{"gene":"TRIP13","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2009,"finding":"TRIP13 AAA-ATPase is required for depletion of HORMAD1 and HORMAD2 from synapsed chromosome axes during meiotic prophase; TRIP13 establishes mutually exclusive HORMAD-rich and synapsed (SYCP1-positive) chromatin domains, suggesting TRIP13 remodels HORMA-domain proteins upon synapsis.","method":"Genetic loss-of-function in mice (Trip13 mutants) combined with immunofluorescence localization of HORMADs and SC components on meiotic chromosomes","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with specific cellular phenotype, replicated in multiple mutant backgrounds","pmids":["19851446"],"is_preprint":false},{"year":2007,"finding":"Mouse TRIP13 is required after strand invasion for completing a subset of meiotic recombination events; TRIP13-deficient spermatocytes retain RAD51, BLM, and RPA on chromosomes despite full synapsis. Double-mutant epistasis with Spo11, Mei1, Rec8, and Dmc1 places TRIP13 downstream of or parallel to these recombination/synapsis genes.","method":"Trip13-null mouse model; immunostaining of recombination markers; okadaic acid progression assay; genetic epistasis with Spo11, Mei1, Rec8, Dmc1 double mutants","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with multiple orthogonal phenotypic readouts plus formal epistasis analysis","pmids":["17696610"],"is_preprint":false},{"year":2010,"finding":"TRIP13 is required for proper synaptonemal complex (SC) formation, efficient synapsis of sex chromosomes, sex body formation, and normal crossover number and distribution; recombination defects appear early after DSB formation, indicating TRIP13 functions in both recombination and higher-order chromosome structure formation.","method":"Distinct Trip13 hypomorph and severe alleles in mice; cytological analysis of SC, crossover markers (MLH1, MLH3), and chiasmata","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple alleles with graded phenotypes and multiple orthogonal readouts in a single study","pmids":["20711356"],"is_preprint":false},{"year":2015,"finding":"TRIP13 is a protein-remodeling AAA+ ATPase that converts the HORMA-family spindle checkpoint protein MAD2 from the signaling-active 'closed' (C-MAD2) conformer to the inactive 'open' (O-MAD2) conformer. This activity requires the adapter protein p31(comet), which recruits C-MAD2 to TRIP13. The overall hexameric architecture resembles the bacterial unfoldase ClpX, and TRIP13 possesses a substrate-recognition domain related to NSF and p97.","method":"Cryo-EM structure of C. elegans PCH-2 (TRIP13 ortholog); in vitro MAD2 conformational conversion assay with purified TRIP13 and p31(comet); biochemical reconstitution","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — structure plus reconstituted in vitro biochemical activity","pmids":["25918846"],"is_preprint":false},{"year":2014,"finding":"TRIP13 binds DNA-PKcs complex proteins that mediate nonhomologous end joining (NHEJ) and promotes NHEJ repair even when homologous recombination is intact; TRIP13 overexpression drives treatment resistance in head and neck cancer, and sensitization to DNA-PKcs inhibitor overcomes this resistance.","method":"Mass spectrometry identification of TRIP13-binding partners (DNA-PKcs complex); NHEJ/HR reporter assays; overexpression and knockdown in cancer cells","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — MS interactome plus functional reporter assays; single lab","pmids":["25078033"],"is_preprint":false},{"year":2014,"finding":"TRIP13 AAA-ATPase, together with p31(comet), disassembles the Mitotic Checkpoint Complex (MCC) composed of Mad2, BubR1, Bub3, and Cdc20, thereby abrogating inhibition of APC/C and silencing the spindle assembly checkpoint. ATP hydrolysis by TRIP13 is essential for MCC disassembly. TRIP13 localizes to kinetochores and its knockdown delays metaphase-to-anaphase transition.","method":"In vitro MCC disassembly assay using HeLa cell extracts; identification of TRIP13 as active factor by fractionation; TRIP13 knockdown in cells with mitotic timing; immunofluorescence showing kinetochore localization","journal":"The Journal of biological chemistry / Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution of MCC disassembly and cellular localization/KD phenotype, replicated across two independent labs (Wang et al. JBC and Eytan et al. PNAS, both 2014)","pmids":["25012665","25092294"],"is_preprint":false},{"year":2015,"finding":"TRIP13 oligomeric form binds both p31(comet) and MCC; p31(comet) and checkpoint complexes mutually promote each other's binding to TRIP13, suggesting the substrate-binding site of TRIP13 contains subsites specific for p31(comet) and C-Mad2-containing complex, and simultaneous occupancy of both subsites is required for high-affinity binding.","method":"Binding assays with purified proteins; TRIP13 pull-down with p31(comet) and MCC components; mutational analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical binding assays with purified components; single lab","pmids":["26324890"],"is_preprint":false},{"year":2017,"finding":"TRIP13 and p31(comet) catalyze conversion of C-Mad2 to O-Mad2 without disrupting the stably folded core of Mad2, instead causing local unfolding of the Mad2 C-terminal region. Crystal structure of human TRIP13 was determined, and functional residues mediating p31(comet)-Mad2 binding and coupling ATP hydrolysis to local Mad2 unfolding were identified. TRIP13-p31(comet) can only disassemble free MCC, not APC/C-bound MCC.","method":"NMR spectroscopy of MAD2 conformational change; crystal structure of human TRIP13; mutagenesis of functional residues; APC/C inhibition assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus NMR plus mutagenesis in a single study","pmids":["29208896"],"is_preprint":false},{"year":2017,"finding":"TRIP13 recognizes C-MAD2 with help of adapter protein p31(comet), which binds to the TRIP13 N-terminal domain and positions the disordered MAD2 N-terminus for engagement by TRIP13 'pore loops', which then unfold MAD2 in the presence of ATP. N-terminal truncation of MAD2 renders it refractory to TRIP13 action in vitro and causes SAC defects in cells. Similarly, N-terminal truncation of HORMAD1 in mouse spermatocytes compromises its TRIP13-mediated removal from meiotic chromosomes, demonstrating a conserved mechanism.","method":"X-ray crystallography; crosslinking mass spectrometry; in vitro TRIP13 remodeling assays with truncation mutants; cellular SAC assays; mouse spermatocyte HORMAD1 localization","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — structure, crosslinking MS, in vitro reconstitution, mutagenesis, and in vivo validation in a single study","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 (MAD2NT) to insert into the axial pore of TRIP13 and distorting the ring to initiate remodeling. Sequential ATP-driven translocation of the hexameric ring along MAD2NT