{"gene":"TRIP13","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2009,"finding":"TRIP13 is required for depletion of HORMAD1 and HORMAD2 from synapsed chromosome axes during meiosis; loss of TRIP13 results in abnormal persistence of HORMADs on synapsed chromosomes and disrupts mutually exclusive HORMAD-rich and synapsed chromatin domains.","method":"Genetic knockout/hypomorph mouse model with immunofluorescence analysis of HORMAD1/HORMAD2 localization on meiotic chromosomes","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO/hypomorph with defined cellular phenotype, replicated across multiple labs in subsequent papers","pmids":["19851446"],"is_preprint":false},{"year":2007,"finding":"Mouse TRIP13 is required for completing a subset of meiotic recombination events after strand invasion; TRIP13-deficient spermatocytes retain recombination intermediates (RAD51, BLM, RPA) despite full synapsis. Epistasis analysis showed SPO11, MEI1, REC8, and DMC1 are epistatic to TRIP13, placing TRIP13 downstream of these recombination factors.","method":"Genetic knockout mouse model with immunofluorescence for recombination markers; double-mutant epistasis analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined molecular phenotype plus genetic epistasis, replicated in subsequent studies","pmids":["17696610"],"is_preprint":false},{"year":2010,"finding":"TRIP13 is required for proper synaptonemal complex formation, efficient synapsis of sex chromosomes, sex body formation, normal crossover numbers and distribution, and early recombination steps after DSB formation in mouse meiosis.","method":"Distinct Trip13 alleles (moderate and severe hypomorphs) analyzed by cytology, immunofluorescence, chiasma counting","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple alleles with graded phenotypes, multiple orthogonal cytological readouts, independent replication","pmids":["20711356"],"is_preprint":false},{"year":2015,"finding":"TRIP13 is a protein-remodeling AAA+ ATPase that, aided by the adapter protein p31(comet), converts the HORMA-family spindle checkpoint protein MAD2 from its signaling-active 'closed' conformer to an inactive 'open' conformer, thereby inactivating the spindle assembly checkpoint and disassembling mitotic checkpoint complexes. The substrate-recognition domain of TRIP13 is related to those of NSF and p97.","method":"Crystal structure of C. elegans PCH-2; in vitro MAD2 conformational conversion assay with TRIP13 and p31(comet)","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro biochemical reconstitution of conformational conversion, replicated by multiple subsequent studies","pmids":["25918846"],"is_preprint":false},{"year":2014,"finding":"TRIP13 binds to DNA-PKcs complex proteins that mediate nonhomologous end joining (NHEJ) and promotes NHEJ repair even when homologous recombination is intact; overexpression of TRIP13 enhances NHEJ-mediated DNA repair and promotes treatment resistance.","method":"Mass spectrometry identification of TRIP13-binding partners; NHEJ reporter assays; overexpression and knockdown in cancer cells","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction with DNA-PKcs complex confirmed by reporter assay; single lab, two orthogonal methods","pmids":["25078033"],"is_preprint":false},{"year":2014,"finding":"Endogenous TRIP13 localizes to kinetochores in mitosis. TRIP13 knockdown delays metaphase-to-anaphase transition by prolonging the presence of the mitotic checkpoint complex (MCC) and its inhibition of APC/C. The ATPase activity of TRIP13 is essential for this checkpoint-silencing function, and TRIP13 is required for p31(comet)-mediated mitotic checkpoint silencing.","method":"Immunofluorescence localization; siRNA knockdown with mitotic timing assays; ATPase-dead mutant rescue experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — kinetochore localization by immunofluorescence, KD with defined phenotype, ATPase mutant functional dissection; replicated by multiple subsequent studies","pmids":["25012665"],"is_preprint":false},{"year":2014,"finding":"TRIP13 AAA-ATPase, acting jointly with p31(comet), promotes ATP-dependent disassembly of the Cdc20-Mad2 subcomplex and the full mitotic checkpoint complex (MCC), releasing Mad2 from MCC and abrogating checkpoint inhibition of APC/C. TRIP13 was identified as the factor in HeLa extracts responsible for ATP- and p31(comet)-dependent MCC disassembly.","method":"Biochemical fractionation of HeLa extracts; in vitro MCC disassembly assay with recombinant TRIP13 and p31(comet); APC/C activity assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of MCC disassembly with purified components, functional readout on APC/C; independently replicated","pmids":["25092294"],"is_preprint":false},{"year":2015,"finding":"The oligomeric form of TRIP13 binds both p31(comet) and MCC. p31(comet) and checkpoint complexes mutually promote each other's binding to oligomeric TRIP13; the substrate-binding site of TRIP13 comprises subsites specific for p31(comet) and the C-Mad2-containing complex, and simultaneous occupancy of both subsites is required for high-affinity binding.","method":"Binding assays with recombinant proteins; co-immunoprecipitation of TRIP13 with p31(comet) and MCC components","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding assays with recombinant components plus reciprocal co-IP; single lab with multiple orthogonal methods","pmids":["26324890"],"is_preprint":false},{"year":2017,"finding":"TRIP13 and p31(comet) catalyze the conversion of C-Mad2 to O-Mad2 by locally unfolding the Mad2 C-terminal region without disrupting its stably folded core; the crystal structure of human TRIP13 was determined and functional TRIP13 residues mediating p31(comet)-Mad2 binding and coupling ATP hydrolysis to local Mad2 unfolding were identified. TRIP13-p31(comet) intercepts and disassembles free MCC not bound to APC/C.","method":"NMR spectroscopy of MAD2 conformational change; crystal structure of human TRIP13; mutagenesis of functional residues; in vitro APC/C inhibition assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus NMR plus mutagenesis plus in vitro functional assay in one study","pmids":["29208896"],"is_preprint":false},{"year":2017,"finding":"TRIP13 recognizes MAD2 through the adapter p31(comet), which binds the TRIP13 N-terminal domain to position the disordered MAD2 N-terminus for engagement by TRIP13 pore loops; TRIP13 then unfolds MAD2 in an ATP-dependent manner. N-terminal truncation of MAD2 renders it refractory to TRIP13 action in vitro and causes SAC defects in cells. Similar truncation of HORMAD1 in spermatocytes impairs TRIP13-mediated removal from meiotic chromosomes, demonstrating a conserved N-terminal engagement mechanism.","method":"X-ray crystallography; crosslinking mass spectrometry; in vitro TRIP13 remodeling assay with truncation mutants; mouse spermatocyte immunofluorescence","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — structure plus crosslinking MS plus in vitro assay plus in vivo validation with truncation mutants","pmids":["28659378"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structures of the TRIP13-p31(comet)-C-MAD2-CDC20 complex reveal that p31(comet) recruits C-MAD2 to a defined site on the TRIP13 hexameric ring, positioning the MAD2 N-terminus to insert into the axial pore. TRIP13 couples sequential ATP-driven translocation along MAD2 N-terminus to push and rotate the p31(comet)-C-MAD2 complex, unwinding the αA helix of C-MAD2 required to stabilize the closed β-sheet, thereby converting C-MAD2 to O-MAD2 and dissociating MAD2 from p31(comet).","method":"Cryo-electron microscopy structure determination of TRIP13-p31comet-C-MAD2-CDC20 complex; molecular modeling of translocation mechanism","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure of the complete remodeling complex with mechanistic modeling; published in Nature","pmids":["29973720"],"is_preprint":false},{"year":2018,"finding":"TRIP13 catalytic activity is required both to maintain a pool of open-state Mad2 for MCC assembly (supporting checkpoint activation) and for timely mitotic exit through catalytic disassembly of MCC. Combining TRIP13 depletion with elimination of APC15-dependent Cdc20 ubiquitination/degradation results in complete inability to exit mitosis even when kinetochore MCC assembly is prevented.","method":"Degron-tagging for rapid TRIP13 depletion; double depletion (TRIP13 + APC15) with mitotic exit assays; Mad2 conformer pool measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — rapid inducible depletion with precise genetic double-mutant analysis; defined biochemical and cell biological phenotypes","pmids":["30341343"],"is_preprint":false},{"year":2020,"finding":"TRIP13 ATPase catalyzes an inactivating conformational change of REV7 (MAD2L2) from its active 'closed' conformation to an inactive 'open' conformation, thereby dissociating the REV7-Shieldin complex and promoting homology-directed repair (HDR). TRIP13 similarly disassembles the REV7-REV3 translesion synthesis (TLS) complex, inhibiting error-prone replicative lesion bypass and interstrand crosslink repair.","method":"Conformational assays for REV7 closed/open states; co-IP of REV7-Shieldin complex; HR reporter assay; PARP inhibitor sensitivity assay in BRCA1-deficient cells","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal assays (conformational, co-IP, functional HR/NHEJ reporters, drug sensitivity), single lab but comprehensive","pmids":["31915374"],"is_preprint":false},{"year":2020,"finding":"p31(comet) binds to the REV7-Shieldin complex in cells, mediates TRIP13-REV7 interaction, promotes REV7 inactivation and dissociation from Shieldin subunit SHLD3, and participates in extraction of REV7 from chromatin. p31(comet) also releases REV7 from the REV3/Pol-ζ complex, counteracting TLS.","method":"Co-IP of p31(comet) with REV7-Shieldin; chromatin fractionation; PARP inhibitor resistance assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and chromatin fractionation, single lab, two orthogonal methods","pmids":["33051298"],"is_preprint":false},{"year":2021,"finding":"Crystal structures of human SHLD3-REV7 binary and fused SHLD2-SHLD3-REV7 ternary complexes show that Shieldin assembly requires SHLD2-SHLD3-induced conformational heterodimerization of O-REV7 and C-REV7. Cryo-EM structures of ATPγS-bound SHLD2-SHLD3-REV7-TRIP13 complexes show that the N-terminus of REV7 inserts into the TRIP13 central channel; the safety-belt segment of C-REV7 contacts a conserved negatively charged TRIP13 loop, and ATP hydrolysis-triggered rotatory motions drive disassembly of the Shieldin complex.","method":"X-ray crystallography of Shieldin sub-complexes; cryo-EM of TRIP13-Shieldin complex; functional disassembly assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal and cryo-EM structures with functional validation in a single rigorous study","pmids":["33597306"],"is_preprint":false},{"year":2021,"finding":"MAD2L2 (REV7) dimerization is required for appropriate shieldin function in NHEJ; dimerization is mediated by SHLD2 and accelerates MAD2L2-SHLD3 interaction. MAD2L2 dimerization combined with SHLD3 presence is required for shieldin interaction with TRIP13 ATPase. Appropriate TRIP13 levels are important for proper shieldin (dis)assembly and activity in DNA repair.","method":"Co-IP of shieldin components; dimerization-defective MAD2L2 mutants; NHEJ reporter assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with defined mutants, functional NHEJ reporter, single lab","pmids":["34521823"],"is_preprint":false},{"year":2020,"finding":"In C. elegans, PCH-2/TRIP13 controls spindle checkpoint strength by regulating the availability of inactive (open-state) Mad2 at and near unattached kinetochores; this function is required in large cells (germline precursor cells) and depends on CMT-1 (p31(comet) ortholog) for PCH-2 localization to unattached kinetochores and its enrichment in germline precursor cells.","method":"C. elegans genetic manipulation of cell volume; PCH-2 localization by immunofluorescence; spindle checkpoint strength assays; genetic epistasis with cmt-1","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus localization with functional readout, single lab, ortholog study in C. elegans","pmids":["32697629"],"is_preprint":false},{"year":2017,"finding":"Biallelic loss-of-function mutations in TRIP13 cause substantial impairment of the spindle assembly checkpoint (SAC), leading to a high rate of chromosome missegregation; restoring TRIP13 function rescues accurate segregation and SAC proficiency in patient cells.","method":"Patient-derived cell lines with TRIP13 mutations; SAC functional assays; chromosome segregation assays; rescue by TRIP13 reintroduction","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient cells with defined loss-of-function mutations, functional rescue, multiple orthogonal readouts","pmids":["28553959"],"is_preprint":false},{"year":2017,"finding":"TRIP13 overexpression significantly reduces, and TRIP13 reduction exacerbates, the mitotic delay associated with Mad2 overexpression (but not microtubule depolymerization-induced delay). Combination of Mad2 overexpression and TRIP13 loss reduces ability of checkpoint complexes to disassemble.","method":"TRIP13 