{"gene":"THRAP3","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2010,"finding":"TRAP150 (THRAP3) co-localizes with splicing factors in nuclear speckles, is required for pre-mRNA splicing in vivo, activates splicing, remains associated with spliced mRNA after splicing, interacts with the exon junction complex (EJC), and when tethered to a precursor mRNA, triggers nuclear mRNA degradation independently of nonsense-mediated decay. Splicing activation and mRNA degradation functions were mapped to separable domains.","method":"Co-localization (immunofluorescence), in vivo splicing assays, RNA tethering assays, co-immunoprecipitation with EJC components","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, splicing assays, tethering assays, domain mapping) in a single focused study; replicated aspects confirmed in later papers","pmids":["20123736"],"is_preprint":false},{"year":2012,"finding":"THRAP3 is excluded from sites of DNA damage following genotoxic stress, and THRAP3 depletion causes cellular hypersensitivity to DNA-damaging agents, implicating it in the DNA damage response through its RNA processing functions.","method":"Mass spectrometry-based phosphoproteomics, immunofluorescence (exclusion from DNA damage foci), siRNA knockdown with clonogenic survival assays","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative phosphoproteomics plus imaging and functional knockdown, but mechanistic detail of exclusion is not fully resolved","pmids":["22424773"],"is_preprint":false},{"year":2013,"finding":"THRAP3 physically associates with HELZ2 and PPARγ in differentiated 3T3-L1 adipocytes. HELZ2 interacts with the serine/arginine-rich domain and BCLAF1-homologous region of THRAP3, while THRAP3 directly binds two helicase motifs in HELZ2. THRAP3 and HELZ2 are co-recruited to PPARγ-response elements in Fabp4/aP2 and Adipoq gene enhancers in a ligand-dependent manner, and THRAP3 knockdown attenuates PPARγ-driven adipocyte differentiation.","method":"Yeast two-hybrid, co-immunoprecipitation, mass spectrometry, chromatin immunoprecipitation (ChIP), siRNA knockdown with gene expression and lipid droplet readouts","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, domain mapping, ChIP, and functional knockdown phenotype across multiple orthogonal methods","pmids":["23525231"],"is_preprint":false},{"year":2013,"finding":"TRAP150 (THRAP3) localizes at active transcription loci in an RNA polymerase II-dependent manner and co-localizes with the EJC protein Magoh. Unlike BCLAF1 (Btf), TRAP150 depletion does not affect nuclear export of β-tropomyosin transcripts or global polyadenylated RNA cytoplasmic distribution, indicating distinct roles for the two paralogs in mRNA distribution.","method":"Immunofluorescence at reporter gene loci, siRNA knockdown, nuclear/cytoplasmic fractionation with RNA quantification","journal":"Nucleus (Austin, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional knockdown, single lab, two orthogonal methods","pmids":["23778535"],"is_preprint":false},{"year":2014,"finding":"THRAP3 (Thrap3) directly interacts with PPARγ specifically when PPARγ is phosphorylated at Ser273 by CDK5, and this interaction controls diabetic gene programming in adipocytes. Knockdown of Thrap3 restores genes dysregulated by CDK5 phosphorylation of PPARγ, and in vivo antisense oligonucleotide-mediated reduction of Thrap3 in adipose tissue improves hyperglycemia and insulin resistance in high-fat-fed mice.","method":"Co-immunoprecipitation, phospho-specific binding assays, siRNA knockdown in cultured adipocytes, antisense oligonucleotide knockdown in mouse adipose tissue, metabolic phenotyping","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP demonstrating phospho-dependent interaction, replicated in vivo with ASO knockdown and metabolic readouts, multiple orthogonal methods","pmids":["25316675"],"is_preprint":false},{"year":2014,"finding":"TRAP150 interacts with the cleavage and polyadenylation specificity factor (CPSF) and co-fractionates with CPSF and RNA polymerase II. TRAP150 preferentially associates with U1 snRNP and activates splicing in composite terminal exons but not authentic terminal exons, providing a mechanism to regulate premature cleavage and polyadenylation (PCPA) transcripts.","method":"Co-immunoprecipitation, co-fractionation, in vivo splicing reporter assays, U1 snRNP inhibition experiments","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and functional reporter assays in one lab with multiple constructs, but replication is limited","pmids":["25326322"],"is_preprint":false},{"year":2015,"finding":"TRAP150 binds the RNA recognition motifs (RRMs) of PSF/SFPQ via a 70-residue PSF-interacting domain (PID). This interaction directly inhibits PSF's binding to RNA through RRM2, but does not prevent PSF dimerization with other DBHS proteins. TRAP150 antagonizes PSF-mediated splicing suppression across ~40 T cell splicing events.","method":"Co-immunoprecipitation, domain mapping with deletion mutants, in vitro RNA-binding competition assays, RASL-Seq, siRNA knockdown","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding competition, domain-level mapping, transcriptome-wide RASL-Seq, and mechanistic epistasis between TRAP150 and PSF","pmids":["26261210"],"is_preprint":false},{"year":2016,"finding":"THRAP3 phosphorylation at Ser248 and Ser253 is significantly reduced in androgen-independent prostate cancer cells. Pull-down assays show that the phosphorylation state at these residues alters THRAP3's interaction partners: 32 proteins uniquely bind the nonphosphorylatable mutant and 31 uniquely bind the phosphomimetic form, with many differentially interacting proteins involved in RNA splicing and processing.","method":"Quantitative phosphoproteomics (mass spectrometry), pull-down assays with phosphomimetic and nonphosphorylatable THRAP3 mutants","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative MS-based phosphoproteomics and pull-down with mutants, single lab, two orthogonal methods","pmids":["26841317"],"is_preprint":false},{"year":2017,"finding":"THRAP3 is a component of a SOX9 transcriptional complex and negatively regulates SOX9 transcriptional activity during chondrogenesis. The interaction is mediated between the proline-, glutamine-, and serine-rich (PQS) domain of SOX9 and the innominate domain of THRAP3. THRAP3 knockdown increases Col2a1 expression, and co-overexpression of THRAP3 and SOX9 reduces Col2a1 levels more than SOX9 alone.","method":"LC-MS/MS purification of FLAG-tagged SOX9-binding proteins from knock-in mice, co-immunoprecipitation, domain mapping, siRNA knockdown, overexpression in chondrogenic cells","journal":"Journal of bone and mineral metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous complex purification by MS plus co-IP and functional knockdown/overexpression, single lab","pmids":["28770354"],"is_preprint":false},{"year":2017,"finding":"Depletion of THRAP3 and/or BCLAF1 causes sensitivity to DNA-damaging agents, defective DNA repair, and genomic instability. THRAP3 and BCLAF1 regulate selective mRNA splicing and nuclear export of transcripts encoding key DDR proteins including ATM kinase. Cancer-associated mutations in THRAP3 deregulate processing of THRAP3/BCLAF1-regulated transcripts and impair DNA repair.","method":"siRNA