pushes upward on and rotates the p31(comet)-C-MAD2 complex, unwinding the αA helix of C-MAD2 required to stabilize the C-MAD2 β-sheet, thus destabilizing C-MAD2 in favor of O-MAD2.","method":"Cryo-electron microscopy structures of TRIP13-p31(comet)-C-MAD2-CDC20 complex; molecular modeling","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structure with mechanistic modeling, published in Nature","pmids":["29973720"],"is_preprint":false},{"year":2018,"finding":"TRIP13 catalytic activity is required to maintain a pool of open-state Mad2 (O-Mad2) for MCC assembly (supporting checkpoint activation) and for timely mitotic exit through catalytic MCC disassembly. Combining TRIP13 depletion with elimination of APC15-dependent Cdc20 ubiquitination/degradation results in complete inability to exit mitosis, demonstrating that mitotic exit requires either TRIP13-catalyzed Mad2 removal or APC15-driven Cdc20 degradation.","method":"Degron-tagging for rapid TRIP13 depletion; combination with APC15 loss; cell biological mitotic timing assays; MCC assembly/disassembly measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — acute depletion with degron plus genetic combination; mechanistic epistasis; multiple orthogonal readouts","pmids":["30341343"],"is_preprint":false},{"year":2020,"finding":"TRIP13 ATPase acts as a negative regulator of REV7 (MAD2L2): TRIP13 catalyzes an inactivating conformational change in REV7 from 'closed' to 'open', dissociating the REV7-Shieldin complex to promote homology-directed repair (HDR). TRIP13 similarly disassembles the REV7-REV3 translesion synthesis (TLS) complex, inhibiting error-prone lesion bypass. TRIP13 overexpression in BRCA1-deficient cancers confers PARP inhibitor resistance by restoring HDR.","method":"Biochemical assays of REV7 conformational change; Co-IP showing TRIP13-REV7-Shieldin interaction; HDR/NHEJ reporter assays; PARP inhibitor resistance assays in BRCA1-deficient cells","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — conformational change assay, reciprocal co-IP, functional reporter assays, and clinical cancer cell validation","pmids":["31915374"],"is_preprint":false},{"year":2020,"finding":"p31(comet) binds to the REV7-Shieldin complex in cells and promotes REV7 inactivation through the TRIP13 ATPase, causing PARP inhibitor resistance. p31(comet) also counteracts REV7 function in TLS by releasing it from REV3 in the Pol ζ complex. p31(comet) is identified as an important mediator of the TRIP13-REV7 interaction.","method":"Co-IP of p31(comet) with REV7-Shieldin complex; REV7 inactivation/chromatin extraction assays; PARP inhibitor resistance assays; TLS bypass assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus multiple functional assays; independently corroborates Clairmont et al. 2020","pmids":["33051298"],"is_preprint":false},{"year":2021,"finding":"MAD2L2 (REV7) dimerization, mediated by SHLD2 and accelerating MAD2L2-SHLD3 interaction, is required for appropriate shieldin function in NHEJ. MAD2L2 dimerization together with SHLD3 allows shieldin to interact with TRIP13 ATPase, and appropriate levels of TRIP13 are important for proper shieldin (dis)assembly and activity in DNA repair.","method":"Biochemical characterization of REV7 dimerization; co-IP of shieldin with TRIP13; functional NHEJ assays; dimerization-defective mutants","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, mutagenesis, and functional assays in a single study","pmids":["34521823"],"is_preprint":false},{"year":2021,"finding":"Crystal structures of human SHLD3-REV7 binary and SHLD2-SHLD3-REV7 ternary complexes reveal that Shieldin assembly requires SHLD2-SHLD3-induced conformational heterodimerization of open (O-REV7) and closed (C-REV7) forms of REV7. Cryo-EM structures of ATPγS-bound SHLD2-SHLD3-REV7-TRIP13 complexes show that the N-terminus of C-REV7 inserts into the central TRIP13 channel, and ATP hydrolysis-triggered rotatory TRIP13 motions pull the unfolded REV7 N-terminal peptide through the channel to disassemble Shieldin.","method":"X-ray crystallography of Shieldin subcomplexes; cryo-EM of TRIP13-Shieldin complex; biochemical disassembly assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus cryo-EM with mechanistic demonstration of TRIP13 disassembly mechanism","pmids":["33597306"],"is_preprint":false},{"year":2021,"finding":"TRIP13 increases cellular deubiquitination by enhancing the association of the deubiquitinase USP7 with its substrates, leading to stabilization of oncoproteins (NEK2) and destabilization of tumor suppressors (PTEN, p53). TRIP13 overexpression accelerates B cell tumor development in transgenic mice.","method":"TRIP13 overexpression in mice and cultured cells; ubiquitination assays; Co-IP of USP7 with substrates; transgenic mouse tumor model; USP7 inhibitor rescue","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, ubiquitination assay, transgenic mouse, pharmacological rescue) in a single study","pmids":["34061780"],"is_preprint":false},{"year":2017,"finding":"Biallelic loss-of-function mutations in TRIP13 cause severe spindle assembly checkpoint (SAC) impairment, leading to a high rate of chromosome missegregation in patient cells; restoring TRIP13 function rescues accurate segregation and SAC proficiency.","method":"Exome sequencing of patients; functional studies in patient-derived cells; SAC assay; chromosome missegregation quantification; TRIP13 rescue experiment","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — patient cell functional studies with rescue, multiple orthogonal readouts","pmids":["28553959"],"is_preprint":false},{"year":2020,"finding":"In C. elegans, the TRIP13 ortholog PCH-2 controls spindle checkpoint strength by regulating the availability of inactive O-Mad2 at and near unattached kinetochores. CMT-1 (p31(comet) ortholog) is required for both PCH-2 localization to unattached kinetochores and its enrichment in germline precursor cells, linking PCH-2 checkpoint function to cell volume and cell fate.","method":"Genetic manipulation of C. elegans cell volume and CMT-1/PCH-2; Mad2 kinetochore recruitment assays; spindle checkpoint functional assays in different cell types","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic manipulation with specific cellular readouts; C. elegans ortholog","pmids":["32697629"],"is_preprint":false},{"year":2024,"finding":"TRIP13 localizes to the synapsed synaptonemal complex (SC) in early pachytene spermatocytes and to telomeres throughout meiotic prophase I. This localization is independent of SC axial element proteins REC8 and SYCP2/SYCP3. TRIP13 functions as a dosage-sensitive regulator of meiosis: heterozygous mice exhibit intermediate meiotic defects between wild-type and null.","method":"Live imaging and immunofluorescence in knockin mice with FLAG-tagged TRIP13; Trip13-null and Trip13+/- mouse analysis; co-localization with SC markers","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — direct