overexpression and knockdown in Mad2-overexpressing cells; mitotic timing; MCC disassembly assays; xenograft proliferation","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined checkpoint readouts, single lab","pmids":["28564602"],"is_preprint":false},{"year":2021,"finding":"TRIP13 increases cellular deubiquitination by enhancing the association of the deubiquitinase USP7 with its substrates (NEK2, PTEN, p53), thereby protecting oncogenic proteins from ubiquitin-mediated degradation; this activity promotes B cell tumor development in transgenic mice. TRIP13-induced resistance to proteasome inhibition can be overcome by a USP7 inhibitor.","method":"Co-IP of TRIP13 with USP7; ubiquitination assays; TRIP13 transgenic mouse tumor model; in vitro and in vivo USP7 inhibitor rescue","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional ubiquitination assays plus in vivo mouse model, single lab","pmids":["34061780"],"is_preprint":false},{"year":2019,"finding":"TRIP13 interacts with ACTN4 and positively regulates ACTN4 expression, thereby activating the AKT/mTOR pathway to promote hepatocellular carcinoma progression.","method":"Co-IP of TRIP13 with ACTN4; gain- and loss-of-function studies; AKT/mTOR pathway western blotting; xenograft models","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirmed interaction, pathway activation shown by western blot, in vivo validation; single lab","pmids":["31533816"],"is_preprint":false},{"year":2019,"finding":"TRIP13 promotes glioblastoma cell proliferation, migration, and invasion by suppressing FBXW7 transcription (by directly binding to the FBXW7 promoter region), thereby stabilizing c-MYC protein levels.","method":"ChIP/promoter binding assay for TRIP13 at FBXW7 promoter; western blot for c-MYC; gain- and loss-of-function in GBM cells","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct promoter binding assay plus functional c-MYC stabilization, single lab, limited mechanistic depth in abstract","pmids":["31740732"],"is_preprint":false},{"year":2017,"finding":"TRIP13 directly interacts with Tetratricopeptide Repeat Domain 5 (TTC5), a p53 co-factor; knockdown of TRIP13 in tubular epithelial cells in the presence of oxidative stress increased p53 activity at Serine 15, linking TRIP13 to suppression of p53-mediated apoptosis.","method":"Co-IP of TRIP13 with TTC5; TRIP13 hypomorph mice with ischemia-reperfusion injury; p53-Ser15 phosphorylation assay after TRIP13 knockdown","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP interaction plus in vivo hypomorph model plus cell-based p53 assay; single lab","pmids":["28256593"],"is_preprint":false},{"year":2022,"finding":"TRIP13 participates in immediate-early DNA damage sensing: it is recruited to DNA damage sites within seconds after damage, interacts with MRE11 (identified by quantitative proximity-labeling proteomics), controls MDC1 recruitment to damage sites by regulating MDC1-MRN complex interaction, and is involved in ATM signaling amplification.","method":"Proximity-labeling quantitative proteomics (BioID); co-IP of TRIP13 with MRE11; MDC1 recruitment assay by immunofluorescence; ATM signaling western blot","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity-labeling MS plus co-IP plus functional MDC1/ATM readouts; single lab","pmids":["36552858"],"is_preprint":false},{"year":2021,"finding":"TRIP13 phosphorylation at tyrosine 56 (Y56) by EGFR promotes NHEJ repair and induces radiation resistance in head and neck cancer; suppression of Y56 phosphorylation abrogates these effects.","method":"Phospho-site identification; EGFR inhibition and TRIP13-Y56 mutant functional studies; NHEJ reporter; radiation survival assay","journal":"Molecular therapy : the journal of the American Society of Gene Therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-site mutagenesis with functional NHEJ and radiation resistance readouts; single lab","pmids":["34111559"],"is_preprint":false},{"year":2024,"finding":"TRIP13 localizes to the synaptonemal complex (SC) of synapsed chromosomes in early pachytene spermatocytes and to telomeres throughout meiotic prophase I. This localization is independent of SC axial element proteins REC8, SYCP2, and SYCP3. TRIP13 is a dosage-sensitive regulator: heterozygous Trip13 mice show meiotic defects less severe than nulls. Loss of TRIP13 causes persistence of HORMAD1 and HORMAD2 on synapsed SC and chromosome asynapsis preferentially affecting XY and centromeric ends.","method":"Live imaging and immunofluorescence of FLAG-tagged TRIP13 knock-in mice; genetic analysis of Trip13 null and heterozygous mice; chromosome spread analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous tagging knock-in mice with functional validation, multiple genetic alleles, direct localization with functional consequences","pmids":["39207914"],"is_preprint":false},{"year":2022,"finding":"TRIP13 interacts with FGFR4 in colorectal cancer cells; this interaction is required for activation of the EGFR-AKT pathway. TRIP13 also participates in WNT signaling regulation and EMT in colorectal cancer.","method":"Co-IP of TRIP13 with FGFR4; pathway western blotting; TRIP13 KD xenograft and metastasis assays","journal":"Molecular oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP for FGFR4 interaction, pathway activation inferred from western blot; single lab","pmids":["33037736"],"is_preprint":false},{"year":2020,"finding":"TRIP13 interacts with LRP6 (co-localization and co-immunoprecipitation in lung cancer cells) and promotes activation of the Wnt/β-catenin signaling pathway, driving proliferation and invasion.","method":"Co-IP and confocal immunofluorescence co-localization of TRIP13 with LRP6; β-catenin activation western blot; colony formation and invasion assays","journal":"Journal of molecular histology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP plus co-localization, pathway downstream readout only; single lab","pmids":["33128167"],"is_preprint":false},{"year":2021,"finding":"TRIP13 directly interacts with HAT1; this interaction inhibits UBE4A-mediated ubiquitination degradation of HAT1, stabilizing HAT1 protein. TRIP13's ATPase activity is required for HAT1 binding, and through HAT1 stabilization TRIP13 promotes Foxp3 expression and Treg expansion downstream of TNF-TNFR2 signaling.","method":"Co-IP of TRIP13 with HAT1 and UBE4A; ubiquitination assay; ATPase-dead TRIP13 mutant; TRIP13 KO mouse colitis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, ATPase mutant functional dissection, in vivo mouse model; single lab","pmids":["41535263"],"is_preprint":false},{"year":2023,"finding":"TRIP13 directly interacts with DDX21 and stabilizes DDX21 expression by restraining its ubiquitination-dependent degradation, thereby promoting gastric cancer progression. HDAC1 acts as an upstream transcriptional activator of TRIP13 by targeting the TRIP13 promoter region.","method":"Co-IP of TRIP13 with DDX21; ubiquitination assay; ChIP of HDAC1 at TRIP13 promoter; gain- and loss-of-function in gastric cancer cells","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ubiquitination assay plus chromatin assay; single lab","pmids":["39187490"],"is_preprint":false},{"year":2024,"finding":"THC (tetrahydrocurcumin) directly targets TRIP13 (confirmed by click chemistry target fishing, CETSA, DARTS, and SPR). In TNBC cells, TRIP13 forms a trimeric complex with USP7 and c-FLIP. THC disrupts this TRIP13/USP7/c-FLIP complex, leading to ubiquitination and degradation of c-FLIP and extrinsic apoptosis.","method":"Click chemistry target fishing; CETSA; DARTS; SPR; co-IP of TRIP13/USP7/c-FLIP complex; in vitro deubiquitination assay; confocal microscopy","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple target engagement methods plus co-IP of trimeric complex plus functional ubiquitination assay; single lab","pmids":["39505147"],"is_preprint":false},{"year":2023,"finding":"DCZ5417 inhibits TRIP13 ATPase activity and disrupts the TRIP13/YWHAE protein complex, thereby suppressing ERK/MAPK signaling and inhibiting multiple myeloma cell proliferation.","method":"Molecular docking; pull-down; surface plasmon resonance; cellular thermal shift assay; ATPase activity assay; co-IP of TRIP13 with YWHAE; ERK/MAPK western blot; xenograft","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal binding assays confirming drug-target interaction plus co-IP of TRIP13/YWHAE complex; single lab","pmids":["38012658"],"is_preprint":false},{"year":2025,"finding":"In KRAS-mutant pancreatic cancer cells, TRIP13 promotes survival specifically in a homologous recombination-dependent manner; TRIP13-depleted KRASG12V-expressing cells acquire HR-deficiency phenotypes (sensitivity to TLS inhibitors and PARP inhibitors), indicating TRIP13 supports HR-mediated tolerance of oncogene-induced replication stress.","method":"Genetic (siRNA/CRISPR) and pharmacological TRIP13 depletion in KRASG12V-expressing HPNE cells; DNA synthesis assays; HR-deficiency phenotype assays (TLS and PARP inhibitor sensitivity)","journal":"NAR cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological tools with defined HR-deficiency phenotypes; single lab","pmids":["40115747"],"is_preprint":false},{"year":2025,"finding":"TRIP13 promotes TNBC cell viability and migration by activating STAT3 signaling; STAT3 in turn binds a STAT3-recognition element in the TRIP13 regulatory region to upregulate TRIP13, forming a positive TRIP13/STAT3 feedback circuit.","method":"Western blot for STAT3 activation; ChIP of STAT3 at TRIP13 promoter; TRIP13 overexpression rescue of bardoxolone-induced apoptosis; in vivo xenograft","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP of STAT3 at TRIP13 promoter, overexpression rescue, in vivo model; single lab","pmids":["39939802"],"is_preprint":false},{"year":2025,"finding":"HSPA9 (exosomal) stabilizes TRIP13 protein by recruiting the deubiquitinase USP1 to TRIP13 via the carboxyl-terminal peptide-binding domain of HSPA9, thereby preventing TRIP13 ubiquitination and degradation; the HSPA9-USP1-TRIP13 complex is stable in the cytoplasm and its integrity promotes bortezomib resistance in multiple myeloma.","method":"Co-IP of HSPA9/USP1/TRIP13 complex; protein truncation test to map HSPA9-USP1 interaction domain; ubiquitination assay; immunofluorescence co-localization; xenograft","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of trimeric complex plus domain mapping plus ubiquitination assay; single lab","pmids":["40140922"],"is_preprint":false}],"current_model":"TRIP13 is a hexameric AAA+ ATPase that acts as a universal remodeler of HORMA-domain proteins: aided by the adapter protein p31(comet), it engages the disordered N-terminus of closed-conformation HORMA clients (MAD2, REV7/MAD2L2, meiotic HORMADs) through its pore loops and couples ATP-driven translocation to conformational conversion (closed→open), thereby disassembling the mitotic checkpoint complex (MCC) to silence the spindle assembly checkpoint, disassembling the REV7-Shieldin complex to promote homologous recombination over NHEJ, disassembling the REV7-REV3/Pol-ζ TLS complex, and removing HORMADs from synapsed meiotic chromosome axes; additionally, TRIP13 has been shown to interact with and regulate USP7-substrate associations (enhancing deubiquitination), interact with MRE11 to amplify ATM signaling, undergo EGFR-mediated phosphorylation at Y56 to enhance NHEJ, and interact with multiple oncogenic partner proteins (ACTN4, FGFR4, LRP6, YWHAE, HAT1, DDX21) to activate diverse cancer-promoting signaling pathways."