knockdown, clonogenic survival assays, comet assay, γH2AX foci, RNA splicing and nuclear export assays, mutant THRAP3 expression","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts (repair, splicing, export) with knockdown and mutant expression, single lab","pmids":["29112714"],"is_preprint":false},{"year":2017,"finding":"Depletion of TRAP150 (THRAP3) causes mitotic chromosome misalignment defects and alters the abundance of transcripts encoding mitotic regulators, suggesting TRAP150 controls mitotic progression through regulation of mitotic checkpoint regulator mRNAs.","method":"siRNA knockdown, immunofluorescence (mitotic defect scoring), RT-PCR for mitotic regulator transcripts","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach with indirect mechanistic link; proposed pathway not directly demonstrated","pmids":["28895891"],"is_preprint":false},{"year":2021,"finding":"Thrap3 interacts with methylated DDX5 (arginine methylation required) and localizes to R-loops. The Thrap3-DDX5 axis recruits XRN2 (5'-3' exoribonuclease 2) to R-loops to promote their resolution. Loss of Thrap3 increases R-loop accumulation and DNA damage.","method":"Co-immunoprecipitation, S9.6 antibody-based R-loop detection (DRIP assay), proximity ligation assays, Thrap3 knockdown with γH2AX readout","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating protein interaction, R-loop accumulation upon knockdown, XRN2 recruitment assay; single lab with multiple orthogonal methods","pmids":["34697388"],"is_preprint":false},{"year":2021,"finding":"Nuclear PD-L1 interacts with THRAP3 to upregulate BUB1 expression, thereby accelerating cell cycle progression in BRAF-mutated colorectal cancer cells. PD-L1 translocation into the nucleus is facilitated by binding of p-ERK.","method":"Co-immunoprecipitation, nuclear fractionation, siRNA knockdown, reporter assays, xenograft models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of nuclear PD-L1 with THRAP3, knockdown with BUB1 expression and cell cycle readouts; single lab","pmids":["34923044"],"is_preprint":false},{"year":2021,"finding":"CLK1 phosphorylates THRAP3 at Ser243, and this phosphorylation is required for THRAP3's regulatory interaction with phosphorylated PPARγ. CLK1-THRAP3 interaction was confirmed by co-immunoprecipitation. This CLK1-THRAP3-PPARγ axis impairs adipose tissue browning and insulin sensitivity.","method":"Phosphoproteomics, co-immunoprecipitation, kinase assay (CLK1 phosphorylation of THRAP3), CLK1 genetic knockout and chemical inhibition in mice","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, in vivo kinase assay, and in vivo mouse phenotyping; single lab with multiple methods","pmids":["34526909"],"is_preprint":false},{"year":2021,"finding":"THRAP3 depletion in 3T3-L1 adipocytes reduces PPARγ mRNA stability (demonstrated by actinomycin D chase), decreases PPARγ protein levels, and attenuates TZD-mediated anti-inflammatory actions including suppression of lipolysis and pro-inflammatory gene expression.","method":"siRNA knockdown, actinomycin D mRNA stability assay, RT-qPCR, Western blot, lipolysis assay","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA stability assay plus functional knockdown phenotype; single lab with two orthogonal methods","pmids":["34370683"],"is_preprint":false},{"year":2023,"finding":"Thrap3 deficiency increases cytosolic translocation of AMPK from the nucleus and enhances AMPK activation through direct physical interaction between AMPK and the C-terminal domain of Thrap3. Liver-specific Thrap3 knockout improves lipid accumulation, enhances autophagy, and improves mitochondrial function in a high-fat diet NAFLD model.","method":"Liver-specific Thrap3 knockout mice, co-immunoprecipitation, subcellular fractionation, AMPK activity assays, autophagic flux assays","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and domain mapping for AMPK interaction, in vivo liver-specific KO with functional readouts; single lab","pmids":["37524868"],"is_preprint":false},{"year":2023,"finding":"Cross-linking mass spectrometry of endogenous immunoprecipitated complexes demonstrates that Thrap3 and Bclaf1 interact closely with each other and with Erh, mapping interaction surfaces to the non-disordered portions of these largely disordered proteins, suggesting they form a novel TEB (Thrap3-Erh-Bclaf1) complex.","method":"Cross-linking mass spectrometry (XL-MS) with MS-cleavable crosslinker DSSO on endogenous immunoprecipitated proteins","journal":"Wellcome open research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural XL-MS method with endogenous proteins mapping interaction surfaces, but single study with limited functional validation","pmids":["35865489"],"is_preprint":false},{"year":2023,"finding":"METTL3-mediated m6A methylation stabilizes THRAP3 mRNA in multiple myeloma cells. Metformin reduces METTL3 activity, decreasing m6A modification on THRAP3 mRNA and reducing its stability and expression. THRAP3 knockdown reverses the pro-proliferative/anti-apoptotic effects of METTL3 overexpression.","method":"MeRIP (m6A RNA immunoprecipitation), siRNA knockdown, METTL3 overexpression, mRNA stability assays, rescue experiments","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP directly detecting m6A on THRAP3 mRNA, functional rescue experiments; single lab","pmids":["36762777"],"is_preprint":false},{"year":2025,"finding":"THRAP3 recruits the splicing factor SLU7 to facilitate GIT2 Exon14 skipping, thereby promoting ferroptosis resistance in AML cells by inhibiting iron accumulation and promoting GSH synthesis. THRAP3 knockdown suppresses AML cell proliferation and delays tumor growth in vivo; inhibition of GIT2 Exon14 skipping reverses THRAP3-induced ferroptosis resistance.","method":"Co-immunoprecipitation (THRAP3-SLU7 interaction), alternative splicing assays, THRAP3 knockdown and overexpression, RSL3/erastin-induced ferroptosis assays, orthotopic and subcutaneous xenograft models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, functional splicing readout, in vivo tumor models; single lab but multiple orthogonal methods","pmids":["41326370"],"is_preprint":false},{"year":2026,"finding":"THRAP3 knockout in C2C12 myotubes suppresses expression of myogenic regulatory factors (Myod1, Mef2c, myosin heavy chain genes), impairs myogenic differentiation and muscle fiber diameter, and attenuates T3 (triiodothyronine)-induced gene expression, establishing THRAP3 as a regulator of myogenesis and thyroid hormone-responsive gene expression in skeletal muscle.","method":"THRAP3 knockout C2C12 cells, RT-qPCR, Western blot, morphological analysis of myotube diameter, T3 stimulation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple gene expression and morphological readouts; single lab, single system","pmids":["41570000"],"is_preprint":false}],"current_model":"THRAP3 (TRAP150) is a multifunctional nuclear SR-like protein that acts as a subunit of the TRAP/Mediator complex and spliceosome: it promotes pre-mRNA splicing and can trigger nuclear mRNA degradation via separable domains; it antagonizes PSF/SFPQ-mediated splicing by binding PSF's RRMs through its PID domain; it selectively regulates mRNA splicing and export of DDR transcripts (including ATM) and promotes R-loop resolution by recruiting methylated DDX5 and XRN2; it is excluded from DNA damage foci and its loss causes genotoxic hypersensitivity; in metabolic contexts it docks on CDK5-phosphorylated PPARγ-Ser273 (a docking event further controlled by CLK1 phosphorylation of THRAP3 at Ser243) to drive diabetic gene programming in adipose tissue, cooperates with HELZ2 at PPARγ-response elements for adipocyte differentiation, maintains PPARγ mRNA stability, and sequesters AMPK in the nucleus to suppress autophagy in the liver; it also negatively regulates SOX9 transcriptional activity during chondrogenesis, and in cancer promotes ferroptosis resistance by recruiting SLU7 to drive GIT2 Exon14 skipping."