localization in knockin mice plus dosage-sensitive genetic analysis with specific phenotypic readouts","pmids":["39207914"],"is_preprint":false},{"year":2017,"finding":"TRIP13 is required to disassemble the MCC through p31(comet)-mediated Mad2 conformational change; overexpression of TRIP13 significantly reduces the mitotic delay caused by Mad2 overexpression, while TRIP13 reduction exacerbates it, identifying an unexpected dependency on TRIP13 in Mad2-overexpressing cells that operates specifically on MCC disassembly.","method":"TRIP13 overexpression and shRNA knockdown combined with Mad2 overexpression; mitotic timing assays; checkpoint complex disassembly measurements; tumor xenograft proliferation assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic interaction with defined mechanistic readout; single lab","pmids":["28564602"],"is_preprint":false},{"year":2022,"finding":"TRIP13 interacts directly with MRE11 (identified by proximity labeling proteomics) and controls the recruitment of MDC1 to DNA damage sites by regulating the MDC1-MRN complex interaction, thereby participating in ATM signaling amplification immediately after DNA strand break sensing.","method":"Quantitative proteomics with proximity labeling (BioID); Co-IP of TRIP13-MRE11; MDC1 recruitment assays at DNA damage sites; ATM signaling pathway analysis","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 — proximity labeling MS plus Co-IP plus functional readout; single lab","pmids":["36552858"],"is_preprint":false},{"year":2017,"finding":"TRIP13 directly interacts with TTC5 (a p53 co-factor); genetic knockdown of TRIP13 in murine tubular cells increases p53 activity at Serine 15, suggesting TRIP13 suppresses p53-dependent apoptosis by sequestering TTC5.","method":"Co-IP of TRIP13 with TTC5; siRNA knockdown of TRIP13 in murine IMCD cells; p53 phosphorylation measurement; in vivo IRI kidney model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP plus KD with functional readout; single lab","pmids":["28256593"],"is_preprint":false},{"year":2021,"finding":"TRIP13 directly interacts with ACTN4 and positively regulates its expression, thereby activating the AKT/mTOR pathway to drive hepatocellular carcinoma tumor progression.","method":"Co-IP of TRIP13 with ACTN4; Western blot for AKT/mTOR pathway components; gain- and loss-of-function in vitro and xenograft in vivo assays","journal":"Journal of experimental & clinical cancer research","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP plus functional KD/OE; single lab; no direct mechanistic reconstitution","pmids":["31533816"],"is_preprint":false},{"year":2019,"finding":"TRIP13 directly binds to the promoter region of FBXW7 and inhibits its transcription, thereby stabilizing c-MYC (an FBXW7 substrate), promoting GBM cell proliferation and invasion.","method":"ChIP showing TRIP13 binding to FBXW7 promoter; TRIP13 knockdown with FBXW7/c-MYC protein measurements; functional proliferation/invasion assays in GBM cells","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 — ChIP plus functional rescue experiment; single lab","pmids":["31740732"],"is_preprint":false},{"year":2021,"finding":"TRIP13 interacts with ACTN4 to activate Wnt/β-catenin signaling in cervical cancer; ACTN4 knockdown reverses TRIP13-mediated Wnt/β-catenin activation, and Wnt/β-catenin inhibition reverses TRIP13-induced cancer-promoting effects.","method":"Co-IP of TRIP13 with ACTN4; Wnt/β-catenin pathway reporter; ACTN4 knockdown epistasis; in vivo xenograft","journal":"Environmental toxicology","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP plus functional KD epistasis; single lab","pmids":["34061428"],"is_preprint":false},{"year":2021,"finding":"TRIP13 interacts with FLNA (filamin A) and activates the PI3K/AKT pathway to promote transcriptional activation of EMT-related genes in melanoma.","method":"RNA sequencing; Co-IP and mass spectrometry identification of FLNA as TRIP13 binding partner; PI3K/AKT pathway measurements; in vitro and in vivo invasion assays","journal":"Journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 — Co-IP/MS interaction plus functional assays; single lab","pmids":["36268276"],"is_preprint":false},{"year":2021,"finding":"TRIP13 regulates progression of gastric cancer by directly interacting with DDX21 and stabilizing its expression by restraining its ubiquitination degradation; HDAC1 acts as an upstream transcriptional regulator of TRIP13 by binding to the TRIP13 promoter region.","method":"Co-IP of TRIP13 with DDX21; ubiquitination assay; ChIP showing HDAC1 at TRIP13 promoter; functional in vitro and in vivo assays","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 — Co-IP and ubiquitination assay plus ChIP; single lab; limited reconstitution","pmids":["39187490"],"is_preprint":false},{"year":2021,"finding":"EGFR phosphorylates TRIP13 at tyrosine 56 in response to radiation, and phospho-TRIP13(Y56) promotes NHEJ repair to confer radiation resistance; suppression of Y56 phosphorylation abrogates these effects.","method":"Site-specific mutagenesis of TRIP13 Y56; co-IP with EGFR; NHEJ repair reporter assay; radiation resistance assays in head and neck cancer cells and patient tumors","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis plus functional reporter plus epistasis with EGFR; single lab","pmids":["34111559"],"is_preprint":false},{"year":2023,"finding":"TRIP13 directly interacts with EGFR, modulates its phosphorylation and downstream signaling in bladder cancer cells; co-immunoprecipitation confirms the TRIP13-EGFR interaction.","method":"Co-IP of TRIP13 with EGFR; Western blot of EGFR pathway; TRIP13 KD functional assays","journal":"International journal of biological sciences","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP; single lab; limited mechanistic follow-up","pmids":["31337978"],"is_preprint":false},{"year":2022,"finding":"TRIP13 forms a trimeric complex with USP7 and c-FLIP in TNBC cells; tetrahydrocurcumin (THC) targets TRIP13 to disrupt the TRIP13/USP7/c-FLIP complex, leading to c-FLIP ubiquitination and extrinsic apoptosis induction.","method":"Click chemistry-based target fishing; CETSA; DARTS; SPR; Co-IP of TRIP13-USP7-c-FLIP; in vitro deubiquitination assay; confocal microscopy","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal target engagement methods plus Co-IP and deubiquitination reconstitution; single lab","pmids":["39505147"],"is_preprint":false},{"year":2023,"finding":"TRIP13 interacts with YWHAE and disrupting the TRIP13/YWHAE complex by DCZ5417 inhibits the ERK/MAPK signaling axis; DCZ5417 inhibits TRIP13 ATPase activity directly.","method":"Molecular docking; pull-down; surface plasmon resonance; cellular thermal shift; ATPase assay; Co-IP of TRIP13-YWHAE; functional MM cell assays","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — multiple binding methods plus ATPase inhibition assay plus Co-IP; single