},"narrative":{"mechanistic_narrative":"TRIP13 is a hexameric AAA+ ATPase that functions as a universal remodeler of HORMA-domain proteins, coupling ATP-driven translocation to conformational conversion of its clients from a signaling-active 'closed' state to an inactive 'open' state [PMID:25918846, PMID:29973720]. Working with the adapter p31(comet), TRIP13 engages the disordered N-terminus of closed-conformation MAD2 through its axial pore loops and locally unfolds the MAD2 C-terminal αA helix, dissociating MAD2 from its partners; this remodeling disassembles the mitotic checkpoint complex and silences the spindle assembly checkpoint to permit anaphase onset, a reaction reconstituted from purified components and visualized by crystal and cryo-EM structures of the remodeling complex [PMID:25918846, PMID:25092294, PMID:29208896, PMID:29973720]. The same N-terminal engagement mechanism is conserved across HORMA clients: TRIP13 removes meiotic HORMAD1/HORMAD2 from synapsed chromosome axes and is required for synaptonemal complex formation, recombination progression after strand invasion, and crossover control during mouse meiosis [PMID:19851446, PMID:17696610, PMID:20711356, PMID:28659378, PMID:39207914]. Beyond mitosis and meiosis, TRIP13 disassembles the REV7(MAD2L2)-Shieldin and REV7-REV3/Pol-ζ complexes by the analogous closed-to-open conversion of REV7, shifting DNA repair toward homologous recombination and away from error-prone end-joining and translesion synthesis [PMID:31915374, PMID:33597306]. Its catalytic activity additionally supports HR-mediated tolerance of oncogene-induced replication stress in KRAS-mutant cells [PMID:40115747]. Biallelic loss-of-function TRIP13 mutations impair the spindle assembly checkpoint and cause chromosome missegregation in patient cells, with rescue upon TRIP13 reintroduction [PMID:28553959]. In cancer contexts, TRIP13 acts through additional partners—enhancing USP7-substrate deubiquitination to stabilize oncoproteins [PMID:34061780], and stabilizing or activating partners including HAT1, DDX21, ACTN4, and YWHAE to drive proliferative signaling [PMID:31533816, PMID:41535263, PMID:39187490, PMID:38012658]; it is also subject to EGFR-mediated Y56 phosphorylation that enhances NHEJ and radioresistance [PMID:34111559].","teleology":[{"year":2007,"claim":"Established that TRIP13 acts in meiotic recombination downstream of DSB formation and strand invasion, defining its first in vivo functional role.","evidence":"Knockout mouse spermatocytes with recombination-marker immunofluorescence and double-mutant epistasis","pmids":["17696610"],"confidence":"High","gaps":["Molecular activity behind the recombination defect not defined at this stage","No biochemical mechanism linking TRIP13 to recombination intermediate resolution"]},{"year":2009,"claim":"Identified HORMAD1/HORMAD2 as in vivo TRIP13-dependent factors whose removal from synapsed axes requires TRIP13, hinting at a HORMA-protein-directed activity.","evidence":"Knockout/hypomorph mouse model with HORMAD immunofluorescence on meiotic chromosomes","pmids":["19851446"],"confidence":"High","gaps":["Whether TRIP13 acts directly on HORMADs vs indirectly was unresolved","No biochemical demonstration of conformational remodeling"]},{"year":2010,"claim":"Defined the breadth of meiotic phenotypes (synapsis, sex body, crossover number/distribution) using graded alleles, establishing TRIP13 dosage sensitivity in meiotic chromosome biology.","evidence":"Multiple hypomorphic alleles analyzed by cytology and chiasma counting","pmids":["20711356"],"confidence":"High","gaps":["Mechanistic link between molecular activity and synapsis/crossover phenotypes not established"]},{"year":2014,"claim":"Established the mitotic function of TRIP13 as a kinetochore-localized, ATPase-dependent silencer of the spindle assembly checkpoint that disassembles the MCC with p31(comet), reconstituted from purified components.","evidence":"Immunofluorescence localization, siRNA knockdown with mitotic timing, ATPase-dead rescue, and in vitro MCC disassembly assays with APC/C readout","pmids":["25012665","25092294"],"confidence":"High","gaps":["Atomic mechanism of MAD2 remodeling not yet resolved","How substrate is selected at the kinetochore not defined"]},{"year":2014,"claim":"Linked TRIP13 to DNA double-strand break repair pathway choice, showing it binds DNA-PKcs complex proteins and promotes NHEJ and treatment resistance.","evidence":"Mass spectrometry of binding partners and NHEJ reporter assays with over/knockdown in cancer cells","pmids":["25078033"],"confidence":"Medium","gaps":["Direct substrate of remodeling in repair not identified at this point","Single lab, mechanism of NHEJ promotion inferred"]},{"year":2015,"claim":"Defined TRIP13 as an AAA+ protein-remodeling ATPase that converts closed MAD2 to open MAD2 via p31(comet), unifying its mitotic and meiotic roles around HORMA conformational conversion.","evidence":"Crystal structure of C. elegans PCH-2 and in vitro MAD2 conversion assay with p31(comet)","pmids":["25918846"],"confidence":"High","gaps":["Structure of the human enzyme-substrate complex not yet solved","Precise coupling of ATP hydrolysis to unfolding undefined"]},{"year":2015,"claim":"Mapped the bipartite substrate-binding architecture, showing oligomeric TRIP13 requires simultaneous p31(comet) and C-MAD2-complex occupancy for high-affinity engagement.","evidence":"Recombinant binding assays and reciprocal co-IP of TRIP13 with p31(comet) and MCC","pmids":["26324890"],"confidence":"High","gaps":["Dynamics of substrate handoff during catalysis not resolved"]},{"year":2017,"claim":"Resolved the human enzyme structure and the molecular mechanism of MAD2 remodeling, showing local C-terminal unfolding and identifying the conserved N-terminal engagement of HORMA clients shared between MAD2 and meiotic HORMAD1.","evidence":"Human TRIP13 crystal structure, NMR of MAD2, crosslinking MS, truncation-mutant remodeling assays, and spermatocyte immunofluorescence","pmids":["29208896","28659378"],"confidence":"High","gaps":["Full translocation trajectory not yet visualized structurally"]},{"year":2017,"claim":"Connected TRIP13 to human disease, demonstrating that biallelic loss-of-function impairs the SAC and causes chromosome missegregation, rescuable by TRIP13 reintroduction.","evidence":"Patient-derived cells with SAC and segregation assays and rescue","pmids":["28553959"],"confidence":"High","gaps":["Genotype-phenotype range across tissues not fully mapped"]},{"year":2018,"claim":"Visualized the complete remodeling complex and established that TRIP13 has a dual role—maintaining the open-MAD2 pool for checkpoint activation and disassembling MCC for mitotic exit.","evidence":"Cryo-EM of TRIP13-p31comet-C-MAD2-CDC20 plus degron depletion with APC15 double-depletion mitotic exit assays","pmids":["29973720","30341343"],"confidence":"High","gaps":["How the same enzyme is biased toward assembly vs disassembly in vivo not fully defined"]},{"year":2020,"claim":"Extended TRIP13's HORMA-remodeling activity to REV7, showing it disassembles REV7-Shieldin and REV7-REV3/Pol-ζ complexes to favor homologous recombination over end-joining and translesion synthesis.","evidence":"REV7 conformational assays, co-IP, HR reporters, and PARP inhibitor sensitivity in BRCA1-deficient cells; p31(comet)-dependence shown by co-IP and chromatin fractionation","pmids":["31915374","33051298"],"confidence":"High","gaps":["In vivo balance between repair-pathway choices across tissues unresolved","p31(comet) role in REV7 extraction shown in a single lab"]},{"year":2021,"claim":"Provided structural mechanism for Shieldin disassembly, showing REV7 N-terminal insertion into the TRIP13 channel and ATP-hydrolysis-driven rotatory disassembly, and defined REV7 dimerization as a prerequisite for TRIP13 engagement.","evidence":"Crystal and cryo-EM structures of Shieldin sub-complexes with TRIP13 plus co-IP with dimerization-defective MAD2L2 mutants and NHEJ reporters","pmids":["33597306","34521823"],"confidence":"High","gaps":["Single co-IP-based confidence for dimerization requirement (medium evidence)"]},{"year":2021,"claim":"Uncovered a non-HORMA, deubiquitination-promoting function in cancer, with TRIP13 enhancing USP7-substrate association to protect oncoproteins and drive tumorigenesis.","evidence":"Co-IP with USP7, ubiquitination assays, transgenic mouse tumor model, and USP7-inhibitor rescue","pmids":["34061780"],"confidence":"Medium","gaps":["Whether ATPase activity is required for the USP7 effect not established here","Single lab"]},{"year":2022,"claim":"Placed TRIP13 in immediate-early DNA damage sensing, linking it to MRE11/MRN, MDC1 recruitment, and ATM signaling amplification.","evidence":"Proximity-labeling proteomics, co-IP with MRE11, MDC1 recruitment imaging, and ATM signaling western blot","pmids":["36552858"],"confidence":"Medium","gaps":["Direct vs indirect MRE11 interaction not fully resolved","Single lab"]},{"year":2024,"claim":"Refined TRIP13 meiotic localization to the synaptonemal complex and telomeres, independent of axial element proteins, and confirmed dosage sensitivity for HORMAD removal and asynapsis phenotypes.","evidence":"FLAG-tagged knock-in mouse live imaging and immunofluorescence with null/heterozygous genetic analysis","pmids":["39207914"],"confidence":"High","gaps":["Recruitment determinants to SC and telomeres not identified"]},{"year":2025,"claim":"Demonstrated that TRIP13's HR-supporting activity confers tolerance to oncogene-induced replication stress, rationalizing its cancer dependency.","evidence":"Genetic and pharmacological TRIP13 depletion in KRASG12V cells with HR-deficiency phenotype assays","pmids":["40115747"],"confidence":"Medium","gaps":["Mechanistic link between HORMA remodeling and replication-stress tolerance not fully traced","Single lab"]},{"year":2025,"claim":"Characterized regulation of TRIP13 protein stability and transcription in cancer, identifying HSPA9-USP1 stabilization and STAT3 feedback control.","evidence":"Co-IP of HSPA9/USP1/TRIP13 complex with domain mapping and ubiquitination assays; STAT3 ChIP at TRIP13 promoter with rescue and xenograft","pmids":["40140922","39939802"],"confidence":"Medium","gaps":["Generality of these regulatory circuits beyond myeloma/TNBC unknown","Single lab each"]},{"year":null,"claim":"How TRIP13's canonical HORMA-remodeling ATPase activity mechanistically relates to its diverse cancer partner interactions (ACTN4, FGFR4, LRP6, YWHAE, HAT1, DDX21, USP7) remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Whether non-HORMA partner effects require ATPase/remodeling activity is not consistently tested","Most oncogenic partner interactions rest on single-lab co-IP evidence","Direct vs indirect nature of several partner interactions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3,5,6,8,10]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,9,10,12,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,6,12,19]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[3,8,10]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[5]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,25]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[21,29,33]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[34]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,6,11,17]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4,12,14,23,32]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1,2,25]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[19,28,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[20,31,33]}],"complexes":["mitotic checkpoint complex (MCC, as remodeling substrate)","TRIP13-p31(comet)-C-MAD2-CDC20 remodeling complex","REV7-Shieldin (as remodeling substrate)","HSPA9-USP1-TRIP13 complex"],"partners":["MAD2","P31(COMET)/MAD2L1BP","REV7/MAD2L2","USP7","MRE11","HAT1","DDX21","YWHAE"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15645","full_name":"Pachytene checkpoint protein 2 homolog","aliases":["Human papillomavirus type 16 E1 protein-binding protein","16E1-BP","HPV16 E1 protein-binding protein","Thyroid hormone receptor interactor 13","Thyroid receptor-interacting protein 13","TR-interacting protein 13","TRIP-13"],"length_aa":432,"mass_kda":48.6,"function":"Plays a key role in chromosome recombination and chromosome structure development during meiosis. Required at early steps in meiotic recombination that leads to non-crossovers pathways. Also needed for efficient completion of homologous synapsis by influencing crossover distribution along the chromosomes affecting both crossovers and non-crossovers pathways. Also required for development of higher-order chromosome structures and is needed for synaptonemal-complex formation. In males, required for efficient synapsis of the sex chromosomes and for sex body formation. Promotes early steps of the DNA double-strand breaks (DSBs) repair process upstream of the assembly of RAD51 complexes. Required for depletion of HORMAD1 and HORMAD2 from synapsed chromosomes (By similarity). Plays a role in mitotic spindle assembly checkpoint (SAC) activation (PubMed:28553959)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q15645/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIP13","classification":"Not Classified","n_dependent_lines":216,"n_total_lines":1208,"dependency_fraction":0.17880794701986755},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRIP13","total_profiled":1310},"omim":[{"mim_id":"619011","title":"OOCYTE/ZYGOTE/EMBRYO MATURATION ARREST 9; OZEMA9","url":"https://www.omim.org/entry/619011"},{"mim_id":"618842","title":"HORMA DOMAIN-CONTAINING PROTEIN 2; HORMAD2","url":"https://www.omim.org/entry/618842"},{"mim_id":"618136","title":"MAD2L1-BINDING PROTEIN; MAD2L1BP","url":"https://www.omim.org/entry/618136"},{"mim_id":"617598","title":"MOSAIC VARIEGATED ANEUPLOIDY SYNDROME 3; MVA3","url":"https://www.omim.org/entry/617598"},{"mim_id":"615774","title":"OOCYTE/ZYGOTE/EMBRYO MATURATION ARREST 1; OZEMA1","url":"https://www.omim.org/entry/615774"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"},{"location":"Acrosome","reliability":"Additional"},{"location":"Equatorial segment","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":27.9}],"url":"https://www.proteinatlas.org/search/TRIP13"},"hgnc":{"alias_symbol":["16E1BP"],"prev_symbol":[]},"alphafold":{"accession":"Q15645","domains":[{"cath_id":"3.40.50.300","chopping":"109-319","consensus_level":"high","plddt":85.705,"start":109,"end":319},{"cath_id":"-","chopping":"325-432","consensus_level":"high","plddt":94.8512,"start":325,"end":432},{"cath_id":"3.10.330","chopping":"21-101","consensus_level":"high","plddt":87.8637,"start":21,"end":101}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15645","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15645-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15645-F1-predicted_aligned_error_v6.png","plddt_mean":86.