},"narrative":{"mechanistic_narrative":"THRAP3 (TRAP150) is a nuclear SR-like RNA-processing protein that couples pre-mRNA splicing to downstream RNA fate, localizing to nuclear speckles and active RNA polymerase II transcription loci where it activates splicing, remains bound to spliced mRNA in association with the exon junction complex, and can trigger nuclear mRNA degradation through a domain separable from its splicing-activation function [PMID:20123736, PMID:23778535]. It tunes splice-site choice through partner interactions: it preferentially associates with U1 snRNP and CPSF to regulate premature cleavage and polyadenylation transcripts [PMID:25326322], and it antagonizes PSF/SFPQ-mediated splicing suppression by binding the RRMs of PSF through a dedicated PSF-interacting domain that blocks PSF's RNA binding [PMID:26261210]. THRAP3 selectively governs splicing and nuclear export of DNA-damage-response transcripts including ATM, and—acting with BCLAF1—its loss or cancer-associated mutation impairs DNA repair and causes genotoxic hypersensitivity and genomic instability [PMID:22424773, PMID:29112714]; it further safeguards genome integrity by interacting with arginine-methylated DDX5 to recruit the exoribonuclease XRN2 and resolve R-loops [PMID:34697388]. In metabolic tissues THRAP3 binds PPARγ specifically when phosphorylated at Ser273 by CDK5—an interaction itself gated by CLK1 phosphorylation of THRAP3 at Ser243—to drive diabetic gene programming, cooperates with HELZ2 at PPARγ-response elements for adipocyte differentiation, maintains PPARγ mRNA stability, and sequesters AMPK in the nucleus to restrain hepatic autophagy [PMID:23525231, PMID:25316675, PMID:34526909, PMID:34370683, PMID:37524868]. THRAP3 also negatively regulates SOX9 during chondrogenesis [PMID:28770354] and, in leukemia, recruits SLU7 to promote GIT2 exon-14 skipping and confer ferroptosis resistance [PMID:41326370].","teleology":[{"year":2010,"claim":"Established THRAP3 as a bona fide splicing activator that physically and functionally links splicing to mRNA fate, answering whether it is merely speckle-associated or mechanistically engaged in RNA processing.","evidence":"In vivo splicing assays, RNA tethering, co-IP with EJC components, and domain mapping in human cells","pmids":["20123736"],"confidence":"High","gaps":["The molecular trigger distinguishing splicing activation from degradation outcomes was not resolved","Endogenous transcript targets were not defined"]},{"year":2012,"claim":"Connected THRAP3's RNA-processing role to the DNA damage response by showing it is actively excluded from damage sites and that its loss sensitizes cells to genotoxins.","evidence":"Phosphoproteomics, immunofluorescence exclusion from damage foci, and knockdown clonogenic survival assays","pmids":["22424773"],"confidence":"Medium","gaps":["Mechanism of exclusion from damage foci unresolved","Direct DDR transcript targets not yet identified"]},{"year":2013,"claim":"Defined a metabolic role by showing THRAP3 partners with HELZ2 and PPARγ at adipogenic enhancers, distinguishing it functionally from its paralog BCLAF1 in mRNA distribution.","evidence":"Yeast two-hybrid, reciprocal co-IP, domain mapping, ChIP at PPARγ-response elements, and paralog-comparison fractionation assays","pmids":["23525231","23778535"],"confidence":"High","gaps":["Whether enhancer recruitment reflects co-transcriptional splicing or transcriptional coactivation not separated","Direct vs indirect contribution to differentiation unclear"]},{"year":2014,"claim":"Revealed phospho-dependent target selection: THRAP3 binds PPARγ only when CDK5 phosphorylates Ser273, providing a mechanistic basis and in vivo rationale for its role in diabetic gene programming.","evidence":"Phospho-specific binding/co-IP, adipocyte knockdown, and ASO knockdown in high-fat-fed mice with metabolic phenotyping","pmids":["25316675"],"confidence":"High","gaps":["How docking translates into gene reprogramming mechanistically not detailed","Downstream transcript targets in vivo not enumerated"]},{"year":2014,"claim":"Clarified THRAP3's splice-site selectivity by linking it to U1 snRNP/CPSF and showing it regulates premature cleavage and polyadenylation in composite terminal exons.","evidence":"Co-IP, co-fractionation, splicing reporter assays, and U1 snRNP inhibition","pmids":["25326322"],"confidence":"Medium","gaps":["Genome-wide PCPA targets not mapped","Single-lab reporter system limits generality"]},{"year":2015,"claim":"Provided a direct biochemical mechanism for splicing antagonism: THRAP3's PID domain occupies PSF/SFPQ RRMs to block its RNA binding without disrupting DBHS dimerization.","evidence":"Domain mapping, in vitro RNA-binding competition, and transcriptome-wide RASL-Seq with knockdown in T cells","pmids":["26261210"],"confidence":"High","gaps":["Structural details of the PID-RRM interface not solved","Generality beyond T-cell splicing events untested"]},{"year":2016,"claim":"Linked THRAP3 phosphorylation status to interactome rewiring, showing Ser248/Ser253 phosphorylation reshapes its association with RNA-processing partners in prostate cancer.","evidence":"Quantitative phosphoproteomics and pull-downs with phosphomimetic/nonphosphorylatable mutants","pmids":["26841317"],"confidence":"Medium","gaps":["Functional consequences of altered interactions not tested","Responsible kinase not identified"]},{"year":2017,"claim":"Extended THRAP3's regulatory reach beyond splicing to transcription-factor control, identifying it as a negative regulator of SOX9 during chondrogenesis.","evidence":"LC-MS/MS purification from knock-in mice, co-IP, domain mapping, and knockdown/overexpression in chondrogenic cells","pmids":["28770354"],"confidence":"Medium","gaps":["Whether repression is transcriptional or post-transcriptional unresolved","In vivo chondrogenesis phenotype not established"]},{"year":2017,"claim":"Mechanistically tied DDR sensitivity to selective splicing/export, showing THRAP3 with BCLAF1 controls processing of DDR transcripts including ATM and that cancer mutations impair repair.","evidence":"Knockdown, comet/γH2AX assays, splicing and export assays, and mutant THRAP3 expression","pmids":["29112714"],"confidence":"Medium","gaps":["Direct vs indirect transcript regulation not fully separated","Single-lab evidence"]},{"year":2017,"claim":"Proposed a mitotic role through regulation of mitotic-regulator mRNA abundance, linking THRAP3 loss to chromosome misalignment.","evidence":"siRNA knockdown, mitotic defect scoring, and RT-PCR of mitotic regulators","pmids":["28895891"],"confidence":"Low","gaps":["Single knockdown approach with only