lab","pmids":["38012658"],"is_preprint":false},{"year":2025,"finding":"TRIP13 promotes survival of KRAS(G12V)-expressing cells specifically through homologous recombination (HR); KRASG12V-expressing cells lacking TRIP13 acquire HR deficiency hallmarks (sensitivity to translesion synthesis inhibitors and PARP inhibitors), establishing TRIP13 as a KRAS-induced HR factor in pancreatic cancer.","method":"Genetic (siRNA/CRISPR) and pharmacological TRIP13 depletion in KRASG12V-expressing HPNE cells; HR reporter assays; DNA damage sensitivity assays; xenograft models","journal":"NAR cancer","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and pharmacological tools with multiple orthogonal functional readouts; single lab","pmids":["40115747"],"is_preprint":false},{"year":2023,"finding":"TRIP13 interacts with EGFR and induces its phosphorylation and downstream pathway activation (EGFR signaling) in NSCLC gefitinib-resistant cells; TRIP13 also improves autophagy to desensitize gefitinib in NSCLC cells.","method":"Co-IP of TRIP13 with EGFR; immunofluorescence; Western blot of phospho-EGFR; autophagy assays; TRIP13 overexpression/knockdown in resistant cells","journal":"Oncology reports","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP plus functional assays; single lab","pmids":["36896765"],"is_preprint":false}],"current_model":"TRIP13 is a hexameric AAA+ ATPase that uses ATP hydrolysis to remodel HORMA-domain proteins by engaging their disordered N-termini through axial pore loops and unfolding their conformationally dynamic regions: with the adapter p31(comet), it converts active closed-MAD2 (C-MAD2) to inactive open-MAD2 (O-MAD2), thereby disassembling the Mitotic Checkpoint Complex (MCC) to silence the spindle assembly checkpoint; it similarly converts closed-REV7 to open-REV7, disassembling the REV7-Shieldin complex to promote homologous recombination over NHEJ; and in meiosis it removes HORMAD1/2 from synapsed chromosome axes to establish proper chromosome domain organization, crossover formation, and checkpoint signaling."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing that TRIP13 functions in meiotic recombination downstream of strand invasion resolved its placement in the meiotic DSB repair pathway and revealed its requirement for completing recombination events.","evidence":"Trip13-null mouse spermatocytes with retained recombination markers; epistasis with Spo11, Dmc1, Mei1, Rec8","pmids":["17696610"],"confidence":"High","gaps":["Molecular substrate of TRIP13 in meiosis unknown","Whether TRIP13 acts catalytically or structurally was unclear"]},{"year":2009,"claim":"Identifying HORMAD1/HORMAD2 as targets of TRIP13-dependent removal from synapsed axes established that TRIP13 remodels HORMA-domain proteins in vivo, linking its ATPase activity to chromosome domain organization during meiosis.","evidence":"Trip13 mutant mice; immunofluorescence showing persistent HORMADs on synapsed chromosomes","pmids":["19851446"],"confidence":"High","gaps":["Biochemical mechanism of HORMAD removal not yet reconstituted","Whether TRIP13 acts directly on HORMADs or through intermediaries was unknown"]},{"year":2010,"claim":"Demonstrating graded meiotic phenotypes with different Trip13 alleles revealed that TRIP13 is required for synaptonemal complex integrity, sex chromosome synapsis, and normal crossover number/distribution, broadening its meiotic role beyond HORMAD removal.","evidence":"Multiple Trip13 hypomorph and severe alleles in mice; cytological analysis of SC, MLH1/MLH3 foci, chiasmata","pmids":["20711356"],"confidence":"High","gaps":["How TRIP13 dosage translates to distinct meiotic outcomes was mechanistically unexplained","Whether TRIP13 acts on recombination intermediates directly remained open"]},{"year":2014,"claim":"Two independent groups demonstrated that TRIP13 and p31(comet) catalytically disassemble the MCC through ATP hydrolysis, establishing TRIP13 as a direct SAC-silencing enzyme and connecting its AAA+ ATPase activity to mitotic checkpoint control.","evidence":"In vitro MCC disassembly from HeLa extracts; biochemical fractionation identifying TRIP13; TRIP13 knockdown delaying anaphase; kinetochore immunofluorescence","pmids":["25012665","25092294"],"confidence":"High","gaps":["Structural basis of TRIP13-MCC interaction unknown","Whether TRIP13 acts on free MCC vs. APC/C-bound MCC was unresolved"]},{"year":2015,"claim":"Cryo-EM of the TRIP13 ortholog PCH-2 and reconstituted MAD2 conformational conversion established that TRIP13 is a hexameric unfoldase resembling ClpX that converts C-MAD2 to O-MAD2 using p31(comet) as an adapter, providing the first structural and biochemical framework for its remodeling mechanism.","evidence":"Cryo-EM of C. elegans PCH-2; in vitro MAD2 conversion assay with purified human TRIP13 and p31(comet)","pmids":["25918846"],"confidence":"High","gaps":["Human TRIP13 structure not yet determined","How the N-terminus of MAD2 is engaged was unknown"]},{"year":2017,"claim":"Crystal structures of human TRIP13 and crosslinking-MS/NMR studies revealed that TRIP13 engages the disordered MAD2 N-terminus through axial pore loops and causes local unfolding of the MAD2 C-terminal region without disrupting the folded core, defining the mechanism as N-terminal threading; the same mechanism was shown to operate on HORMAD1 in meiosis.","evidence":"X-ray crystallography of human TRIP13; NMR of MAD2 conformational change; crosslinking-MS; MAD2 and HORMAD1 N-terminal truncation mutants in vitro and in vivo","pmids":["29208896","28659378"],"confidence":"High","gaps":["Full substrate-engaged complex structure not yet available","TRIP13 selectivity for free vs. APC/C-bound MCC only partly addressed"]},{"year":2017,"claim":"Discovery that biallelic TRIP13 loss-of-function mutations cause severe SAC impairment and chromosome missegregation in human patients established TRIP13 as a disease gene and confirmed its essential SAC role in humans.","evidence":"Exome sequencing of patients; functional rescue of SAC and segregation fidelity in patient-derived cells","pmids":["28553959"],"confidence":"High","gaps":["Full clinical spectrum of TRIP13 deficiency not delineated","Relative contribution of meiotic vs. mitotic defects to patient phenotype unclear"]},{"year":2018,"claim":"Cryo-EM structures of the TRIP13–p31(comet)–C-MAD2–CDC20 complex revealed the complete substrate-engaged architecture: p31(comet) positions the MAD2 N-terminus into the TRIP13 pore, and sequential ATP-driven translocation unwinds the αA helix to destabilize C-MAD2, providing an atomic-resolution mechanism for HORMA-domain remodeling.","evidence":"Cryo-EM of the quaternary complex; molecular modeling of translocation cycle","pmids":["29973720"],"confidence":"High","gaps":["Real-time dynamics of translocation not observed","Whether all six protomers fire sequentially was inferred, not directly shown"]},{"year":2018,"claim":"Acute depletion experiments