","citation_count":7,"is_preprint":false},{"pmid":"31935505","id":"PMC_31935505","title":"Identification, expression profiling and localization of thoc in common carp ovary: Influence of thoc3-siRNA transient silencing.","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/31935505","citation_count":7,"is_preprint":false},{"pmid":"32065701","id":"PMC_32065701","title":"Human THO maintains the stability of repetitive DNA.","date":"2020","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/32065701","citation_count":7,"is_preprint":false},{"pmid":"41397876","id":"PMC_41397876","title":"Rapid disassembly and Piwi-independent reassembly of Drosophila piRNA cluster heterochromatin following acute heat shock.","date":"2026","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/41397876","citation_count":1,"is_preprint":false},{"pmid":"41938520","id":"PMC_41938520","title":"Integrative Multi-Omics and Single-Cell Analysis Reveal THOC3 and THOC7 as Oncogenic RNA Processing Regulators in Lung Adenocarcinoma.","date":"2026","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41938520","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11222,"output_tokens":3120,"usd":0.040233,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10480,"output_tokens":3551,"usd":0.070587,"stage2_stop_reason":"end_turn"},"total_usd":0.11082,"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\": 2004,\n      \"finding\": \"Drosophila THO complex is composed of THO2, HPR1, THOC5, THOC6, and THOC7 (the latter three having no orthologs in budding yeast). Depletion of THO components showed that export of heat-shock mRNAs under heat stress is strictly dependent on THO function, while <20% of the transcriptome is regulated by THO under normal conditions.\",\n      \"method\": \"Gene expression profiling (microarray) in Drosophila cells depleted of THO components; RNAi knockdown\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi depletion with transcriptome-wide readout in Drosophila, single lab but multiple components tested and replicated across subunits\",\n      \"pmids\": [\"15133499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"THOC7 does not contain a nuclear localization signal and resides mainly in the cytoplasm in the absence of FMIP (THOC5). THOC7 (amino acids 50–137) directly binds the N-terminal portion (aa 1–199) of FMIP, and this interaction is required for THOC7 nuclear localization; a THOC7 mutant lacking the FMIP-binding site fails to co-localize with FMIP in the nucleus.\",\n      \"method\": \"Co-immunoprecipitation, deletion mapping, fluorescence microscopy (co-localization), direct binding assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding mapped to defined domains, co-localization imaging, and functional mutant validation in a single lab\",\n      \"pmids\": [\"19059247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"THOC7 is a component of the mammalian THO subcomplex (together with THOC1, THOC2, THOC5, THOC6), which is part of the TREX complex required for nuclear export of specific mRNAs. In THOC5-knockout mouse embryo fibroblasts, 10 genes were identified that were spliced but not exported to the cytoplasm; these mRNAs co-purified with THOC5, placing THO at the mRNA export step. Hsp70 mRNA export required THOC5 under heat shock (42°C) but not under normal conditions (37°C).\",\n      \"method\": \"Conditional knockout (Cre/lox), transcriptome analysis of cytoplasmic RNA, RNA co-immunoprecipitation with THOC5\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with cytoplasmic RNA fractionation and RNA co-IP, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"21525145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Drosophila, mutations in thoc7 (and thoc5) disrupt interactions among the remaining THO subunits and reduce UAP56 binding to the core THO subunit Hpr1, thereby disrupting piRNA precursor complex assembly. THOC7 mutations are viable but cause sterility and impair piRNA biogenesis. Furthermore, thoc7 mutations reduce Rhino (HP1 homolog) binding to piRNA clusters and trigger ectopic Rhino binding across the genome, demonstrating that THO complexes restrict Rhino localization to cluster heterochromatin.