correlative mechanistic link","Specific causal transcripts not validated"]},{"year":2021,"claim":"Defined THRAP3's R-loop resolution mechanism: it reads methylated DDX5 and recruits XRN2 to R-loops, connecting its RNA-processing role to genome stability.","evidence":"Co-IP, DRIP, proximity ligation, and knockdown with γH2AX readout","pmids":["34697388"],"confidence":"Medium","gaps":["Which methyltransferase marks DDX5 not addressed","Genome-wide R-loop targets not mapped"]},{"year":2021,"claim":"Identified an upstream kinase layer controlling THRAP3-PPARγ docking, showing CLK1 phosphorylation of Ser243 is required and that the CLK1-THRAP3-PPARγ axis impairs adipose browning.","evidence":"Phosphoproteomics, kinase assay, co-IP, and CLK1 knockout/inhibition in mice","pmids":["34526909"],"confidence":"Medium","gaps":["Interplay between Ser243 phosphorylation and PPARγ Ser273 phosphorylation not structurally resolved"]},{"year":2021,"claim":"Revealed a post-transcriptional metabolic function: THRAP3 stabilizes PPARγ mRNA and is required for TZD anti-inflammatory action in adipocytes.","evidence":"Knockdown, actinomycin D chase, RT-qPCR/Western, and lipolysis assays","pmids":["34370683"],"confidence":"Medium","gaps":["Mechanism of mRNA stabilization not defined","Direct binding to PPARγ mRNA not shown"]},{"year":2021,"claim":"Connected THRAP3 to oncogenic cell-cycle control by showing nuclear PD-L1 recruits it to upregulate BUB1 in BRAF-mutant colorectal cancer.","evidence":"Co-IP, nuclear fractionation, knockdown, reporter assays, and xenografts","pmids":["34923044"],"confidence":"Medium","gaps":["How THRAP3 drives BUB1 expression mechanistically unclear","Direct vs scaffold role not separated"]},{"year":2023,"claim":"Uncovered a non-splicing metabolic mechanism: THRAP3 sequesters AMPK in the nucleus via its C-terminus to suppress hepatic autophagy, with liver-specific knockout improving NAFLD.","evidence":"Liver-specific knockout mice, co-IP, fractionation, AMPK activity, and autophagic flux assays","pmids":["37524868"],"confidence":"Medium","gaps":["Structural basis of AMPK sequestration not resolved","Reconciliation with nuclear RNA-processing roles unaddressed"]},{"year":2023,"claim":"Structurally defined THRAP3's core complex, mapping a Thrap3-Erh-Bclaf1 (TEB) assembly through interaction surfaces on otherwise disordered proteins.","evidence":"Cross-linking mass spectrometry (DSSO) of endogenous immunoprecipitated complexes","pmids":["35865489"],"confidence":"Medium","gaps":["Functional role of the TEB complex not validated","Stoichiometry and high-resolution structure unknown"]},{"year":2023,"claim":"Showed THRAP3 itself is an m6A-regulated target, with METTL3-mediated methylation stabilizing its mRNA to support myeloma proliferation, an axis suppressed by metformin.","evidence":"MeRIP, METTL3 overexpression, knockdown, mRNA stability, and rescue experiments","pmids":["36762777"],"confidence":"Medium","gaps":["Reader protein mediating stabilization not identified","Downstream THRAP3 effector pathway in myeloma not defined"]},{"year":2025,"claim":"Demonstrated a cancer splicing-effector role: THRAP3 recruits SLU7 to drive GIT2 exon-14 skipping and confer ferroptosis resistance in AML.","evidence":"Co-IP, alternative splicing assays, knockdown/overexpression, ferroptosis assays, and xenografts","pmids":["41326370"],"confidence":"Medium","gaps":["How GIT2 isoform alters iron/GSH metabolism mechanistically not fully traced","Breadth of THRAP3-SLU7 splicing program unknown"]},{"year":2026,"claim":"Extended THRAP3 into skeletal muscle, showing it is required for myogenic differentiation and thyroid hormone-responsive gene expression.","evidence":"THRAP3 knockout C2C12 myotubes, RT-qPCR/Western, myotube morphology, and T3 stimulation","pmids":["41570000"],"confidence":"Medium","gaps":["Whether effect is via splicing or transcriptional regulation unresolved","Direct muscle gene targets not mapped"]},{"year":null,"claim":"How THRAP3 integrates its disparate roles—co-transcriptional splicing, mRNA stability/degradation, R-loop resolution, transcription-factor docking, and AMPK sequestration—into a unified mechanism, and how its phosphorylation state selects among them, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model of THRAP3 domains coordinating splicing vs non-RNA functions","No comprehensive transcriptome map of direct THRAP3 RNA targets across tissues","Regulatory logic linking specific phosphosites to specific partner choices undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,6,11]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,5,18]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,11,16]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,15]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,15]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,5,6]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,9,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,8]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,14,15]}],"complexes":["TEB complex (THRAP3-ERH-BCLAF1)","exon junction complex (associated)"],"partners":["BCLAF1","PPARG","HELZ2","SFPQ","DDX5","XRN2","SOX9","SLU7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y2W1","full_name":"Thyroid hormone receptor-associated protein 3","aliases":["BCLAF1 and THRAP3 family member 2","Thyroid hormone receptor-associated protein complex 150 kDa component","Trap150"],"length_aa":955,"mass_kda":108.7,"function":"Involved in pre-mRNA splicing. Remains associated with spliced mRNA after splicing which probably involves interactions with the exon junction complex (EJC). Can trigger mRNA decay which seems to be independent of nonsense-mediated decay involving premature stop codons (PTC) recognition. May be involved in nuclear mRNA decay. Involved in regulation of signal-induced alternative splicing. During splicing of PTPRC/CD45 is proposed to sequester phosphorylated SFPQ from PTPRC/CD45 pre-mRNA in resting T-cells. Involved in cyclin-D1/CCND1 mRNA stability probably by acting as component of the SNARP complex which associates with both the 3'end of the CCND1 gene and its mRNA. Involved in response to DNA damage. Is excluced from DNA damage sites in a manner that parallels transcription inhibition; the function may involve the SNARP complex. Initially thought to play a role in transcriptional coactivation through its association with the TRAP complex; however, it is not regarded as a stable Mediator complex subunit. Cooperatively with HELZ2, enhances the transcriptional activation mediated by PPARG, maybe through the stabilization of the PPARG binding to DNA in presence of ligand. May play a role in the terminal stage of adipocyte differentiation. Plays a role in the positive regulation of the circadian clock. Acts as a coactivator of the CLOCK-BMAL1 heterodimer and promotes its transcriptional activator activity and binding to circadian target genes (PubMed:24043798)","subcellular_location":"Nucleus; Nucleus, nucleoplasm; Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/Q9Y2W1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/THRAP3","classification":"Not