demonstrated that TRIP13 is required both to maintain the O-MAD2 pool needed for checkpoint activation and for catalytic MCC disassembly for checkpoint silencing, resolving the apparent paradox that TRIP13 functions in both SAC activation and inactivation; combining TRIP13 loss with APC15 loss caused permanent mitotic arrest.","evidence":"Degron-mediated acute TRIP13 depletion combined with APC15 knockout; mitotic timing and MCC measurements","pmids":["30341343"],"confidence":"High","gaps":["Quantitative balance between O-MAD2 generation and MCC disassembly rates not modeled","Whether TRIP13 is rate-limiting for SAC activation in normal cells unclear"]},{"year":2020,"claim":"Extending TRIP13's substrate repertoire beyond MAD2, biochemical and cellular studies showed that TRIP13 converts closed REV7 to open REV7 via p31(comet), disassembling the REV7–Shieldin complex to promote HDR and disassembling REV7–REV3 to suppress translesion synthesis, establishing TRIP13 as a general HORMA-domain remodeler controlling DNA repair pathway choice.","evidence":"REV7 conformational change assays; Co-IP of TRIP13–REV7–Shieldin; HDR/NHEJ reporters; PARP inhibitor resistance in BRCA1-deficient cells","pmids":["31915374","33051298"],"confidence":"High","gaps":["Structural basis of TRIP13–REV7 engagement not yet determined at this point","Relative kinetics of REV7 vs. MAD2 remodeling unknown"]},{"year":2021,"claim":"Crystal and cryo-EM structures of the SHLD2–SHLD3–REV7–TRIP13 complex revealed that the C-REV7 N-terminus inserts into the TRIP13 central channel analogously to MAD2, and ATP hydrolysis drives rotatory pulling to disassemble Shieldin, providing the structural basis for TRIP13's role in DNA repair pathway choice.","evidence":"X-ray crystallography of SHLD3–REV7 and SHLD2–SHLD3–REV7; cryo-EM of ATPγS-bound TRIP13–Shieldin complex","pmids":["33597306"],"confidence":"High","gaps":["Dynamics of full Shieldin disassembly cycle not captured","Whether additional co-factors regulate TRIP13–Shieldin interaction in vivo unknown"]},{"year":2021,"claim":"TRIP13 was shown to enhance USP7-mediated deubiquitination of oncoproteins (NEK2) and tumor suppressors (p53, PTEN), and TRIP13 overexpression accelerated B cell tumorigenesis in transgenic mice, revealing a non-HORMA-domain function in ubiquitin pathway regulation with oncogenic consequences.","evidence":"Co-IP of USP7 with substrates; ubiquitination assays; TRIP13 transgenic mouse tumor model; USP7 inhibitor rescue","pmids":["34061780"],"confidence":"High","gaps":["Whether TRIP13 ATPase activity is required for USP7 enhancement not determined","Mechanism by which TRIP13 enhances USP7–substrate association is unclear","Whether this function operates through HORMA-domain remodeling or an independent mechanism is unknown"]},{"year":2024,"claim":"Direct localization of endogenous TRIP13 to the synaptonemal complex and telomeres throughout meiotic prophase I, independent of axial element proteins, together with dosage-sensitive meiotic defects in heterozygotes, refined understanding of where and when TRIP13 acts during meiosis.","evidence":"FLAG-tagged TRIP13 knockin mice; live imaging and immunofluorescence; Trip13+/− phenotypic analysis","pmids":["39207914"],"confidence":"High","gaps":["Telomeric function of TRIP13 is unexplained mechanistically","Identity of TRIP13 recruitment factors at SC and telomeres unknown"]},{"year":null,"claim":"Key unresolved questions include the structural basis of TRIP13's telomeric function, whether TRIP13's enhancement of USP7 deubiquitination requires its ATPase or HORMA-domain remodeling activity, quantitative modeling of how TRIP13 balances O-MAD2 generation with MCC disassembly in living cells, and whether additional non-HORMA substrates exist.","evidence":"","pmids":[],"confidence":"Low","gaps":["Telomeric mechanism unknown","USP7 interaction mechanism unresolved","No comprehensive substrate profiling beyond HORMA-domain proteins","In vivo quantitative flux through TRIP13-dependent pathways not measured"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3,5,7,8,9,10,11,14]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,7,8,9,11,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,11,15]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,2,18]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,10]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,5,7,9,10,16,19]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4,11,12,27,31]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1,2,8,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,7,8,9,14,15]}],"complexes":["TRIP13 hexamer","TRIP13–p31(comet)–C-MAD2 complex","TRIP13–p31(comet)–REV7–Shieldin complex"],"partners":["MAD2L1","MAD2L2","MAD1L1BP (P31COMET/MAD2L1BP)","CDC20","USP7","SHLD3","SHLD2","EGFR"],"other_free_text":[]},"mechanistic_narrative":"TRIP13 is a hexameric AAA+ ATPase that remodels HORMA-domain proteins by threading their disordered N-termini through its central pore, converting them from closed/active to open/inactive conformations, thereby controlling the spindle assembly checkpoint, DNA damage repair pathway choice, and meiotic chromosome dynamics. Using the adapter p31(comet), TRIP13 converts closed MAD2 (C-MAD2) to open MAD2 (O-MAD2), disassembling the Mitotic Checkpoint Complex (MCC) to silence the spindle assembly checkpoint and permit anaphase onset; this activity, together with APC15-dependent Cdc20 degradation, constitutes the two essential routes for mitotic exit [PMID:25918846, PMID:29973720, PMID:30341343]. TRIP13 similarly converts closed REV7 to open REV7 via p31(comet), disassembling the REV7–Shieldin complex to promote homologous recombination over NHEJ and disassembling REV7–REV3 to suppress translesion synthesis [PMID:31915374, PMID:33597306]. In meiosis, TRIP13 localizes to the synaptonemal complex and telomeres, where it removes HORMAD1/HORMAD2 from synapsed axes through the same N-terminal threading mechanism, establishing proper chromosome domain organization and enabling crossover formation; biallelic TRIP13 loss-of-function mutations in humans cause severe chromosome missegregation due to spindle assembly checkpoint impairment [PMID:19851446, PMID:39207914, PMID:28553959]."},"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 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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":"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":3,"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":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. 