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIP13","jax_strain_url":"https://www.jax.org/strain/search?query=TRIP13"},"sequence":{"accession":"Q15645","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15645.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15645/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15645"}},"corpus_meta":[{"pmid":"19851446","id":"PMC_19851446","title":"Mouse HORMAD1 and HORMAD2, two conserved meiotic chromosomal proteins, are depleted from synapsed chromosome axes with the help of TRIP13 AAA-ATPase.","date":"2009","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19851446","citation_count":333,"is_preprint":false},{"pmid":"17696610","id":"PMC_17696610","title":"Mouse pachytene checkpoint 2 (trip13) is required for completing meiotic recombination but not synapsis.","date":"2007","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17696610","citation_count":177,"is_preprint":false},{"pmid":"20711356","id":"PMC_20711356","title":"Mouse TRIP13/PCH2 is required for recombination and normal higher-order chromosome structure during meiosis.","date":"2010","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20711356","citation_count":161,"is_preprint":false},{"pmid":"25918846","id":"PMC_25918846","title":"TRIP13 is a protein-remodeling AAA+ ATPase that catalyzes MAD2 conformation switching.","date":"2015","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/25918846","citation_count":143,"is_preprint":false},{"pmid":"25078033","id":"PMC_25078033","title":"TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25078033","citation_count":131,"is_preprint":false},{"pmid":"31915374","id":"PMC_31915374","title":"TRIP13 regulates DNA repair pathway choice through REV7 conformational change.","date":"2020","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31915374","citation_count":129,"is_preprint":false},{"pmid":"31932165","id":"PMC_31932165","title":"HORMA Domain Proteins and a Trip13-like ATPase Regulate Bacterial cGAS-like Enzymes to Mediate Bacteriophage Immunity.","date":"2020","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/31932165","citation_count":129,"is_preprint":false},{"pmid":"25012665","id":"PMC_25012665","title":"Thyroid hormone receptor interacting protein 13 (TRIP13) AAA-ATPase is a novel mitotic checkpoint-silencing protein.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25012665","citation_count":124,"is_preprint":false},{"pmid":"28553959","id":"PMC_28553959","title":"Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation.","date":"2017","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28553959","citation_count":119,"is_preprint":false},{"pmid":"29973720","id":"PMC_29973720","title":"Mechanism for remodelling of the cell cycle checkpoint protein MAD2 by the ATPase TRIP13.","date":"2018","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/29973720","citation_count":111,"is_preprint":false},{"pmid":"25092294","id":"PMC_25092294","title":"Disassembly of mitotic checkpoint complexes by the joint action of the AAA-ATPase TRIP13 and p31(comet).","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25092294","citation_count":108,"is_preprint":false},{"pmid":"32473092","id":"PMC_32473092","title":"Bi-allelic Missense Pathogenic Variants in TRIP13 Cause Female Infertility Characterized by Oocyte Maturation Arrest.","date":"2020","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32473092","citation_count":102,"is_preprint":false},{"pmid":"25895724","id":"PMC_25895724","title":"Pch2(TRIP13): controlling cell division through regulation of HORMA domains.","date":"2015","source":"Chromosoma","url":"https://pubmed.ncbi.nlm.nih.gov/25895724","citation_count":78,"is_preprint":false},{"pmid":"28659378","id":"PMC_28659378","title":"The AAA+ ATPase TRIP13 remodels HORMA domains through N-terminal engagement and unfolding.","date":"2017","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/28659378","citation_count":71,"is_preprint":false},{"pmid":"30685303","id":"PMC_30685303","title":"MiR-515-5p acts as a tumor suppressor via targeting TRIP13 in prostate cancer.","date":"2019","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/30685303","citation_count":65,"is_preprint":false},{"pmid":"26324890","id":"PMC_26324890","title":"Mode of interaction of TRIP13 AAA-ATPase with the Mad2-binding protein p31comet and with mitotic checkpoint complexes.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26324890","citation_count":64,"is_preprint":false},{"pmid":"31533816","id":"PMC_31533816","title":"Elevated TRIP13 drives the AKT/mTOR pathway to induce the progression of hepatocellular carcinoma via interacting with ACTN4.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31533816","citation_count":63,"is_preprint":false},{"pmid":"31321001","id":"PMC_31321001","title":"Insights into a Crucial Role of TRIP13 in Human Cancer.","date":"2019","source":"Computational and structural biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/31321001","citation_count":61,"is_preprint":false},{"pmid":"31740732","id":"PMC_31740732","title":"TRIP13 promotes the cell proliferation, migration and invasion of glioblastoma through the FBXW7/c-MYC axis.","date":"2019","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31740732","citation_count":61,"is_preprint":false},{"pmid":"33648560","id":"PMC_33648560","title":"HMGA1-TRIP13 axis promotes stemness and epithelial mesenchymal transition of perihilar cholangiocarcinoma in a positive feedback loop dependent on c-Myc.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33648560","citation_count":49,"is_preprint":false},{"pmid":"30564064","id":"PMC_30564064","title":"Silencing TRIP13 inhibits cell growth and metastasis of hepatocellular carcinoma by activating of TGF-β1/smad3.","date":"2018","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/30564064","citation_count":47,"is_preprint":false},{"pmid":"33037736","id":"PMC_33037736","title":"TRIP13 promotes metastasis of colorectal cancer regardless of p53 and microsatellite instability status.","date":"2020","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33037736","citation_count":45,"is_preprint":false},{"pmid":"30341343","id":"PMC_30341343","title":"TRIP13 and APC15 drive mitotic exit by turnover of interphase- and unattached kinetochore-produced MCC.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30341343","citation_count":45,"is_preprint":false},{"pmid":"35194944","id":"PMC_35194944","title":"DCZ0415, a small-molecule inhibitor targeting TRIP13, inhibits EMT and metastasis via inactivation of the FGFR4/STAT3 axis and the Wnt/β-catenin pathway in colorectal cancer.","date":"2022","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35194944","citation_count":44,"is_preprint":false},{"pmid":"28564602","id":"PMC_28564602","title":"Mad2 Overexpression Uncovers a Critical Role for TRIP13 in Mitotic Exit.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28564602","citation_count":42,"is_preprint":false},{"pmid":"34061780","id":"PMC_34061780","title":"TRIP13 modulates protein deubiquitination and accelerates tumor development and progression of B cell malignancies.","date":"2021","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/34061780","citation_count":36,"is_preprint":false},{"pmid":"28105232","id":"PMC_28105232","title":"TRIP13 is expressed in colorectal cancer and promotes cancer cell invasion.","date":"2016","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/28105232","citation_count":36,"is_preprint":false},{"pmid":"29208896","id":"PMC_29208896","title":"Mechanistic insight into TRIP13-catalyzed Mad2 structural transition and spindle checkpoint silencing.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29208896","citation_count":36,"is_preprint":false},{"pmid":"34521823","id":"PMC_34521823","title":"MAD2L2 dimerization and TRIP13 control shieldin activity in DNA repair.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34521823","citation_count":34,"is_preprint":false},{"pmid":"33051298","id":"PMC_33051298","title":"p31comet promotes homologous recombination by inactivating REV7 through the TRIP13 ATPase.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33051298","citation_count":30,"is_preprint":false},{"pmid":"31396344","id":"PMC_31396344","title":"Elevated TRIP13 drives cell proliferation and drug resistance in bladder cancer.","date":"2019","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/31396344","citation_count":28,"is_preprint":false},{"pmid":"36031387","id":"PMC_36031387","title":"Trip13 Depletion in Liver Cancer Induces a Lipogenic Response Contributing to Plin2-Dependent Mitotic Cell Death.","date":"2022","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/36031387","citation_count":28,"is_preprint":false},{"pmid":"31337978","id":"PMC_31337978","title":"Increased expression of TRIP13 drives the tumorigenesis of bladder cancer in association with the EGFR signaling pathway.","date":"2019","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31337978","citation_count":27,"is_preprint":false},{"pmid":"33136091","id":"PMC_33136091","title":"TRIP13 promotes lung cancer cell growth and metastasis through AKT/mTORC1/c-Myc signaling.","date":"2021","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/33136091","citation_count":25,"is_preprint":false},{"pmid":"30720159","id":"PMC_30720159","title":"TRIP13 promotes proliferation and invasion of epithelial ovarian cancer cells through Notch signaling pathway.","date":"2019","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30720159","citation_count":24,"is_preprint":false},{"pmid":"35322916","id":"PMC_35322916","title":"Evaluation of the TRIP13 level in breast cancer and insights into potential molecular pathways.","date":"2022","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35322916","citation_count":24,"is_preprint":false},{"pmid":"34307457","id":"PMC_34307457","title":"Hsa_circRNA_100146 Promotes Prostate Cancer Progression by Upregulating TRIP13 via Sponging miR-615-5p.","date":"2021","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/34307457","citation_count":24,"is_preprint":false},{"pmid":"33597306","id":"PMC_33597306","title":"Molecular mechanisms of assembly and TRIP13-mediated remodeling of the human Shieldin complex.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33597306","citation_count":22,"is_preprint":false},{"pmid":"37669963","id":"PMC_37669963","title":"Osimertinib induces paraptosis and TRIP13 confers resistance in glioblastoma cells.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37669963","citation_count":21,"is_preprint":false},{"pmid":"33128167","id":"PMC_33128167","title":"TRIP13 promotes the proliferation and invasion of lung cancer cells via the Wnt signaling pathway and epithelial-mesenchymal transition.","date":"2020","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/33128167","citation_count":20,"is_preprint":false},{"pmid":"34184074","id":"PMC_34184074","title":"Upregulation of TRIP13 promotes the malignant progression of lung cancer via the EMT pathway.","date":"2021","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/34184074","citation_count":20,"is_preprint":false},{"pmid":"34111559","id":"PMC_34111559","title":"Phosphorylation of TRIP13 at Y56 induces radiation resistance but sensitizes head and neck cancer to cetuximab.","date":"2021","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34111559","citation_count":19,"is_preprint":false},{"pmid":"28256593","id":"PMC_28256593","title":"TRIP13-deficient tubular epithelial cells are susceptible to apoptosis following acute kidney injury.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28256593","citation_count":19,"is_preprint":false},{"pmid":"32694945","id":"PMC_32694945","title":"Long non-coding RNA NORAD exhaustion represses prostate cancer progression through inhibiting TRIP13 expression via competitively binding to miR-495-3p.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/32694945","citation_count":19,"is_preprint":false},{"pmid":"34061428","id":"PMC_34061428","title":"TRIP13 exerts a cancer-promoting role in cervical cancer by enhancing Wnt/β-catenin signaling via ACTN4.","date":"2021","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/34061428","citation_count":17,"is_preprint":false},{"pmid":"36896765","id":"PMC_36896765","title":"TRIP13 overexpression promotes gefitinib resistance in non‑small cell lung cancer via regulating autophagy and phosphorylation of the EGFR signaling pathway.","date":"2023","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/36896765","citation_count":17,"is_preprint":false},{"pmid":"35075117","id":"PMC_35075117","title":"TRIP13, identified as a hub gene of tumor progression, is the target of microRNA-4693-5p and a potential therapeutic target for colorectal cancer.