Classified","n_dependent_lines":154,"n_total_lines":1208,"dependency_fraction":0.12748344370860928},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CD2BP2","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"PRPF4B","stoichiometry":0.2},{"gene":"RBM33","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"RBM42","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/THRAP3","total_profiled":1310},"omim":[{"mim_id":"616453","title":"ZINC FINGER CCCH DOMAIN-CONTAINING PROTEIN 13; ZC3H13","url":"https://www.omim.org/entry/616453"},{"mim_id":"616447","title":"VIR-LIKE M6A METHYLTRANSFERASE-ASSOCIATED PROTEIN; VIRMA","url":"https://www.omim.org/entry/616447"},{"mim_id":"612588","title":"BCL2-ASSOCIATED TRANSCRIPTION FACTOR 1; BCLAF1","url":"https://www.omim.org/entry/612588"},{"mim_id":"606872","title":"CAS-BR-M MURINE ECTOPIC RETROVIRAL TRANSFORMING SEQUENCE LIKE-1; CBLL1","url":"https://www.omim.org/entry/606872"},{"mim_id":"606077","title":"RNA-BINDING MOTIF PROTEIN 15; RBM15","url":"https://www.omim.org/entry/606077"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear speckles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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nonsense-mediated decay. Splicing activation and mRNA degradation functions were mapped to separable domains.\",\n      \"method\": \"Co-localization (immunofluorescence), in vivo splicing assays, RNA tethering assays, co-immunoprecipitation with EJC components\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, splicing assays, tethering assays, domain mapping) in a single focused study; replicated aspects confirmed in later papers\",\n      \"pmids\": [\"20123736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"THRAP3 is excluded from sites of DNA damage following genotoxic stress, and THRAP3 depletion causes cellular hypersensitivity to DNA-damaging agents, implicating it in the DNA damage response through its RNA processing functions.\",\n      \"method\": \"Mass spectrometry-based phosphoproteomics, immunofluorescence (exclusion from DNA damage foci), siRNA knockdown with clonogenic survival assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative phosphoproteomics plus imaging and functional knockdown, but mechanistic detail of exclusion is not fully resolved\",\n      \"pmids\": [\"22424773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"THRAP3 physically associates with HELZ2 and PPARγ in differentiated 3T3-L1 adipocytes. HELZ2 interacts with the serine/arginine-rich domain and BCLAF1-homologous region of THRAP3, while THRAP3 directly binds two helicase motifs in HELZ2. THRAP3 and HELZ2 are co-recruited to PPARγ-response elements in Fabp4/aP2 and Adipoq gene enhancers in a ligand-dependent manner, and THRAP3 knockdown attenuates PPARγ-driven adipocyte differentiation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, mass spectrometry, chromatin immunoprecipitation (ChIP), siRNA knockdown with gene expression and lipid droplet readouts\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, domain mapping, ChIP, and functional knockdown phenotype across multiple orthogonal methods\",\n      \"pmids\": [\"23525231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRAP150 (THRAP3) localizes at active transcription loci in an RNA polymerase II-dependent manner and co-localizes with the EJC protein Magoh. Unlike BCLAF1 (Btf), TRAP150 depletion does not affect nuclear export of β-tropomyosin transcripts or global polyadenylated RNA cytoplasmic distribution, indicating distinct roles for the two paralogs in mRNA distribution.\",\n      \"method\": \"Immunofluorescence at reporter gene loci, siRNA knockdown, nuclear/cytoplasmic fractionation with RNA quantification\",\n      \"journal\": \"Nucleus (Austin, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional knockdown, single lab, two orthogonal methods\",\n      \"pmids\": [\"23778535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"THRAP3 (Thrap3) directly interacts with PPARγ specifically when PPARγ is phosphorylated at Ser273 by CDK5, and this interaction controls diabetic gene programming in adipocytes. Knockdown of Thrap3 restores genes dysregulated by CDK5 phosphorylation of PPARγ, and in vivo antisense oligonucleotide-mediated reduction of Thrap3 in adipose tissue improves hyperglycemia and insulin resistance in high-fat-fed mice.\",\n      \"method\": \"Co-immunoprecipitation, phospho-specific binding assays, siRNA knockdown in cultured adipocytes, antisense oligonucleotide knockdown in mouse adipose tissue, metabolic phenotyping\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP demonstrating phospho-dependent interaction, replicated in vivo with ASO knockdown and metabolic readouts, multiple orthogonal methods\",\n      \"pmids\": [\"25316675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRAP150 interacts with the cleavage and polyadenylation specificity factor (CPSF) and co-fractionates with CPSF and RNA polymerase II. TRAP150 preferentially associates with U1 snRNP and activates splicing in composite terminal exons but not authentic terminal exons, providing a mechanism to regulate premature cleavage and polyadenylation (PCPA) transcripts.\",\n      \"method\": \"Co-immunoprecipitation, co-fractionation, in vivo splicing reporter assays, U1 snRNP inhibition experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and functional reporter assays in one lab with multiple constructs, but replication is limited\",\n      \"pmids\": [\"25326322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRAP150 binds the RNA recognition motifs (RRMs) of PSF/SFPQ via a 70-residue PSF-interacting domain (PID). This interaction directly inhibits PSF's binding to RNA through RRM2, but does not prevent PSF dimerization with other DBHS proteins. TRAP150 antagonizes PSF-mediated splicing suppression across ~40 T cell splicing events.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping with deletion mutants, in vitro RNA-binding competition assays, RASL-Seq, siRNA knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding competition, domain-level mapping, transcriptome-wide RASL-Seq, and mechanistic epistasis between TRAP150 and PSF\",\n      \"pmids\": [\"26261210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"THRAP3 phosphorylation at Ser248 and Ser253 is significantly reduced in androgen-independent prostate cancer cells. Pull-down assays show that the phosphorylation state at these residues alters THRAP3's interaction partners: 32 proteins uniquely bind the nonphosphorylatable mutant and 31 uniquely bind the phosphomimetic form, with many differentially interacting proteins involved in RNA splicing and processing.\",\n      \"method\": \"Quantitative phosphoproteomics (mass spectrometry), pull-down assays with phosphomimetic and nonphosphorylatable THRAP3 mutants\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative MS-based phosphoproteomics and pull-down with mutants, single lab, two orthogonal methods\",\n      \"pmids\": [\"26841317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"THRAP3 is a component of a SOX9 transcriptional complex and negatively regulates SOX9 transcriptional activity during chondrogenesis. The interaction is mediated between the proline-, glutamine-, and serine-rich (PQS) domain of SOX9 and the innominate domain of THRAP3. THRAP3 knockdown increases Col2a1 expression, and co-overexpression of THRAP3 and SOX9 reduces Col2a1 levels more than SOX9 alone.