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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":"38464090","id":"PMC_38464090","title":"Genome-wide methylation profiling of Peripheral T-cell lymphomas identifies TRIP13 as a critical driver of tumor proliferation and survival.","date":"2024","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/38464090","citation_count":1,"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":1,"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":"40702521","id":"PMC_40702521","title":"A homozygous TRIP13 pathogenic variant associated with familiar oocyte arrest and prematurely condensed sperm chromosomes.","date":"2025","source":"Molecular cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/40702521","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48806,"output_tokens":8166,"usd":0.134454},"stage2":{"model":"claude-opus-4-6","input_tokens":11926,"output_tokens":3811,"usd":0.232357},"total_usd":0.366811,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"TRIP13 AAA-ATPase is required for depletion of HORMAD1 and HORMAD2 from synapsed chromosome axes during meiotic prophase; TRIP13 establishes mutually exclusive HORMAD-rich and synapsed (SYCP1-positive) chromatin domains, suggesting TRIP13 remodels HORMA-domain proteins upon synapsis.\",\n      \"method\": \"Genetic loss-of-function in mice (Trip13 mutants) combined with immunofluorescence localization of HORMADs and SC components on meiotic chromosomes\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with specific cellular phenotype, replicated in multiple mutant backgrounds\",\n      \"pmids\": [\"19851446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mouse TRIP13 is required after strand invasion for completing a subset of meiotic recombination events; TRIP13-deficient spermatocytes retain RAD51, BLM, and RPA on chromosomes despite full synapsis. Double-mutant epistasis with Spo11, Mei1, Rec8, and Dmc1 places TRIP13 downstream of or parallel to these recombination/synapsis genes.\",\n      \"method\": \"Trip13-null mouse model; immunostaining of recombination markers; okadaic acid progression assay; genetic epistasis with Spo11, Mei1, Rec8, Dmc1 double mutants\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with multiple orthogonal phenotypic readouts plus formal epistasis analysis\",\n      \"pmids\": [\"17696610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRIP13 is required for proper synaptonemal complex (SC) formation, efficient synapsis of sex chromosomes, sex body formation, and normal crossover number and distribution; recombination defects appear early after DSB formation, indicating TRIP13 functions in both recombination and higher-order chromosome structure formation.\",\n      \"method\": \"Distinct Trip13 hypomorph and severe alleles in mice; cytological analysis of SC, crossover markers (MLH1, MLH3), and chiasmata\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple alleles with graded phenotypes and multiple orthogonal readouts in a single study\",\n      \"pmids\": [\"20711356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIP13 is a protein-remodeling AAA+ ATPase that converts the HORMA-family spindle checkpoint protein MAD2 from the signaling-active 'closed' (C-MAD2) conformer to the inactive 'open' (O-MAD2) conformer. This activity requires the adapter protein p31(comet), which recruits C-MAD2 to TRIP13. The overall hexameric architecture resembles the bacterial unfoldase ClpX, and TRIP13 possesses a substrate-recognition domain related to NSF and p97.\",\n      \"method\": \"Cryo-EM structure of C. elegans PCH-2 (TRIP13 ortholog); in vitro MAD2 conformational conversion assay with purified TRIP13 and p31(comet); biochemical reconstitution\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure plus reconstituted in vitro biochemical activity\",\n      \"pmids\": [\"25918846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIP13 binds DNA-PKcs complex proteins that mediate nonhomologous end joining (NHEJ) and promotes NHEJ repair even when homologous recombination is intact; TRIP13 overexpression drives treatment resistance in head and neck cancer, and sensitization to DNA-PKcs inhibitor overcomes this resistance.\",\n      \"method\": \"Mass spectrometry identification of TRIP13-binding partners (DNA-PKcs complex); NHEJ/HR reporter assays; overexpression and knockdown in cancer cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS interactome plus functional reporter assays; single lab\",\n      \"pmids\": [\"25078033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIP13 AAA-ATPase, together with p31(comet), disassembles the Mitotic Checkpoint Complex (MCC) composed of Mad2, BubR1, Bub3, and Cdc20, thereby abrogating inhibition of APC/C and silencing the spindle assembly checkpoint. ATP hydrolysis by TRIP13 is essential for MCC disassembly. TRIP13 localizes to kinetochores and its knockdown delays metaphase-to-anaphase transition.\",\n      \"method\": \"In vitro MCC disassembly assay using HeLa cell extracts; identification of TRIP13 as active factor by fractionation; TRIP13 knockdown in cells with mitotic timing; immunofluorescence showing kinetochore localization\",\n      \"journal\": \"The Journal of biological chemistry / Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution of MCC disassembly and cellular localization/KD phenotype, replicated across two independent labs (Wang et al. JBC and Eytan et al. PNAS, both 2014)\",\n      \"pmids\": [\"25012665\", \"25092294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIP13 oligomeric form binds both p31(comet) and MCC; p31(comet) and checkpoint complexes mutually promote each other's binding to TRIP13, suggesting the substrate-binding site of TRIP13 contains subsites specific for p31(comet) and C-Mad2-containing complex, and simultaneous occupancy of both subsites is required for high-affinity binding.\",\n      \"method\": \"Binding assays with purified proteins; TRIP13 pull-down with p31(comet) and MCC components; mutational analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical binding assays with purified components; single lab\",\n      \"pmids\": [\"26324890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIP13 and p31(comet) catalyze conversion of C-Mad2 to O-Mad2 without disrupting the stably folded core of Mad2, instead causing local unfolding of the Mad2 C-terminal region. Crystal structure of human TRIP13 was determined, and functional residues mediating p31(comet)-Mad2 binding and coupling ATP hydrolysis to local Mad2 unfolding were identified. TRIP13-p31(comet) can only disassemble free MCC, not APC/C-bound MCC.\",\n      \"method\": \"NMR spectroscopy of MAD2 conformational change; crystal structure of human TRIP13; mutagenesis of functional residues; APC/C inhibition assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus NMR plus mutagenesis in a single study\",\n      \"pmids\": [\"29208896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIP13 recognizes C-MAD2 with help of adapter protein p31(comet), which binds to the TRIP13 N-terminal domain and positions the disordered MAD2 N-terminus for engagement by TRIP13 'pore loops', which then unfold MAD2 in the presence of ATP. N-terminal truncation of MAD2 renders it refractory to TRIP13 action in vitro and causes SAC defects in cells. Similarly, N-terminal truncation of HORMAD1 in mouse spermatocytes compromises its TRIP13-mediated removal from meiotic chromosomes, demonstrating a conserved mechanism.