\",\n      \"method\": \"Genetic epistasis (viable thoc7 mutations), co-immunoprecipitation (subunit interaction mapping), germline sterility assay, ChIP for Rhino\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mutations, reciprocal co-IP for subunit interactions, ChIP, and functional piRNA/Rhino localization assays, replicated with multiple THO subunit alleles\",\n      \"pmids\": [\"30257203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"THOC7 negatively regulates the cellular antiviral innate immune response by promoting K48-linked polyubiquitination and proteasomal degradation of TBK1. THOC7 overexpression inhibited Sendai virus- or polyI:C-induced IRF3 dimerization/phosphorylation and IFN-β production, while THOC7 knockdown had opposite effects. THOC7 was found to associate with the MAVS signalosome and acts at the TBK1 level of the RLR/MAVS signaling cascade.\",\n      \"method\": \"Overexpression and knockdown (siRNA), co-immunoprecipitation (MAVS signalosome), ubiquitination assay (K48 polyubiquitination), IRF3 dimerization/phosphorylation assay, IFN-β reporter assay\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, ubiquitination assay, and gain/loss-of-function with defined molecular readouts; single lab\",\n      \"pmids\": [\"30769920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human THOC7 occupies repetitive genomic sequences (microsatellite repeats in genic/intergenic regions and telomeric repeats) as determined by ChIP-seq; THOC7 ChIP peaks overlap with those of elongating RNA Pol II and R-loops, indicating accumulation at transcriptionally active repeat regions. Knockdown of THOC5 (an RNA-binding THO subunit) induces γH2AX accumulation at repeat regions and telomere aberrations, linking the THO complex to maintenance of genome stability at repetitive sequences.\",\n      \"method\": \"Chromatin immunoprecipitation sequencing (ChIP-seq) of THOC7, siRNA knockdown of THOC5, γH2AX immunofluorescence, R-loop co-localization\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq for direct genomic localization of THOC7 protein, functional consequence shown by γH2AX after THOC5 KD; single lab\",\n      \"pmids\": [\"32065701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Depletion of THOC7 (along with THOC5) selectively reduced the level of unspliced (but not spliced) murine leukemia virus (MLV) transcripts in the cytoplasm, and THOC5 RNA immunoprecipitation showed association specifically with the unspliced viral transcript, placing THOC7/THOC5 in the nuclear export pathway for unspliced viral RNAs via the NXF1 pathway.\",\n      \"method\": \"siRNA knockdown of THOC7/THOC5, cytoplasmic RNA quantification, RNA immunoprecipitation (THOC5)\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — selective knockdown with transcript fractionation and RNA-protein interaction (RIP), single lab, two orthogonal methods\",\n      \"pmids\": [\"24618812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Drosophila, null thoc7 mutations displace Thoc5 and Thoc6 from a Tho2-Hpr1 subcomplex. Despite reducing expression of a subset of germline piRNAs and increasing transposon transcription, thoc7-null mutations do not reduce anti-sense piRNAs targeting half of the activated transposon families, do not reduce piRNA-guided H3K9me3, and do not block Panoramix-dependent silencing of a reporter. Unspliced transposon transcripts co-precipitate with THO through a Piwi- and Panoramix-independent mechanism. Piwi mutations dominantly enhance germline defects in thoc7-null alleles, establishing that THO acts in a piRNA-independent transposon-silencing pathway cooperatively with Piwi.\",\n      \"method\": \"Genetic epistasis (null thoc7 alleles, piwi mutations, double mutants), RNA co-immunoprecipitation (transposon transcript-THO), H3K9me3 ChIP, piRNA sequencing, reporter transgene assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (genetic epistasis, RNA co-IP, ChIP, piRNA-seq, reporter assay) in a single rigorous study establishing a piRNA-independent mechanism\",\n      \"pmids\": [\"34547226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"THOC7 directly binds lncRNA Pnky as confirmed by colocalization and RNA immunoprecipitation (RIP) assays, and this interaction is proposed to couple mRNA splicing and nuclear export of NSC migration-related mRNAs.\",\n      \"method\": \"RNA immunoprecipitation (RIP), colocalization assay\",\n      \"journal\": \"Cellular and molecular neurobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RIP assay and colocalization for THOC7-Pnky binding; functional consequence attributed to the lncRNA pathway, not directly to THOC7 alone; single lab\",\n      \"pmids\": [\"35748966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In Drosophila, thoc7 mutations (which disrupt piRNA precursor binding to the THO complex) delay RDC (Rhino-Deadlock-Cuff) relocalization to piRNA clusters after acute heat shock, while piwi mutations accelerate it. This places THOC7-dependent THO complex assembly upstream of RDC cluster reassembly after stress, and demonstrates that maternally deposited piRNAs are dispensable for RDC localization to the major 42AB cluster.