\",\n      \"method\": \"LC-MS/MS purification of FLAG-tagged SOX9-binding proteins from knock-in mice, co-immunoprecipitation, domain mapping, siRNA knockdown, overexpression in chondrogenic cells\",\n      \"journal\": \"Journal of bone and mineral metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous complex purification by MS plus co-IP and functional knockdown/overexpression, single lab\",\n      \"pmids\": [\"28770354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Depletion of THRAP3 and/or BCLAF1 causes sensitivity to DNA-damaging agents, defective DNA repair, and genomic instability. THRAP3 and BCLAF1 regulate selective mRNA splicing and nuclear export of transcripts encoding key DDR proteins including ATM kinase. Cancer-associated mutations in THRAP3 deregulate processing of THRAP3/BCLAF1-regulated transcripts and impair DNA repair.\",\n      \"method\": \"siRNA knockdown, clonogenic survival assays, comet assay, γH2AX foci, RNA splicing and nuclear export assays, mutant THRAP3 expression\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts (repair, splicing, export) with knockdown and mutant expression, single lab\",\n      \"pmids\": [\"29112714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Depletion of TRAP150 (THRAP3) causes mitotic chromosome misalignment defects and alters the abundance of transcripts encoding mitotic regulators, suggesting TRAP150 controls mitotic progression through regulation of mitotic checkpoint regulator mRNAs.\",\n      \"method\": \"siRNA knockdown, immunofluorescence (mitotic defect scoring), RT-PCR for mitotic regulator transcripts\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach with indirect mechanistic link; proposed pathway not directly demonstrated\",\n      \"pmids\": [\"28895891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Thrap3 interacts with methylated DDX5 (arginine methylation required) and localizes to R-loops. The Thrap3-DDX5 axis recruits XRN2 (5'-3' exoribonuclease 2) to R-loops to promote their resolution. Loss of Thrap3 increases R-loop accumulation and DNA damage.\",\n      \"method\": \"Co-immunoprecipitation, S9.6 antibody-based R-loop detection (DRIP assay), proximity ligation assays, Thrap3 knockdown with γH2AX readout\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating protein interaction, R-loop accumulation upon knockdown, XRN2 recruitment assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34697388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nuclear PD-L1 interacts with THRAP3 to upregulate BUB1 expression, thereby accelerating cell cycle progression in BRAF-mutated colorectal cancer cells. PD-L1 translocation into the nucleus is facilitated by binding of p-ERK.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, siRNA knockdown, reporter assays, xenograft models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of nuclear PD-L1 with THRAP3, knockdown with BUB1 expression and cell cycle readouts; single lab\",\n      \"pmids\": [\"34923044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CLK1 phosphorylates THRAP3 at Ser243, and this phosphorylation is required for THRAP3's regulatory interaction with phosphorylated PPARγ. CLK1-THRAP3 interaction was confirmed by co-immunoprecipitation. This CLK1-THRAP3-PPARγ axis impairs adipose tissue browning and insulin sensitivity.\",\n      \"method\": \"Phosphoproteomics, co-immunoprecipitation, kinase assay (CLK1 phosphorylation of THRAP3), CLK1 genetic knockout and chemical inhibition in mice\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, in vivo kinase assay, and in vivo mouse phenotyping; single lab with multiple methods\",\n      \"pmids\": [\"34526909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"THRAP3 depletion in 3T3-L1 adipocytes reduces PPARγ mRNA stability (demonstrated by actinomycin D chase), decreases PPARγ protein levels, and attenuates TZD-mediated anti-inflammatory actions including suppression of lipolysis and pro-inflammatory gene expression.\",\n      \"method\": \"siRNA knockdown, actinomycin D mRNA stability assay, RT-qPCR, Western blot, lipolysis assay\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA stability assay plus functional knockdown phenotype; single lab with two orthogonal methods\",\n      \"pmids\": [\"34370683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Thrap3 deficiency increases cytosolic translocation of AMPK from the nucleus and enhances AMPK activation through direct physical interaction between AMPK and the C-terminal domain of Thrap3. Liver-specific Thrap3 knockout improves lipid accumulation, enhances autophagy, and improves mitochondrial function in a high-fat diet NAFLD model.\",\n      \"method\": \"Liver-specific Thrap3 knockout mice, co-immunoprecipitation, subcellular fractionation, AMPK activity assays, autophagic flux assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and domain mapping for AMPK interaction, in vivo liver-specific KO with functional readouts; single lab\",\n      \"pmids\": [\"37524868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cross-linking mass spectrometry of endogenous immunoprecipitated complexes demonstrates that Thrap3 and Bclaf1 interact closely with each other and with Erh, mapping interaction surfaces to the non-disordered portions of these largely disordered proteins, suggesting they form a novel TEB (Thrap3-Erh-Bclaf1) complex.\",\n      \"method\": \"Cross-linking mass spectrometry (XL-MS) with MS-cleavable crosslinker DSSO on endogenous immunoprecipitated proteins\",\n      \"journal\": \"Wellcome open research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural XL-MS method with endogenous proteins mapping interaction surfaces, but single study with limited functional validation\",\n      \"pmids\": [\"35865489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL3-mediated m6A methylation stabilizes THRAP3 mRNA in multiple myeloma cells. Metformin reduces METTL3 activity, decreasing m6A modification on THRAP3 mRNA and reducing its stability and expression. THRAP3 knockdown reverses the pro-proliferative/anti-apoptotic effects of METTL3 overexpression.\",\n      \"method\": \"MeRIP (m6A RNA immunoprecipitation), siRNA knockdown, METTL3 overexpression, mRNA stability assays, rescue experiments\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP directly detecting m6A on THRAP3 mRNA, functional rescue experiments; single lab\",\n      \"pmids\": [\"36762777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"THRAP3 recruits the splicing factor SLU7 to facilitate GIT2 Exon14 skipping, thereby promoting ferroptosis resistance in AML cells by inhibiting iron accumulation and promoting GSH synthesis. THRAP3 knockdown suppresses AML cell proliferation and delays tumor growth in vivo; inhibition of GIT2 Exon14 skipping reverses THRAP3-induced ferroptosis resistance.\",\n      \"method\": \"Co-immunoprecipitation (THRAP3-SLU7 interaction), alternative splicing assays, THRAP3 knockdown and overexpression, RSL3/erastin-induced ferroptosis assays, orthotopic and subcutaneous xenograft models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, functional splicing readout, in vivo tumor models; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41326370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"THRAP3 knockout in C2C12 myotubes suppresses expression of myogenic regulatory factors (Myod1, Mef2c, myosin heavy chain genes), impairs myogenic differentiation and muscle fiber diameter, and attenuates T3 (triiodothyronine)-induced gene expression, establishing THRAP3 as a regulator of myogenesis and thyroid hormone-responsive gene expression in skeletal muscle.