\",\n      \"method\": \"X-ray crystallography; crosslinking mass spectrometry; in vitro TRIP13 remodeling assays with truncation mutants; cellular SAC assays; mouse spermatocyte HORMAD1 localization\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure, crosslinking MS, in vitro reconstitution, mutagenesis, and in vivo validation in a single study\",\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 (MAD2NT) to insert into the axial pore of TRIP13 and distorting the ring to initiate remodeling. Sequential ATP-driven translocation of the hexameric ring along MAD2NT pushes upward on and rotates the p31(comet)-C-MAD2 complex, unwinding the αA helix of C-MAD2 required to stabilize the C-MAD2 β-sheet, thus destabilizing C-MAD2 in favor of O-MAD2.\",\n      \"method\": \"Cryo-electron microscopy structures of TRIP13-p31(comet)-C-MAD2-CDC20 complex; molecular modeling\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structure 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 to maintain a pool of open-state Mad2 (O-Mad2) for MCC assembly (supporting checkpoint activation) and for timely mitotic exit through catalytic MCC disassembly. Combining TRIP13 depletion with elimination of APC15-dependent Cdc20 ubiquitination/degradation results in complete inability to exit mitosis, demonstrating that mitotic exit requires either TRIP13-catalyzed Mad2 removal or APC15-driven Cdc20 degradation.\",\n      \"method\": \"Degron-tagging for rapid TRIP13 depletion; combination with APC15 loss; cell biological mitotic timing assays; MCC assembly/disassembly measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — acute depletion with degron plus genetic combination; mechanistic epistasis; multiple orthogonal readouts\",\n      \"pmids\": [\"30341343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIP13 ATPase acts as a negative regulator of REV7 (MAD2L2): TRIP13 catalyzes an inactivating conformational change in REV7 from 'closed' to 'open', dissociating the REV7-Shieldin complex to promote homology-directed repair (HDR). TRIP13 similarly disassembles the REV7-REV3 translesion synthesis (TLS) complex, inhibiting error-prone lesion bypass. TRIP13 overexpression in BRCA1-deficient cancers confers PARP inhibitor resistance by restoring HDR.\",\n      \"method\": \"Biochemical assays of REV7 conformational change; Co-IP showing TRIP13-REV7-Shieldin interaction; HDR/NHEJ reporter assays; PARP inhibitor resistance assays in BRCA1-deficient cells\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — conformational change assay, reciprocal co-IP, functional reporter assays, and clinical cancer cell validation\",\n      \"pmids\": [\"31915374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"p31(comet) binds to the REV7-Shieldin complex in cells and promotes REV7 inactivation through the TRIP13 ATPase, causing PARP inhibitor resistance. p31(comet) also counteracts REV7 function in TLS by releasing it from REV3 in the Pol ζ complex. p31(comet) is identified as an important mediator of the TRIP13-REV7 interaction.\",\n      \"method\": \"Co-IP of p31(comet) with REV7-Shieldin complex; REV7 inactivation/chromatin extraction assays; PARP inhibitor resistance assays; TLS bypass assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus multiple functional assays; independently corroborates Clairmont et al. 2020\",\n      \"pmids\": [\"33051298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAD2L2 (REV7) dimerization, mediated by SHLD2 and accelerating MAD2L2-SHLD3 interaction, is required for appropriate shieldin function in NHEJ. MAD2L2 dimerization together with SHLD3 allows shieldin to interact with TRIP13 ATPase, and appropriate levels of TRIP13 are important for proper shieldin (dis)assembly and activity in DNA repair.\",\n      \"method\": \"Biochemical characterization of REV7 dimerization; co-IP of shieldin with TRIP13; functional NHEJ assays; dimerization-defective mutants\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, mutagenesis, and functional assays in a single study\",\n      \"pmids\": [\"34521823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structures of human SHLD3-REV7 binary and SHLD2-SHLD3-REV7 ternary complexes reveal that Shieldin assembly requires SHLD2-SHLD3-induced conformational heterodimerization of open (O-REV7) and closed (C-REV7) forms of REV7. Cryo-EM structures of ATPγS-bound SHLD2-SHLD3-REV7-TRIP13 complexes show that the N-terminus of C-REV7 inserts into the central TRIP13 channel, and ATP hydrolysis-triggered rotatory TRIP13 motions pull the unfolded REV7 N-terminal peptide through the channel to disassemble Shieldin.\",\n      \"method\": \"X-ray crystallography of Shieldin subcomplexes; cryo-EM of TRIP13-Shieldin complex; biochemical 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 — crystal structure plus cryo-EM with mechanistic demonstration of TRIP13 disassembly mechanism\",\n      \"pmids\": [\"33597306\"],\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, leading to stabilization of oncoproteins (NEK2) and destabilization of tumor suppressors (PTEN, p53). TRIP13 overexpression accelerates B cell tumor development in transgenic mice.\",\n      \"method\": \"TRIP13 overexpression in mice and cultured cells; ubiquitination assays; Co-IP of USP7 with substrates; transgenic mouse tumor model; USP7 inhibitor rescue\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, ubiquitination assay, transgenic mouse, pharmacological rescue) in a single study\",\n      \"pmids\": [\"34061780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Biallelic loss-of-function mutations in TRIP13 cause severe spindle assembly checkpoint (SAC) impairment, leading to a high rate of chromosome missegregation in patient cells; restoring TRIP13 function rescues accurate segregation and SAC proficiency.\",\n      \"method\": \"Exome sequencing of patients; functional studies in patient-derived cells; SAC assay; chromosome missegregation quantification; TRIP13 rescue experiment\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — patient cell functional studies with rescue, multiple orthogonal readouts\",\n      \"pmids\": [\"28553959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In C. elegans, the TRIP13 ortholog PCH-2 controls spindle checkpoint strength by regulating the availability of inactive O-Mad2 at and near unattached kinetochores. CMT-1 (p31(comet) ortholog) is required for both PCH-2 localization to unattached kinetochores and its enrichment in germline precursor cells, linking PCH-2 checkpoint function to cell volume and cell fate.