\",\n      \"method\": \"Genetic epistasis (thoc7 mutants, piwi mutants), live imaging of RDC localization, fluorescence microscopy after heat shock recovery\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with defined alleles and imaging-based functional readout; single lab, single study\",\n      \"pmids\": [\"41397876\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"THOC7 is a structural subunit of the evolutionarily conserved THO/TREX complex that, through direct interaction with THOC5/FMIP (required for its own nuclear import), participates in co-transcriptional mRNA processing and selective nuclear export of specific transcripts (including heat-shock mRNAs and unspliced viral RNAs); in the Drosophila germline, THOC7 is required for THO complex integrity (its absence displaces THOC5/6 from the Tho2-Hpr1 core), promotes piRNA precursor association with the THO complex to restrict Rhino heterochromatin to cluster loci, and supports a piRNA-independent transposon-silencing pathway acting cooperatively with Piwi; in addition, human THOC7 localizes to transcriptionally active repetitive genomic regions (microsatellites, telomeres) where it helps maintain genome stability, and in the innate immune context THOC7 negatively regulates antiviral signaling by promoting K48-polyubiquitination and proteasomal degradation of TBK1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"THOC7 is a structural subunit of the evolutionarily conserved THO/TREX complex that participates in co-transcriptional mRNA processing and selective nuclear export of specific transcripts, including heat-shock mRNAs and unspliced viral RNAs [#0, #2, #6]. THOC7 lacks a nuclear localization signal and depends on a direct interaction between its central region (aa 50–137) and the N-terminus of THOC5/FMIP for its own nuclear import [#1]. In the Drosophila germline, THOC7 is essential for THO complex integrity: its loss displaces THOC5 and THOC6 from the Tho2–Hpr1 core and weakens UAP56 binding, disrupting piRNA precursor complex assembly and causing sterility, while restricting Rhino (RDC) heterochromatin to piRNA cluster loci [#3, #7, #9]. THO/THOC7 additionally supports a piRNA-independent transposon-silencing pathway that acts cooperatively with Piwi, capturing unspliced transposon transcripts independently of Panoramix [#7]. In human cells THOC7 occupies transcriptionally active repetitive genomic regions (microsatellites and telomeres) coincident with elongating RNA Pol II and R-loops, contributing to genome stability at these sequences [#5]. Beyond its RNA-handling roles, THOC7 negatively regulates antiviral innate immunity by associating with the MAVS signalosome and promoting K48-linked polyubiquitination and proteasomal degradation of TBK1, dampening IRF3 activation and IFN-β production [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established THOC7 as a metazoan-specific subunit of the THO complex and defined the complex's selective role in stress-induced mRNA export, answering whether THO acts globally or on specific transcripts.\",\n      \"evidence\": \"Microarray expression profiling after RNAi depletion of THO subunits in Drosophila cells\",\n      \"pmids\": [\"15133499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not map THOC7's contribution distinct from other subunits\", \"No mechanism for transcript selectivity\", \"No structural placement of THOC7 within the complex\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved how THOC7 enters the nucleus, showing that it has no intrinsic NLS and is imported via direct binding to THOC5/FMIP, defining a subunit dependency for assembly.\",\n      \"evidence\": \"Co-immunoprecipitation, deletion mapping (THOC7 aa 50–137 to FMIP aa 1–199), and co-localization microscopy with a binding-deficient mutant\",\n      \"pmids\": [\"19059247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface not validated by structure\", \"Did not test whether import is required for THO function\", \"Single-lab mapping\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Confirmed THOC7 as a mammalian THO subunit and placed the complex at the post-splicing mRNA export step, distinguishing export from splicing defects.\",\n      \"evidence\": \"Conditional THOC5 knockout MEFs, cytoplasmic RNA transcriptome analysis, and RNA co-IP with THOC5\",\n      \"pmids\": [\"21525145\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"THOC7-specific contribution inferred from THOC5 knockout\", \"Only 10 export-dependent genes identified\", \"No reconstitution of the export step\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended THO/THOC7 function to viral RNA biology, showing selective export of unspliced retroviral transcripts via the NXF1 pathway.