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35075117","citation_count":17,"is_preprint":false},{"pmid":"35972731","id":"PMC_35972731","title":"Combined TRIP13 and Aurora Kinase Inhibition Induces Apoptosis in Human Papillomavirus-Driven Cancers.","date":"2022","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/35972731","citation_count":16,"is_preprint":false},{"pmid":"39207914","id":"PMC_39207914","title":"TRIP13 localizes to synapsed chromosomes and functions as a dosage-sensitive regulator of meiosis.","date":"2024","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/39207914","citation_count":16,"is_preprint":false},{"pmid":"35251343","id":"PMC_35251343","title":"KIF18B promotes breast cancer cell proliferation, migration and invasion by targeting TRIP13 and activating the Wnt/β-catenin signaling pathway.","date":"2022","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/35251343","citation_count":16,"is_preprint":false},{"pmid":"38039923","id":"PMC_38039923","title":"Targeting of oncogenic AAA-ATPase TRIP13 reduces progression of pancreatic ductal adenocarcinoma.","date":"2023","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/38039923","citation_count":15,"is_preprint":false},{"pmid":"31648166","id":"PMC_31648166","title":"TRIP13 interference inhibits the proliferation and metastasis of thyroid cancer cells through regulating TTC5/p53 pathway and epithelial-mesenchymal transition related genes expression.","date":"2019","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/31648166","citation_count":15,"is_preprint":false},{"pmid":"33208020","id":"PMC_33208020","title":"CETSA MS Profiling for a Comparative Assessment of FDA-Approved Antivirals Repurposed for COVID-19 Therapy Identifies TRIP13 as a Remdesivir Off-Target.","date":"2020","source":"SLAS discovery : advancing life sciences R & D","url":"https://pubmed.ncbi.nlm.nih.gov/33208020","citation_count":14,"is_preprint":false},{"pmid":"35032258","id":"PMC_35032258","title":"TRIP13 knockdown inhibits the proliferation, migration, invasion, and promotes apoptosis by suppressing PI3K/AKT signaling pathway in U2OS cells.","date":"2022","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/35032258","citation_count":12,"is_preprint":false},{"pmid":"39505147","id":"PMC_39505147","title":"Tetrahydrocurcumin targets TRIP13 inhibiting the interaction of TRIP13/USP7/c-FLIP to mediate c-FLIP ubiquitination in triple-negative breast cancer.","date":"2024","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/39505147","citation_count":11,"is_preprint":false},{"pmid":"38012658","id":"PMC_38012658","title":"The novel norcantharidin derivative DCZ5417 suppresses multiple myeloma progression by targeting the TRIP13-MAPK-YWHAE signaling pathway.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38012658","citation_count":11,"is_preprint":false},{"pmid":"34066132","id":"PMC_34066132","title":"Clinical Significance and Systematic Expression Analysis of the Thyroid Receptor Interacting Protein 13 (TRIP13) as Human Gliomas Biomarker.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34066132","citation_count":11,"is_preprint":false},{"pmid":"31934178","id":"PMC_31934178","title":"The oncogenic role of TRIP13 in regulating proliferation, invasion, and cell cycle checkpoint in NSCLC cells.","date":"2019","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31934178","citation_count":11,"is_preprint":false},{"pmid":"35517402","id":"PMC_35517402","title":"Inducing Synergistic DNA Damage by TRIP13 and PARP1 Inhibitors Provides a Potential Treatment for Hepatocellular Carcinoma.","date":"2022","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35517402","citation_count":10,"is_preprint":false},{"pmid":"34806647","id":"PMC_34806647","title":"DNA damage is overcome by TRIP13 overexpression during cisplatin nephrotoxicity.","date":"2021","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/34806647","citation_count":10,"is_preprint":false},{"pmid":"35601150","id":"PMC_35601150","title":"TRIP13 Induces Nedaplatin Resistance in Esophageal Squamous Cell Carcinoma by Enhancing Repair of DNA Damage and Inhibiting Apoptosis.","date":"2022","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/35601150","citation_count":10,"is_preprint":false},{"pmid":"37627217","id":"PMC_37627217","title":"Oncogenic Targets Regulated by Tumor-Suppressive miR-30c-1-3p and miR-30c-2-3p: TRIP13 Facilitates Cancer Cell Aggressiveness in Breast Cancer.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37627217","citation_count":9,"is_preprint":false},{"pmid":"32697629","id":"PMC_32697629","title":"The conserved AAA-ATPase PCH-2 TRIP13 regulates spindle checkpoint strength.","date":"2020","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/32697629","citation_count":9,"is_preprint":false},{"pmid":"33712914","id":"PMC_33712914","title":"Getting there: understanding the chromosomal recruitment of the AAA+ ATPase Pch2/TRIP13 during meiosis.","date":"2021","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33712914","citation_count":9,"is_preprint":false},{"pmid":"32420796","id":"PMC_32420796","title":"Disassembly of the Shieldin Complex by TRIP13.","date":"2020","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/32420796","citation_count":8,"is_preprint":false},{"pmid":"36552858","id":"PMC_36552858","title":"TRIP13 Participates in Immediate-Early Sensing of DNA Strand Breaks and ATM Signaling Amplification through MRE11.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36552858","citation_count":8,"is_preprint":false},{"pmid":"36268276","id":"PMC_36268276","title":"TRIP13/FLNA Complex Promotes Tumor Progression and Is Associated with Unfavorable Outcomes in Melanoma.","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36268276","citation_count":8,"is_preprint":false},{"pmid":"37800638","id":"PMC_37800638","title":"Targeting TRIP13 for overcoming anticancer drug resistance (Review).","date":"2023","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/37800638","citation_count":8,"is_preprint":false},{"pmid":"38589567","id":"PMC_38589567","title":"Targeting TRIP13 in favorable histology Wilms tumor with nuclear export inhibitors synergizes with doxorubicin.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/38589567","citation_count":8,"is_preprint":false},{"pmid":"38067275","id":"PMC_38067275","title":"Identification of Tumor-Suppressive miR-139-3p-Regulated Genes: TRIP13 as a Therapeutic Target in Lung Adenocarcinoma.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/38067275","citation_count":8,"is_preprint":false},{"pmid":"39187490","id":"PMC_39187490","title":"TRIP13 regulates progression of gastric cancer through stabilising the expression of DDX21.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39187490","citation_count":7,"is_preprint":false},{"pmid":"38347785","id":"PMC_38347785","title":"TRIP13 Activates Glycolysis to Promote Cell Stemness and Strengthen Doxorubicin Resistance of Colorectal Cancer Cells.","date":"2024","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38347785","citation_count":7,"is_preprint":false},{"pmid":"35362548","id":"PMC_35362548","title":"MiR-129-5p/TRIP13 affects malignant phenotypes of colorectal cancer cells.","date":"2022","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/35362548","citation_count":7,"is_preprint":false},{"pmid":"38092072","id":"PMC_38092072","title":"Design and synthesis of cantharidin derivative DCZ5418 as a TRIP13 inhibitor with anti-multiple myeloma activity in vitro and in vivo.","date":"2023","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/38092072","citation_count":7,"is_preprint":false},{"pmid":"40115747","id":"PMC_40115747","title":"TRIP13 protects pancreatic cancer cells against intrinsic and therapy-induced DNA replication stress.","date":"2025","source":"NAR cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40115747","citation_count":6,"is_preprint":false},{"pmid":"39939802","id":"PMC_39939802","title":"Bardoxolone displays potent activity against triple negative breast cancer by inhibiting the TRIP13/STAT3 circuit.","date":"2025","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/39939802","citation_count":6,"is_preprint":false},{"pmid":"39389496","id":"PMC_39389496","title":"Lnc-LINC00511 promotes gastric cancer progression by regulating MiR-29c-3p/TRIP13 axis through AKT/mTOR pathway.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39389496","citation_count":6,"is_preprint":false},{"pmid":"39398261","id":"PMC_39398261","title":"TRIP13: A promising cancer immunotherapy target.","date":"2024","source":"Cancer innovation","url":"https://pubmed.ncbi.nlm.nih.gov/39398261","citation_count":5,"is_preprint":false},{"pmid":"40140922","id":"PMC_40140922","title":"Exosome-transmitted HSPA9 facilitates bortezomib resistance by targeting TRIP13/USP1 signaling in multiple myeloma.","date":"2025","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/40140922","citation_count":5,"is_preprint":false},{"pmid":"37942576","id":"PMC_37942576","title":"TI17, a novel compound, exerts anti-MM activity by impairing Trip13 function of DSBs repair and enhancing DNA damage.","date":"2023","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37942576","citation_count":5,"is_preprint":false},{"pmid":"31666112","id":"PMC_31666112","title":"Correction to: Elevated TRIP13 drives the AKT/mTOR pathway to induce the progression of hepatocellular carcinoma via interacting with ACTN4.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31666112","citation_count":5,"is_preprint":false},{"pmid":"39436503","id":"PMC_39436503","title":"Role of TRIP13 in human cancer development.","date":"2024","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/39436503","citation_count":4,"is_preprint":false},{"pmid":"38074464","id":"PMC_38074464","title":"An integrated computational biology approach defines the crucial role of TRIP13 in pancreatic cancer.","date":"2023","source":"Computational and structural biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/38074464","citation_count":4,"is_preprint":false},{"pmid":"28810332","id":"PMC_28810332","title":"[Study on the expression of TRIP13 mRNA in chronic lymphocytic leukemia B lymphocyte and the molecular mechanism of TRIP13 mediated JVM-2 cell proliferation and apoptosis].","date":"2017","source":"Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi","url":"https://pubmed.ncbi.nlm.nih.gov/28810332","citation_count":4,"is_preprint":false},{"pmid":"40790482","id":"PMC_40790482","title":"TRIP13-induced NUSAP1 upregulation promotes CcRCC progression through EMT and PI3K/AKT/mTOR pathway.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40790482","citation_count":3,"is_preprint":false},{"pmid":"37808842","id":"PMC_37808842","title":"TRIP13 localizes to synapsed chromosomes and functions as a dosage-sensitive regulator of meiosis.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37808842","citation_count":3,"is_preprint":false},{"pmid":"38492425","id":"PMC_38492425","title":"High expression of TRIP13 is associated with tumor progression in H. pylori infection induced gastric cancer.","date":"2024","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/38492425","citation_count":3,"is_preprint":false},{"pmid":"39297991","id":"PMC_39297991","title":"Identification of a novel splicing variant of thyroid hormone receptor interaction protein 13 (TRIP13) in female infertility characterized by oocyte maturation arrest.","date":"2024","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39297991","citation_count":3,"is_preprint":false},{"pmid":"38911763","id":"PMC_38911763","title":"TRIP13 Plays an Important Role in the Sensitivity of Leukemia Cell Response to Sulforaphane Therapy.","date":"2024","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/38911763","citation_count":2,"is_preprint":false},{"pmid":"37340965","id":"PMC_37340965","title":"Novel mutations in TRIP13 lead to female infertility with oocyte maturation arrest.","date":"2023","source":"Yi chuan = Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/37340965","citation_count":2,"is_preprint":false},{"pmid":"39547519","id":"PMC_39547519","title":"Integrated multiomic analysis identifies TRIP13 as a mediator of alveolar epithelial type II cell dysfunction in idiopathic pulmonary fibrosis.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/39547519","citation_count":2,"is_preprint":false},{"pmid":"39189258","id":"PMC_39189258","title":"Genome-Wide Methylation Profiling of Peripheral T-Cell Lymphomas Identifies TRIP13 as a Critical Driver of Tumor Proliferation and Survival.","date":"2024","source":"Epigenomes","url":"https://pubmed.ncbi.nlm.nih.gov/39189258","citation_count":2,"is_preprint":false},{"pmid":"39762328","id":"PMC_39762328","title":"Repeated ionizing radiation exposure induces TRIP13 expression, conferring radioresistance in lung cancer cells.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39762328","citation_count":2,"is_preprint":false},{"pmid":"39042962","id":"PMC_39042962","title":"TRIP13 - a potential drug target in cancer pharmacotherapy.","date":"2024","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39042962","citation_count":1,"is_preprint":false},{"pmid":"37750623","id":"PMC_37750623","title":"CYP24A1, AHR, CPEB4, TRIP13, and PIK3CA genes expression in colorectal cancer patients: novel diagnostic biomarkers.","date":"2023","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37750623","citation_count":1,"is_preprint":false},{"pmid":"40592337","id":"PMC_40592337","title":"Ping-Chong-Jiang-Ni Formula effectively inhibits migration and invasion of endometriosis 12Z cell line via TRIP13.","date":"2025","source":"Journal of food and drug analysis","url":"https://pubmed.ncbi.nlm.nih.gov/40592337","citation_count":1,"is_preprint":false},{"pmid":"40337305","id":"PMC_40337305","title":"Discovery of novel antimyeloma agents targeting TRIP13 by molecular modeling and bioassay.","date":"2025","source":"RSC medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40337305","citation_count":1,"is_preprint":false},{"pmid":"34627428","id":"PMC_34627428","title":"[Regulation of TRIP13 on Proliferation and Apoptosis of B-Cell Lymphoma Cells and Its Mechanism].","date":"2021","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/34627428","citation_count":1,"is_preprint":false},{"pmid":"38296621","id":"PMC_38296621","title":"[TRIP13 Enhances Radioresistance of Lung Adenocarcinoma Cells 