\",\n      \"method\": \"THRAP3 knockout C2C12 cells, RT-qPCR, Western blot, morphological analysis of myotube diameter, T3 stimulation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple gene expression and morphological readouts; single lab, single system\",\n      \"pmids\": [\"41570000\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"THRAP3 (TRAP150) is a multifunctional nuclear SR-like protein that acts as a subunit of the TRAP/Mediator complex and spliceosome: it promotes pre-mRNA splicing and can trigger nuclear mRNA degradation via separable domains; it antagonizes PSF/SFPQ-mediated splicing by binding PSF's RRMs through its PID domain; it selectively regulates mRNA splicing and export of DDR transcripts (including ATM) and promotes R-loop resolution by recruiting methylated DDX5 and XRN2; it is excluded from DNA damage foci and its loss causes genotoxic hypersensitivity; in metabolic contexts it docks on CDK5-phosphorylated PPARγ-Ser273 (a docking event further controlled by CLK1 phosphorylation of THRAP3 at Ser243) to drive diabetic gene programming in adipose tissue, cooperates with HELZ2 at PPARγ-response elements for adipocyte differentiation, maintains PPARγ mRNA stability, and sequesters AMPK in the nucleus to suppress autophagy in the liver; it also negatively regulates SOX9 transcriptional activity during chondrogenesis, and in cancer promotes ferroptosis resistance by recruiting SLU7 to drive GIT2 Exon14 skipping.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"THRAP3 (TRAP150) is a nuclear SR-like RNA-processing protein that couples pre-mRNA splicing to downstream RNA fate, localizing to nuclear speckles and active RNA polymerase II transcription loci where it activates splicing, remains bound to spliced mRNA in association with the exon junction complex, and can trigger nuclear mRNA degradation through a domain separable from its splicing-activation function [#0, #3]. It tunes splice-site choice through partner interactions: it preferentially associates with U1 snRNP and CPSF to regulate premature cleavage and polyadenylation transcripts [#5], and it antagonizes PSF/SFPQ-mediated splicing suppression by binding the RRMs of PSF through a dedicated PSF-interacting domain that blocks PSF's RNA binding [#6]. THRAP3 selectively governs splicing and nuclear export of DNA-damage-response transcripts including ATM, and—acting with BCLAF1—its loss or cancer-associated mutation impairs DNA repair and causes genotoxic hypersensitivity and genomic instability [#1, #9]; it further safeguards genome integrity by interacting with arginine-methylated DDX5 to recruit the exoribonuclease XRN2 and resolve R-loops [#11]. In metabolic tissues THRAP3 binds PPARγ specifically when phosphorylated at Ser273 by CDK5—an interaction itself gated by CLK1 phosphorylation of THRAP3 at Ser243—to drive diabetic gene programming, cooperates with HELZ2 at PPARγ-response elements for adipocyte differentiation, maintains PPARγ mRNA stability, and sequesters AMPK in the nucleus to restrain hepatic autophagy [#2, #4, #13, #14, #15]. THRAP3 also negatively regulates SOX9 during chondrogenesis [#8] and, in leukemia, recruits SLU7 to promote GIT2 exon-14 skipping and confer ferroptosis resistance [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established THRAP3 as a bona fide splicing activator that physically and functionally links splicing to mRNA fate, answering whether it is merely speckle-associated or mechanistically engaged in RNA processing.\",\n      \"evidence\": \"In vivo splicing assays, RNA tethering, co-IP with EJC components, and domain mapping in human cells\",\n      \"pmids\": [\"20123736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The molecular trigger distinguishing splicing activation from degradation outcomes was not resolved\", \"Endogenous transcript targets were not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected THRAP3's RNA-processing role to the DNA damage response by showing it is actively excluded from damage sites and that its loss sensitizes cells to genotoxins.\",\n      \"evidence\": \"Phosphoproteomics, immunofluorescence exclusion from damage foci, and knockdown clonogenic survival assays\",\n      \"pmids\": [\"22424773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of exclusion from damage foci unresolved\", \"Direct DDR transcript targets not yet identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a metabolic role by showing THRAP3 partners with HELZ2 and PPARγ at adipogenic enhancers, distinguishing it functionally from its paralog BCLAF1 in mRNA distribution.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, domain mapping, ChIP at PPARγ-response elements, and paralog-comparison fractionation assays\",\n      \"pmids\": [\"23525231\", \"23778535\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether enhancer recruitment reflects co-transcriptional splicing or transcriptional coactivation not separated\", \"Direct vs indirect contribution to differentiation unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed phospho-dependent target selection: THRAP3 binds PPARγ only when CDK5 phosphorylates Ser273, providing a mechanistic basis and in vivo rationale for its role in diabetic gene programming.\",\n      \"evidence\": \"Phospho-specific binding/co-IP, adipocyte knockdown, and ASO knockdown in high-fat-fed mice with metabolic phenotyping\",\n      \"pmids\": [\"25316675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How docking translates into gene reprogramming mechanistically not detailed\", \"Downstream transcript targets in vivo not enumerated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Clarified THRAP3's splice-site selectivity by linking it to U1 snRNP/CPSF and showing it regulates premature cleavage and polyadenylation in composite terminal exons.\",\n      \"evidence\": \"Co-IP, co-fractionation, splicing reporter assays, and U1 snRNP inhibition\",\n      \"pmids\": [\"25326322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genome-wide PCPA targets not mapped\", \"Single-lab reporter system limits generality\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided a direct biochemical mechanism for splicing antagonism: THRAP3's PID domain occupies PSF/SFPQ RRMs to block its RNA binding without disrupting DBHS dimerization.\",\n      \"evidence\": \"Domain mapping, in vitro RNA-binding competition, and transcriptome-wide RASL-Seq with knockdown in T cells\",\n      \"pmids\": [\"26261210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of the PID-RRM interface not solved\", \"Generality beyond T-cell splicing events untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked THRAP3 phosphorylation status to interactome rewiring, showing Ser248/Ser253 phosphorylation reshapes its association with RNA-processing partners in prostate cancer.