\",\n      \"evidence\": \"siRNA knockdown of THOC7/THOC5, cytoplasmic RNA quantification, and THOC5 RNA immunoprecipitation of unspliced MLV transcripts\",\n      \"pmids\": [\"24618812\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct THOC7-RNA contact not demonstrated\", \"Mechanism distinguishing spliced from unspliced transcripts unresolved\", \"Single virus model\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined THOC7 as required for THO complex integrity in the germline and for restricting Rhino heterochromatin to piRNA clusters, linking complex assembly to piRNA biogenesis.\",\n      \"evidence\": \"Viable thoc7 mutations, reciprocal co-IP subunit mapping, sterility assays, and Rhino ChIP in Drosophila\",\n      \"pmids\": [\"30257203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of UAP56 recruitment loss not detailed\", \"How THO restricts Rhino spreading mechanistically unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Uncovered a non-RNA-export role for THOC7 as a negative regulator of antiviral signaling, identifying TBK1 as a degradation target.\",\n      \"evidence\": \"Gain/loss-of-function (overexpression/siRNA), MAVS signalosome co-IP, K48 ubiquitination assay, IRF3 dimerization, and IFN-β reporter assays\",\n      \"pmids\": [\"30769920\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating TBK1 ubiquitination not identified\", \"Whether THOC7 acts as part of THO complex here is unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Localized human THOC7 directly to transcriptionally active repetitive sequences and tied the THO complex to genome stability at these loci.\",\n      \"evidence\": \"THOC7 ChIP-seq overlapping elongating Pol II and R-loops, plus γH2AX immunofluorescence and telomere aberration scoring after THOC5 knockdown\",\n      \"pmids\": [\"32065701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genome-instability phenotype shown via THOC5, not THOC7, knockdown\", \"Mechanism linking THOC7 occupancy to R-loop resolution unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that THO acts in a piRNA- and Panoramix-independent transposon-silencing pathway cooperatively with Piwi, separating THO's silencing role from canonical piRNA-guided heterochromatin.\",\n      \"evidence\": \"Null thoc7 and piwi alleles and double mutants, RNA co-IP of transposon transcripts, H3K9me3 ChIP, piRNA-seq, and reporter assays\",\n      \"pmids\": [\"34547226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effector of the piRNA-independent silencing not identified\", \"How THO selects unspliced transposon transcripts unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Proposed a direct THOC7–lncRNA Pnky interaction coupling splicing and export of NSC migration mRNAs.\",\n      \"evidence\": \"RNA immunoprecipitation and colocalization assays\",\n      \"pmids\": [\"35748966\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single RIP without reciprocal or functional validation of THOC7 alone\", \"Functional outcome attributed to the lncRNA pathway, not THOC7 directly\", \"No binding interface mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed THOC7-dependent THO assembly upstream of RDC cluster reassembly after heat stress and showed maternal piRNAs are dispensable for RDC localization at the major cluster.\",\n      \"evidence\": \"Genetic epistasis (thoc7, piwi mutants) with live imaging of RDC relocalization after heat shock recovery in Drosophila\",\n      \"pmids\": [\"41397876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between THO assembly and RDC kinetics undefined\", \"Generality beyond the 42AB cluster untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single subunit reconciles THOC7's roles in mRNA export, repeat genome stability, piRNA-cluster heterochromatin, and TBK1 degradation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of THOC7 within the THO/TREX complex\", \"E3 ligase and complex context for TBK1 degradation unknown\", \"Whether the immune and RNA-export functions share a mechanism is untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 7]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [\n      \"THO complex\",\n      \"TREX complex\"\n    ],\n    \"partners\": [\n      \"THOC5\",\n      \"THOC6\",\n      \"THOC2\",\n      \"THOC1\",\n      \"UAP56\",\n      \"TBK1\",\n      \"MAVS\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}