through the Homologous Recombination Pathway].","date":"2024","source":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38296621","citation_count":1,"is_preprint":false},{"pmid":"41535263","id":"PMC_41535263","title":"TRIP13 promotes the expansion and immunosuppression of CD4+Foxp3+ regulatory T cells by sustaining HAT1 stability.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41535263","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49556,"output_tokens":8893,"usd":0.141032,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18912,"output_tokens":5584,"usd":0.11708,"stage2_stop_reason":"end_turn"},"total_usd":0.258112,"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\": 2009,\n      \"finding\": \"TRIP13 is required for depletion of HORMAD1 and HORMAD2 from synapsed chromosome axes during meiosis; loss of TRIP13 results in abnormal persistence of HORMADs on synapsed chromosomes and disrupts mutually exclusive HORMAD-rich and synapsed chromatin domains.\",\n      \"method\": \"Genetic knockout/hypomorph mouse model with immunofluorescence analysis of HORMAD1/HORMAD2 localization on meiotic chromosomes\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO/hypomorph with defined cellular phenotype, replicated across multiple labs in subsequent papers\",\n      \"pmids\": [\"19851446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mouse TRIP13 is required for completing a subset of meiotic recombination events after strand invasion; TRIP13-deficient spermatocytes retain recombination intermediates (RAD51, BLM, RPA) despite full synapsis. Epistasis analysis showed SPO11, MEI1, REC8, and DMC1 are epistatic to TRIP13, placing TRIP13 downstream of these recombination factors.\",\n      \"method\": \"Genetic knockout mouse model with immunofluorescence for recombination markers; double-mutant epistasis analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined molecular phenotype plus genetic epistasis, replicated in subsequent studies\",\n      \"pmids\": [\"17696610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRIP13 is required for proper synaptonemal complex formation, efficient synapsis of sex chromosomes, sex body formation, normal crossover numbers and distribution, and early recombination steps after DSB formation in mouse meiosis.\",\n      \"method\": \"Distinct Trip13 alleles (moderate and severe hypomorphs) analyzed by cytology, immunofluorescence, chiasma counting\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple alleles with graded phenotypes, multiple orthogonal cytological readouts, independent replication\",\n      \"pmids\": [\"20711356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIP13 is a protein-remodeling AAA+ ATPase that, aided by the adapter protein p31(comet), converts the HORMA-family spindle checkpoint protein MAD2 from its signaling-active 'closed' conformer to an inactive 'open' conformer, thereby inactivating the spindle assembly checkpoint and disassembling mitotic checkpoint complexes. The substrate-recognition domain of TRIP13 is related to those of NSF and p97.\",\n      \"method\": \"Crystal structure of C. elegans PCH-2; in vitro MAD2 conformational conversion assay with TRIP13 and p31(comet)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro biochemical reconstitution of conformational conversion, replicated by multiple subsequent studies\",\n      \"pmids\": [\"25918846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIP13 binds to DNA-PKcs complex proteins that mediate nonhomologous end joining (NHEJ) and promotes NHEJ repair even when homologous recombination is intact; overexpression of TRIP13 enhances NHEJ-mediated DNA repair and promotes treatment resistance.\",\n      \"method\": \"Mass spectrometry identification of TRIP13-binding partners; NHEJ reporter assays; overexpression and knockdown in cancer cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction with DNA-PKcs complex confirmed by reporter assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"25078033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Endogenous TRIP13 localizes to kinetochores in mitosis. TRIP13 knockdown delays metaphase-to-anaphase transition by prolonging the presence of the mitotic checkpoint complex (MCC) and its inhibition of APC/C. The ATPase activity of TRIP13 is essential for this checkpoint-silencing function, and TRIP13 is required for p31(comet)-mediated mitotic checkpoint silencing.\",\n      \"method\": \"Immunofluorescence localization; siRNA knockdown with mitotic timing assays; ATPase-dead mutant rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — kinetochore localization by immunofluorescence, KD with defined phenotype, ATPase mutant functional dissection; replicated by multiple subsequent studies\",\n      \"pmids\": [\"25012665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIP13 AAA-ATPase, acting jointly with p31(comet), promotes ATP-dependent disassembly of the Cdc20-Mad2 subcomplex and the full mitotic checkpoint complex (MCC), releasing Mad2 from MCC and abrogating checkpoint inhibition of APC/C. TRIP13 was identified as the factor in HeLa extracts responsible for ATP- and p31(comet)-dependent MCC disassembly.\",\n      \"method\": \"Biochemical fractionation of HeLa extracts; in vitro MCC disassembly assay with recombinant TRIP13 and p31(comet); APC/C activity assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of MCC disassembly with purified components, functional readout on APC/C; independently replicated\",\n      \"pmids\": [\"25092294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The oligomeric form of TRIP13 binds both p31(comet) and MCC. p31(comet) and checkpoint complexes mutually promote each other's binding to oligomeric TRIP13; the substrate-binding site of TRIP13 comprises subsites specific for p31(comet) and the C-Mad2-containing complex, and simultaneous occupancy of both subsites is required for high-affinity binding.\",\n      \"method\": \"Binding assays with recombinant proteins; co-immunoprecipitation of TRIP13 with p31(comet) and MCC components\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding assays with recombinant components plus reciprocal co-IP; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26324890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIP13 and p31(comet) catalyze the conversion of C-Mad2 to O-Mad2 by locally unfolding the Mad2 C-terminal region without disrupting its stably folded core; the crystal structure of human TRIP13 was determined and functional TRIP13 residues mediating p31(comet)-Mad2 binding and coupling ATP hydrolysis to local Mad2 unfolding were identified. TRIP13-p31(comet) intercepts and disassembles free MCC not bound to APC/C.\",\n      \"method\": \"NMR spectroscopy of MAD2 conformational change; crystal structure of human TRIP13; mutagenesis of functional residues; in vitro APC/C inhibition assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus NMR plus mutagenesis plus in vitro functional assay in one study\",\n      \"pmids\": [\"29208896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIP13 recognizes MAD2 through the adapter p31(comet), which binds the TRIP13 N-terminal domain to position the disordered MAD2 N-terminus for engagement by TRIP13 pore loops; TRIP13 then unfolds MAD2 in an ATP-dependent manner. N-terminal truncation of MAD2 renders it refractory to TRIP13 action in vitro and causes SAC defects in cells. Similar truncation of HORMAD1 in spermatocytes impairs TRIP13-mediated removal from meiotic chromosomes, demonstrating a conserved N-terminal engagement mechanism.\",\n      \"method\": \"X-ray crystallography; crosslinking mass spectrometry; in vitro TRIP13 remodeling assay with truncation mutants; mouse spermatocyte immunofluorescence\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structure plus crosslinking MS plus in vitro assay plus in vivo validation with truncation mutants\",\n      \"pmids\": [\"28659378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structures of the TRIP13-p31(comet)-C-MAD2-CDC20 complex reveal that p31(comet) recruits C-MAD2 to a defined site on the TRIP13 hexameric ring, positioning the MAD2 N-terminus to insert into the axial pore. TRIP13 couples sequential ATP-driven translocation along MAD2 N-terminus to push and rotate the p31(comet)-C-MAD2 complex, unwinding the αA helix of C-MAD2 required to stabilize the closed β-sheet, thereby converting C-MAD2 to O-MAD2 and dissociating MAD2 from p31(comet).\",\n      \"method\": \"Cryo-electron microscopy structure determination of TRIP13-p31comet-C-MAD2-CDC20 complex; molecular modeling of translocation mechanism\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure of the complete remodeling complex with mechanistic modeling; published in Nature\",\n      \"pmids\": [\"29973720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIP13 catalytic activity is required both to maintain a pool of open-state Mad2 for MCC assembly (supporting checkpoint activation) and for timely mitotic exit through catalytic disassembly of MCC. Combining TRIP13 depletion with elimination of APC15-dependent Cdc20 ubiquitination/degradation results in complete inability to exit mitosis even when kinetochore MCC assembly is prevented.\",\n      \"method\": \"Degron-tagging for rapid TRIP13 depletion; double depletion (TRIP13 + APC15) with mitotic exit assays; Mad2 conformer pool measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rapid inducible depletion with precise genetic double-mutant analysis; defined biochemical and cell biological phenotypes\",\n      \"pmids\": [\"30341343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIP13 ATPase catalyzes an inactivating conformational change of REV7 (MAD2L2) from its active 'closed' conformation to an inactive 'open' conformation, thereby dissociating the REV7-Shieldin complex and promoting homology-directed repair (HDR). TRIP13 similarly disassembles the REV7-REV3 translesion synthesis (TLS) complex, inhibiting error-prone replicative lesion bypass and interstrand crosslink repair.\",\n      \"method\": \"Conformational assays for REV7 closed/open states; co-IP of REV7-Shieldin complex; HR reporter assay; PARP inhibitor sensitivity assay in BRCA1-deficient cells\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal assays (conformational, co-IP, functional HR/NHEJ reporters, drug sensitivity), single lab but comprehensive\",\n      \"pmids\": [\"31915374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"p31(comet) binds to the REV7-Shieldin complex in cells, mediates TRIP13-REV7 interaction, promotes REV7 inactivation and dissociation from Shieldin subunit SHLD3, and participates in extraction of REV7 from chromatin. p31(comet) also releases REV7 from the REV3/Pol-ζ complex, counteracting TLS.\",\n      \"method\": \"Co-IP of p31(comet) with REV7-Shieldin; chromatin fractionation; PARP inhibitor resistance assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and chromatin fractionation, single lab, two orthogonal methods\",\n      \"pmids\": [\"33051298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structures of human SHLD3-REV7 binary and fused SHLD2-SHLD3-REV7 ternary complexes show that Shieldin assembly requires SHLD2-SHLD3-induced conformational heterodimerization of O-REV7 and C-REV7. Cryo-EM structures of ATPγS-bound SHLD2-SHLD3-REV7-TRIP13 complexes show that the N-terminus of REV7 inserts into the TRIP13 central channel; the safety-belt segment of C-REV7 contacts a conserved negatively charged TRIP13 loop, and ATP hydrolysis-triggered rotatory motions drive disassembly of the Shieldin complex.\",\n      \"method\": \"X-ray crystallography of Shieldin sub-complexes; cryo-EM of TRIP13-Shieldin complex; functional disassembly assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal and cryo-EM structures with functional validation in a single rigorous study\",\n      \"pmids\": [\"33597306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAD2L2 (REV7) dimerization is required for appropriate shieldin function in NHEJ; dimerization is mediated by SHLD2 and accelerates MAD2L2-SHLD3 interaction. MAD2L2 dimerization combined with SHLD3 presence is required for shieldin interaction with TRIP13 ATPase. Appropriate TRIP13 levels are important for proper shieldin (dis)assembly and activity in DNA repair.