\",\n      \"evidence\": \"Quantitative phosphoproteomics and pull-downs with phosphomimetic/nonphosphorylatable mutants\",\n      \"pmids\": [\"26841317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences of altered interactions not tested\", \"Responsible kinase not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended THRAP3's regulatory reach beyond splicing to transcription-factor control, identifying it as a negative regulator of SOX9 during chondrogenesis.\",\n      \"evidence\": \"LC-MS/MS purification from knock-in mice, co-IP, domain mapping, and knockdown/overexpression in chondrogenic cells\",\n      \"pmids\": [\"28770354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether repression is transcriptional or post-transcriptional unresolved\", \"In vivo chondrogenesis phenotype not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mechanistically tied DDR sensitivity to selective splicing/export, showing THRAP3 with BCLAF1 controls processing of DDR transcripts including ATM and that cancer mutations impair repair.\",\n      \"evidence\": \"Knockdown, comet/γH2AX assays, splicing and export assays, and mutant THRAP3 expression\",\n      \"pmids\": [\"29112714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect transcript regulation not fully separated\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Proposed a mitotic role through regulation of mitotic-regulator mRNA abundance, linking THRAP3 loss to chromosome misalignment.\",\n      \"evidence\": \"siRNA knockdown, mitotic defect scoring, and RT-PCR of mitotic regulators\",\n      \"pmids\": [\"28895891\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single knockdown approach with only correlative mechanistic link\", \"Specific causal transcripts not validated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined THRAP3's R-loop resolution mechanism: it reads methylated DDX5 and recruits XRN2 to R-loops, connecting its RNA-processing role to genome stability.\",\n      \"evidence\": \"Co-IP, DRIP, proximity ligation, and knockdown with γH2AX readout\",\n      \"pmids\": [\"34697388\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which methyltransferase marks DDX5 not addressed\", \"Genome-wide R-loop targets not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified an upstream kinase layer controlling THRAP3-PPARγ docking, showing CLK1 phosphorylation of Ser243 is required and that the CLK1-THRAP3-PPARγ axis impairs adipose browning.\",\n      \"evidence\": \"Phosphoproteomics, kinase assay, co-IP, and CLK1 knockout/inhibition in mice\",\n      \"pmids\": [\"34526909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between Ser243 phosphorylation and PPARγ Ser273 phosphorylation not structurally resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a post-transcriptional metabolic function: THRAP3 stabilizes PPARγ mRNA and is required for TZD anti-inflammatory action in adipocytes.\",\n      \"evidence\": \"Knockdown, actinomycin D chase, RT-qPCR/Western, and lipolysis assays\",\n      \"pmids\": [\"34370683\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of mRNA stabilization not defined\", \"Direct binding to PPARγ mRNA not shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected THRAP3 to oncogenic cell-cycle control by showing nuclear PD-L1 recruits it to upregulate BUB1 in BRAF-mutant colorectal cancer.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, knockdown, reporter assays, and xenografts\",\n      \"pmids\": [\"34923044\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How THRAP3 drives BUB1 expression mechanistically unclear\", \"Direct vs scaffold role not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered a non-splicing metabolic mechanism: THRAP3 sequesters AMPK in the nucleus via its C-terminus to suppress hepatic autophagy, with liver-specific knockout improving NAFLD.\",\n      \"evidence\": \"Liver-specific knockout mice, co-IP, fractionation, AMPK activity, and autophagic flux assays\",\n      \"pmids\": [\"37524868\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of AMPK sequestration not resolved\", \"Reconciliation with nuclear RNA-processing roles unaddressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Structurally defined THRAP3's core complex, mapping a Thrap3-Erh-Bclaf1 (TEB) assembly through interaction surfaces on otherwise disordered proteins.\",\n      \"evidence\": \"Cross-linking mass spectrometry (DSSO) of endogenous immunoprecipitated complexes\",\n      \"pmids\": [\"35865489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the TEB complex not validated\", \"Stoichiometry and high-resolution structure unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed THRAP3 itself is an m6A-regulated target, with METTL3-mediated methylation stabilizing its mRNA to support myeloma proliferation, an axis suppressed by metformin.\",\n      \"evidence\": \"MeRIP, METTL3 overexpression, knockdown, mRNA stability, and rescue experiments\",\n      \"pmids\": [\"36762777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reader protein mediating stabilization not identified\", \"Downstream THRAP3 effector pathway in myeloma not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated a cancer splicing-effector role: THRAP3 recruits SLU7 to drive GIT2 exon-14 skipping and confer ferroptosis resistance in AML.\",\n      \"evidence\": \"Co-IP, alternative splicing assays, knockdown/overexpression, ferroptosis assays, and xenografts\",\n      \"pmids\": [\"41326370\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How GIT2 isoform alters iron/GSH metabolism mechanistically not fully traced\", \"Breadth of THRAP3-SLU7 splicing program unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended THRAP3 into skeletal muscle, showing it is required for myogenic differentiation and thyroid hormone-responsive gene expression.\",\n      \"evidence\": \"THRAP3 knockout C2C12 myotubes, RT-qPCR/Western, myotube morphology, and T3 stimulation\",\n      \"pmids\": [\"41570000\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether effect is via splicing or transcriptional regulation unresolved\", \"Direct muscle gene targets not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How THRAP3 integrates its disparate roles—co-transcriptional splicing, mRNA stability/degradation, R-loop resolution, transcription-factor docking, and AMPK sequestration—into a unified mechanism, and how its phosphorylation state selects among them, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model of THRAP3 domains coordinating splicing vs non-RNA functions\", \"No comprehensive transcriptome map of direct THRAP3 RNA targets across tissues\", \"Regulatory logic linking specific phosphosites to specific partner choices undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 6, 11]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 5, 18]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 11, 16]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 9, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 14, 15]}\n    ],\n    \"complexes\": [\n      \"TEB complex (THRAP3-ERH-BCLAF1)\",\n      \"exon junction complex (associated)\"\n    ],\n    \"partners\": [\n      \"BCLAF1\",\n      \"PPARG\",\n      \"HELZ2\",\n      \"SFPQ\",\n      \"DDX5\",\n      \"XRN2\",\n      \"SOX9\",\n      \"SLU7\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}