\",\n      \"method\": \"Co-IP of shieldin components; dimerization-defective MAD2L2 mutants; NHEJ reporter assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with defined mutants, functional NHEJ reporter, single lab\",\n      \"pmids\": [\"34521823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In C. elegans, PCH-2/TRIP13 controls spindle checkpoint strength by regulating the availability of inactive (open-state) Mad2 at and near unattached kinetochores; this function is required in large cells (germline precursor cells) and depends on CMT-1 (p31(comet) ortholog) for PCH-2 localization to unattached kinetochores and its enrichment in germline precursor cells.\",\n      \"method\": \"C. elegans genetic manipulation of cell volume; PCH-2 localization by immunofluorescence; spindle checkpoint strength assays; genetic epistasis with cmt-1\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus localization with functional readout, single lab, ortholog study in C. elegans\",\n      \"pmids\": [\"32697629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Biallelic loss-of-function mutations in TRIP13 cause substantial impairment of the spindle assembly checkpoint (SAC), leading to a high rate of chromosome missegregation; restoring TRIP13 function rescues accurate segregation and SAC proficiency in patient cells.\",\n      \"method\": \"Patient-derived cell lines with TRIP13 mutations; SAC functional assays; chromosome segregation assays; rescue by TRIP13 reintroduction\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient cells with defined loss-of-function mutations, functional rescue, multiple orthogonal readouts\",\n      \"pmids\": [\"28553959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIP13 overexpression significantly reduces, and TRIP13 reduction exacerbates, the mitotic delay associated with Mad2 overexpression (but not microtubule depolymerization-induced delay). Combination of Mad2 overexpression and TRIP13 loss reduces ability of checkpoint complexes to disassemble.\",\n      \"method\": \"TRIP13 overexpression and knockdown in Mad2-overexpressing cells; mitotic timing; MCC disassembly assays; xenograft proliferation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined checkpoint readouts, single lab\",\n      \"pmids\": [\"28564602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIP13 increases cellular deubiquitination by enhancing the association of the deubiquitinase USP7 with its substrates (NEK2, PTEN, p53), thereby protecting oncogenic proteins from ubiquitin-mediated degradation; this activity promotes B cell tumor development in transgenic mice. TRIP13-induced resistance to proteasome inhibition can be overcome by a USP7 inhibitor.\",\n      \"method\": \"Co-IP of TRIP13 with USP7; ubiquitination assays; TRIP13 transgenic mouse tumor model; in vitro and in vivo USP7 inhibitor rescue\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional ubiquitination assays plus in vivo mouse model, single lab\",\n      \"pmids\": [\"34061780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIP13 interacts with ACTN4 and positively regulates ACTN4 expression, thereby activating the AKT/mTOR pathway to promote hepatocellular carcinoma progression.\",\n      \"method\": \"Co-IP of TRIP13 with ACTN4; gain- and loss-of-function studies; AKT/mTOR pathway western blotting; xenograft models\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP confirmed interaction, pathway activation shown by western blot, in vivo validation; single lab\",\n      \"pmids\": [\"31533816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIP13 promotes glioblastoma cell proliferation, migration, and invasion by suppressing FBXW7 transcription (by directly binding to the FBXW7 promoter region), thereby stabilizing c-MYC protein levels.\",\n      \"method\": \"ChIP/promoter binding assay for TRIP13 at FBXW7 promoter; western blot for c-MYC; gain- and loss-of-function in GBM cells\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct promoter binding assay plus functional c-MYC stabilization, single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"31740732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIP13 directly interacts with Tetratricopeptide Repeat Domain 5 (TTC5), a p53 co-factor; knockdown of TRIP13 in tubular epithelial cells in the presence of oxidative stress increased p53 activity at Serine 15, linking TRIP13 to suppression of p53-mediated apoptosis.\",\n      \"method\": \"Co-IP of TRIP13 with TTC5; TRIP13 hypomorph mice with ischemia-reperfusion injury; p53-Ser15 phosphorylation assay after TRIP13 knockdown\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP interaction plus in vivo hypomorph model plus cell-based p53 assay; single lab\",\n      \"pmids\": [\"28256593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIP13 participates in immediate-early DNA damage sensing: it is recruited to DNA damage sites within seconds after damage, interacts with MRE11 (identified by quantitative proximity-labeling proteomics), controls MDC1 recruitment to damage sites by regulating MDC1-MRN complex interaction, and is involved in ATM signaling amplification.\",\n      \"method\": \"Proximity-labeling quantitative proteomics (BioID); co-IP of TRIP13 with MRE11; MDC1 recruitment assay by immunofluorescence; ATM signaling western blot\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity-labeling MS plus co-IP plus functional MDC1/ATM readouts; single lab\",\n      \"pmids\": [\"36552858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIP13 phosphorylation at tyrosine 56 (Y56) by EGFR promotes NHEJ repair and induces radiation resistance in head and neck cancer; suppression of Y56 phosphorylation abrogates these effects.\",\n      \"method\": \"Phospho-site identification; EGFR inhibition and TRIP13-Y56 mutant functional studies; NHEJ reporter; radiation survival assay\",\n      \"journal\": \"Molecular therapy : the journal of the American Society of Gene Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-site mutagenesis with functional NHEJ and radiation resistance readouts; single lab\",\n      \"pmids\": [\"34111559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIP13 localizes to the synaptonemal complex (SC) of synapsed chromosomes in early pachytene spermatocytes and to telomeres throughout meiotic prophase I. This localization is independent of SC axial element proteins REC8, SYCP2, and SYCP3. TRIP13 is a dosage-sensitive regulator: heterozygous Trip13 mice show meiotic defects less severe than nulls. Loss of TRIP13 causes persistence of HORMAD1 and HORMAD2 on synapsed SC and chromosome asynapsis preferentially affecting XY and centromeric ends.\",\n      \"method\": \"Live imaging and immunofluorescence of FLAG-tagged TRIP13 knock-in mice; genetic analysis of Trip13 null and heterozygous mice; chromosome spread analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous tagging knock-in mice with functional validation, multiple genetic alleles, direct localization with functional consequences\",\n      \"pmids\": [\"39207914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIP13 interacts with FGFR4 in colorectal cancer cells; this interaction is required for activation of the EGFR-AKT pathway. TRIP13 also participates in WNT signaling regulation and EMT in colorectal cancer.\",\n      \"method\": \"Co-IP of TRIP13 with FGFR4; pathway western blotting; TRIP13 KD xenograft and metastasis assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP for FGFR4 interaction, pathway activation inferred from western blot; single lab\",\n      \"pmids\": [\"33037736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIP13 interacts with LRP6 (co-localization and co-immunoprecipitation in lung cancer cells) and promotes activation of the Wnt/β-catenin signaling pathway, driving proliferation and invasion.\",\n      \"method\": \"Co-IP and confocal immunofluorescence co-localization of TRIP13 with LRP6; β-catenin activation western blot; colony formation and invasion assays\",\n      \"journal\": \"Journal of molecular histology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP plus co-localization, pathway downstream readout only; single lab\",\n      \"pmids\": [\"33128167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIP13 directly interacts with HAT1; this interaction inhibits UBE4A-mediated ubiquitination degradation of HAT1, stabilizing HAT1 protein. TRIP13's ATPase activity is required for HAT1 binding, and through HAT1 stabilization TRIP13 promotes Foxp3 expression and Treg expansion downstream of TNF-TNFR2 signaling.\",\n      \"method\": \"Co-IP of TRIP13 with HAT1 and UBE4A; ubiquitination assay; ATPase-dead TRIP13 mutant; TRIP13 KO mouse colitis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, ATPase mutant functional dissection, in vivo mouse model; single lab\",\n      \"pmids\": [\"41535263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIP13 directly interacts with DDX21 and stabilizes DDX21 expression by restraining its ubiquitination-dependent degradation, thereby promoting gastric cancer progression. HDAC1 acts as an upstream transcriptional activator of TRIP13 by targeting the TRIP13 promoter region.\",\n      \"method\": \"Co-IP of TRIP13 with DDX21; ubiquitination assay; ChIP of HDAC1 at TRIP13 promoter; gain- and loss-of-function in gastric cancer cells\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ubiquitination assay plus chromatin assay; single lab\",\n      \"pmids\": [\"39187490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"THC (tetrahydrocurcumin) directly targets TRIP13 (confirmed by click chemistry target fishing, CETSA, DARTS, and SPR). In TNBC cells, TRIP13 forms a trimeric complex with USP7 and c-FLIP. THC disrupts this TRIP13/USP7/c-FLIP complex, leading to ubiquitination and degradation of c-FLIP and extrinsic apoptosis.\",\n      \"method\": \"Click chemistry target fishing; CETSA; DARTS; SPR; co-IP of TRIP13/USP7/c-FLIP complex; in vitro deubiquitination assay; confocal microscopy\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple target engagement methods plus co-IP of trimeric complex plus functional ubiquitination assay; single lab\",\n      \"pmids\": [\"39505147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DCZ5417 inhibits TRIP13 ATPase activity and disrupts the TRIP13/YWHAE protein complex, thereby suppressing ERK/MAPK signaling and inhibiting multiple myeloma cell proliferation.\",\n      \"method\": \"Molecular docking; pull-down; surface plasmon resonance; cellular thermal shift assay; ATPase activity assay; co-IP of TRIP13 with YWHAE; ERK/MAPK western blot; xenograft\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal binding assays confirming drug-target interaction plus co-IP of TRIP13/YWHAE complex; single lab\",\n      \"pmids\": [\"38012658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In KRAS-mutant pancreatic cancer cells, TRIP13 promotes survival specifically in a homologous recombination-dependent manner; TRIP13-depleted KRASG12V-expressing cells acquire HR-deficiency phenotypes (sensitivity to TLS inhibitors and PARP inhibitors), indicating TRIP13 supports HR-mediated tolerance of oncogene-induced replication stress.\",\n      \"method\": \"Genetic (siRNA/CRISPR) and pharmacological TRIP13 depletion in KRASG12V-expressing HPNE cells; DNA synthesis assays; HR-deficiency phenotype assays (TLS and PARP inhibitor sensitivity)\",\n      \"journal\": \"NAR cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological tools with defined HR-deficiency phenotypes; single lab\",\n      \"pmids\": [\"40115747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIP13 promotes TNBC cell viability and migration by activating STAT3 signaling; STAT3 in turn binds a STAT3-recognition element in the TRIP13 regulatory region to upregulate TRIP13, forming a positive TRIP13/STAT3 feedback circuit.\",\n      \"method\": \"Western blot for STAT3 activation; ChIP of STAT3 at TRIP13 promoter; TRIP13 overexpression rescue of bardoxolone-induced apoptosis; in vivo xenograft\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP of STAT3 at TRIP13 promoter, overexpression rescue, in vivo model; single lab\",\n      \"pmids\": [\"39939802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HSPA9 (exosomal) stabilizes TRIP13 protein by recruiting the deubiquitinase USP1 to TRIP13 via the carboxyl-terminal peptide-binding domain of HSPA9, thereby preventing TRIP13 ubiquitination and degradation; the HSPA9-USP1-TRIP13 complex is stable in the cytoplasm and its integrity promotes bortezomib resistance in multiple myeloma.\",\n      \"method\": \"Co-IP of HSPA9/USP1/TRIP13 complex; protein truncation test to map HSPA9-USP1 interaction domain; ubiquitination assay; immunofluorescence co-localization; xenograft\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of trimeric complex plus domain mapping plus ubiquitination assay; single lab\",\n      \"pmids\": [\"40140922\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIP13 is a hexameric AAA+ ATPase that acts as a universal remodeler of HORMA-domain proteins: aided by the adapter protein p31(comet), it engages the disordered N-terminus of closed-conformation HORMA clients (MAD2, REV7/MAD2L2, meiotic HORMADs) through its pore loops and couples ATP-driven translocation to conformational conversion (closed→open), thereby disassembling the mitotic checkpoint complex (MCC) to silence the spindle assembly checkpoint, disassembling the REV7-Shieldin complex to promote homologous recombination over NHEJ, disassembling the REV7-REV3/Pol-ζ TLS complex, and removing HORMADs from synapsed meiotic chromosome axes; additionally, TRIP13 has been shown to interact with and regulate USP7-substrate associations (enhancing deubiquitination), interact with MRE11 to amplify ATM signaling, undergo EGFR-mediated phosphorylation at Y56 to enhance NHEJ, and interact with multiple oncogenic partner proteins (ACTN4, FGFR4, LRP6, YWHAE, HAT1, DDX21) to activate diverse cancer-promoting signaling pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIP13 is a hexameric AAA+ ATPase that functions as a universal remodeler of HORMA-domain proteins, coupling ATP-driven translocation to conformational conversion of its clients from a signaling-active 'closed' state to an inactive 'open' state [#3, #10]. Working with the adapter p31(comet), TRIP13 engages the disordered N-terminus of closed-conformation MAD2 through its axial pore loops and locally unfolds the MAD2 C-terminal αA helix, dissociating MAD2 from its partners; this remodeling disassembles the mitotic checkpoint complex and silences the spindle assembly checkpoint to permit anaphase onset, a reaction reconstituted from purified components and visualized by crystal and cryo-EM structures of the remodeling complex [#3, #6, #8, #10]. The same N-terminal engagement mechanism is conserved across HORMA clients: TRIP13 removes meiotic HORMAD1/HORMAD2 from synapsed chromosome axes and is required for synaptonemal complex formation, recombination progression after strand invasion, and crossover control during mouse meiosis [#0, #1, #2, #9, #25]. Beyond mitosis and meiosis, TRIP13 disassembles the REV7(MAD2L2)-Shieldin and REV7-REV3/Pol-ζ complexes by the analogous closed-to-open conversion of REV7, shifting DNA repair toward homologous recombination and away from error-prone end-joining and translesion synthesis [#12, #14]. Its catalytic activity additionally supports HR-mediated tolerance of oncogene-induced replication stress in KRAS-mutant cells [#32]. Biallelic loss-of-function TRIP13 mutations impair the spindle assembly checkpoint and cause chromosome missegregation in patient cells, with rescue upon TRIP13 reintroduction [#17]. In cancer contexts, TRIP13 acts through additional partners—enhancing USP7-substrate deubiquitination to stabilize oncoproteins [#19], and stabilizing or activating partners including HAT1, DDX21, ACTN4, and YWHAE to drive proliferative signaling [#20, #28, #29, #31]; it is also subject to EGFR-mediated Y56 phosphorylation that enhances NHEJ and radioresistance [#24].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that TRIP13 acts in meiotic recombination downstream of DSB formation and strand invasion, defining its first in vivo functional role.\",\n      \"evidence\": \"Knockout mouse spermatocytes with recombination-marker immunofluorescence and double-mutant epistasis\",\n      \"pmids\": [\"17696610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular activity behind the recombination defect not defined at this stage\", \"No biochemical mechanism linking TRIP13 to recombination intermediate resolution\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified HORMAD1/HORMAD2 as in vivo TRIP13-dependent factors whose removal from synapsed axes requires TRIP13, hinting at a HORMA-protein-directed activity.\",\n      \"evidence\": \"Knockout/hypomorph mouse model with HORMAD immunofluorescence on meiotic chromosomes\",\n      \"pmids\": [\"19851446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIP13 acts directly on HORMADs vs indirectly was unresolved\", \"No biochemical demonstration of conformational remodeling\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the breadth of meiotic phenotypes (synapsis, sex body, crossover number/distribution) using graded alleles, establishing TRIP13 dosage sensitivity in meiotic chromosome biology.\",\n      \"evidence\": \"Multiple hypomorphic alleles analyzed by cytology and chiasma counting\",\n      \"pmids\": [\"20711356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between molecular activity and synapsis/crossover phenotypes not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the mitotic function of TRIP13 as a kinetochore-localized, ATPase-dependent silencer of the spindle assembly checkpoint that disassembles the MCC with p31(comet), reconstituted from purified components.\",\n      \"evidence\": \"Immunofluorescence localization, siRNA knockdown with mitotic timing, ATPase-dead rescue, and in vitro MCC disassembly assays with APC/C readout\",\n      \"pmids\": [\"25012665\", \"25092294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic mechanism of MAD2 remodeling not yet resolved\", \"How substrate is selected at the kinetochore not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked TRIP13 to DNA double-strand break repair pathway choice, showing it binds DNA-PKcs complex proteins and promotes NHEJ and treatment resistance.\",\n      \"evidence\": \"Mass spectrometry of binding partners and NHEJ reporter assays with over/knockdown in cancer cells\",\n      \"pmids\": [\"25078033\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate of remodeling in repair not identified at this point\", \"Single lab, mechanism of NHEJ promotion inferred\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined TRIP13 as an AAA+ protein-remodeling ATPase that converts closed MAD2 to open MAD2 via p31(comet), unifying its mitotic and meiotic roles around HORMA conformational conversion.\",\n      \"evidence\": \"Crystal structure of C. elegans PCH-2 and in vitro MAD2 conversion assay with p31(comet)\",\n      \"pmids\": [\"25918846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the human enzyme-substrate complex not yet solved\", \"Precise coupling of ATP hydrolysis to unfolding undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped the bipartite substrate-binding architecture, showing oligomeric TRIP13 requires simultaneous p31(comet) and C-MAD2-complex occupancy for high-affinity engagement.\",\n      \"evidence\": \"Recombinant binding assays and reciprocal co-IP of TRIP13 with p31(comet) and MCC\",\n      \"pmids\": [\"26324890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of substrate handoff during catalysis not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the human enzyme structure and the molecular mechanism of MAD2 remodeling, showing local C-terminal unfolding and identifying the conserved N-terminal engagement of HORMA clients shared between MAD2 and meiotic HORMAD1.\",\n      \"evidence\": \"Human TRIP13 crystal structure, NMR of MAD2, crosslinking MS, truncation-mutant remodeling assays, and spermatocyte immunofluorescence\",\n      \"pmids\": [\"29208896\", \"28659378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full translocation trajectory not yet visualized structurally\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected TRIP13 to human disease, demonstrating that biallelic loss-of-function impairs the SAC and causes chromosome missegregation, rescuable by TRIP13 reintroduction.\",\n      \"evidence\": \"Patient-derived cells with SAC and segregation assays and rescue\",\n      \"pmids\": [\"28553959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype range across tissues not fully mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Visualized the complete remodeling complex and established that TRIP13 has a dual role—maintaining the open-MAD2 pool for checkpoint activation and disassembling MCC for mitotic exit.\",\n      \"evidence\": \"Cryo-EM of TRIP13-p31comet-C-MAD2-CDC20 plus degron depletion with APC15 double-depletion mitotic exit assays\",\n      \"pmids\": [\"29973720\", \"30341343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same enzyme is biased toward assembly vs disassembly in vivo not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended TRIP13's HORMA-remodeling activity to REV7, showing it disassembles REV7-Shieldin and REV7-REV3/Pol-ζ complexes to favor homologous recombination over end-joining and translesion synthesis.\",\n      \"evidence\": \"REV7 conformational assays, co-IP, HR reporters, and PARP inhibitor sensitivity in BRCA1-deficient cells; p31(comet)-dependence shown by co-IP and chromatin fractionation\",\n      \"pmids\": [\"31915374\", \"33051298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo balance between repair-pathway choices across tissues unresolved\", \"p31(comet) role in REV7 extraction shown in a single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided structural mechanism for Shieldin disassembly, showing REV7 N-terminal insertion into the TRIP13 channel and ATP-hydrolysis-driven rotatory disassembly, and defined REV7 dimerization as a prerequisite for TRIP13 engagement.\",\n      \"evidence\": \"Crystal and cryo-EM structures of Shieldin sub-complexes with TRIP13 plus co-IP with dimerization-defective MAD2L2 mutants and NHEJ reporters\",\n      \"pmids\": [\"33597306\", \"34521823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single co-IP-based confidence for dimerization requirement (medium evidence)\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered a non-HORMA, deubiquitination-promoting function in cancer, with TRIP13 enhancing USP7-substrate association to protect oncoproteins and drive tumorigenesis.\",\n      \"evidence\": \"Co-IP with USP7, ubiquitination assays, transgenic mouse tumor model, and USP7-inhibitor rescue\",\n      \"pmids\": [\"34061780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ATPase activity is required for the USP7 effect not established here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed TRIP13 in immediate-early DNA damage sensing, linking it to MRE11/MRN, MDC1 recruitment, and ATM signaling amplification.\",\n      \"evidence\": \"Proximity-labeling proteomics, co-IP with MRE11, MDC1 recruitment imaging, and ATM signaling western blot\",\n      \"pmids\": [\"36552858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect MRE11 interaction not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined TRIP13 meiotic localization to the synaptonemal complex and telomeres, independent of axial element proteins, and confirmed dosage sensitivity for HORMAD removal and asynapsis phenotypes.\",\n      \"evidence\": \"FLAG-tagged knock-in mouse live imaging and immunofluorescence with null/heterozygous genetic analysis\",\n      \"pmids\": [\"39207914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recruitment determinants to SC and telomeres not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that TRIP13's HR-supporting activity confers tolerance to oncogene-induced replication stress, rationalizing its cancer dependency.\",\n      \"evidence\": \"Genetic and pharmacological TRIP13 depletion in KRASG12V cells with HR-deficiency phenotype assays\",\n      \"pmids\": [\"40115747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between HORMA remodeling and replication-stress tolerance not fully traced\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Characterized regulation of TRIP13 protein stability and transcription in cancer, identifying HSPA9-USP1 stabilization and STAT3 feedback control.\",\n      \"evidence\": \"Co-IP of HSPA9/USP1/TRIP13 complex with domain mapping and ubiquitination assays; STAT3 ChIP at TRIP13 promoter with rescue and xenograft\",\n      \"pmids\": [\"40140922\", \"39939802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of these regulatory circuits beyond myeloma/TNBC unknown\", \"Single lab each\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRIP13's canonical HORMA-remodeling ATPase activity mechanistically relates to its diverse cancer partner interactions (ACTN4, FGFR4, LRP6, YWHAE, HAT1, DDX21, USP7) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Whether non-HORMA partner effects require ATPase/remodeling activity is not consistently tested\", \"Most oncogenic partner interactions rest on single-lab co-IP evidence\", \"Direct vs indirect nature of several partner interactions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3, 5, 6, 8, 10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 9, 10, 12, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 6, 12, 19]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [3, 8, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 25]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [21, 29, 33]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [34]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 6, 11, 17]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4, 12, 14, 23, 32]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 1, 2, 25]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [19, 28, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [20, 31, 33]}\n    ],\n    \"complexes\": [\n      \"mitotic checkpoint complex (MCC, as remodeling substrate)\",\n      \"TRIP13-p31(comet)-C-MAD2-CDC20 remodeling complex\",\n      \"REV7-Shieldin (as remodeling substrate)\",\n      \"HSPA9-USP1-TRIP13 complex\"\n    ],\n    \"partners\": [\n      \"MAD2\",\n      \"p31(comet)/MAD2L1BP\",\n      \"REV7/MAD2L2\",\n      \"USP7\",\n      \"MRE11\",\n      \"HAT1\",\n      \"DDX21\",\n      \"YWHAE\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}