\",\n      \"method\": \"Genetic manipulation of C. elegans cell volume and CMT-1/PCH-2; Mad2 kinetochore recruitment assays; spindle checkpoint functional assays in different cell types\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic manipulation with specific cellular readouts; C. elegans ortholog\",\n      \"pmids\": [\"32697629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIP13 localizes to the synapsed synaptonemal complex (SC) in early pachytene spermatocytes and to telomeres throughout meiotic prophase I. This localization is independent of SC axial element proteins REC8 and SYCP2/SYCP3. TRIP13 functions as a dosage-sensitive regulator of meiosis: heterozygous mice exhibit intermediate meiotic defects between wild-type and null.\",\n      \"method\": \"Live imaging and immunofluorescence in knockin mice with FLAG-tagged TRIP13; Trip13-null and Trip13+/- mouse analysis; co-localization with SC markers\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization in knockin mice plus dosage-sensitive genetic analysis with specific phenotypic readouts\",\n      \"pmids\": [\"39207914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIP13 is required to disassemble the MCC through p31(comet)-mediated Mad2 conformational change; overexpression of TRIP13 significantly reduces the mitotic delay caused by Mad2 overexpression, while TRIP13 reduction exacerbates it, identifying an unexpected dependency on TRIP13 in Mad2-overexpressing cells that operates specifically on MCC disassembly.\",\n      \"method\": \"TRIP13 overexpression and shRNA knockdown combined with Mad2 overexpression; mitotic timing assays; checkpoint complex disassembly measurements; tumor xenograft proliferation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic interaction with defined mechanistic readout; single lab\",\n      \"pmids\": [\"28564602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIP13 interacts directly with MRE11 (identified by proximity labeling proteomics) and controls the recruitment of MDC1 to DNA damage sites by regulating the MDC1-MRN complex interaction, thereby participating in ATM signaling amplification immediately after DNA strand break sensing.\",\n      \"method\": \"Quantitative proteomics with proximity labeling (BioID); Co-IP of TRIP13-MRE11; MDC1 recruitment assays at DNA damage sites; ATM signaling pathway analysis\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — proximity labeling MS plus Co-IP plus functional readout; single lab\",\n      \"pmids\": [\"36552858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIP13 directly interacts with TTC5 (a p53 co-factor); genetic knockdown of TRIP13 in murine tubular cells increases p53 activity at Serine 15, suggesting TRIP13 suppresses p53-dependent apoptosis by sequestering TTC5.\",\n      \"method\": \"Co-IP of TRIP13 with TTC5; siRNA knockdown of TRIP13 in murine IMCD cells; p53 phosphorylation measurement; in vivo IRI kidney model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus KD with functional readout; single lab\",\n      \"pmids\": [\"28256593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIP13 directly interacts with ACTN4 and positively regulates its expression, thereby activating the AKT/mTOR pathway to drive hepatocellular carcinoma tumor progression.\",\n      \"method\": \"Co-IP of TRIP13 with ACTN4; Western blot for AKT/mTOR pathway components; gain- and loss-of-function in vitro and xenograft in vivo assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus functional KD/OE; single lab; no direct mechanistic reconstitution\",\n      \"pmids\": [\"31533816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIP13 directly binds to the promoter region of FBXW7 and inhibits its transcription, thereby stabilizing c-MYC (an FBXW7 substrate), promoting GBM cell proliferation and invasion.\",\n      \"method\": \"ChIP showing TRIP13 binding to FBXW7 promoter; TRIP13 knockdown with FBXW7/c-MYC protein measurements; functional proliferation/invasion assays in GBM cells\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ChIP plus functional rescue experiment; single lab\",\n      \"pmids\": [\"31740732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIP13 interacts with ACTN4 to activate Wnt/β-catenin signaling in cervical cancer; ACTN4 knockdown reverses TRIP13-mediated Wnt/β-catenin activation, and Wnt/β-catenin inhibition reverses TRIP13-induced cancer-promoting effects.\",\n      \"method\": \"Co-IP of TRIP13 with ACTN4; Wnt/β-catenin pathway reporter; ACTN4 knockdown epistasis; in vivo xenograft\",\n      \"journal\": \"Environmental toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus functional KD epistasis; single lab\",\n      \"pmids\": [\"34061428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIP13 interacts with FLNA (filamin A) and activates the PI3K/AKT pathway to promote transcriptional activation of EMT-related genes in melanoma.\",\n      \"method\": \"RNA sequencing; Co-IP and mass spectrometry identification of FLNA as TRIP13 binding partner; PI3K/AKT pathway measurements; in vitro and in vivo invasion assays\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP/MS interaction plus functional assays; single lab\",\n      \"pmids\": [\"36268276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIP13 regulates progression of gastric cancer by directly interacting with DDX21 and stabilizing its expression by restraining its ubiquitination degradation; HDAC1 acts as an upstream transcriptional regulator of TRIP13 by binding to the TRIP13 promoter region.\",\n      \"method\": \"Co-IP of TRIP13 with DDX21; ubiquitination assay; ChIP showing HDAC1 at TRIP13 promoter; functional in vitro and in vivo assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and ubiquitination assay plus ChIP; single lab; limited reconstitution\",\n      \"pmids\": [\"39187490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EGFR phosphorylates TRIP13 at tyrosine 56 in response to radiation, and phospho-TRIP13(Y56) promotes NHEJ repair to confer radiation resistance; suppression of Y56 phosphorylation abrogates these effects.\",\n      \"method\": \"Site-specific mutagenesis of TRIP13 Y56; co-IP with EGFR; NHEJ repair reporter assay; radiation resistance assays in head and neck cancer cells and patient tumors\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis plus functional reporter plus epistasis with EGFR; single lab\",\n      \"pmids\": [\"34111559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIP13 directly interacts with EGFR, modulates its phosphorylation and downstream signaling in bladder cancer cells; co-immunoprecipitation confirms the TRIP13-EGFR interaction.\",\n      \"method\": \"Co-IP of TRIP13 with EGFR; Western blot of EGFR pathway; TRIP13 KD functional assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP; single lab; limited mechanistic follow-up\",\n      \"pmids\": [\"31337978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIP13 forms a trimeric complex with USP7 and c-FLIP in TNBC cells; tetrahydrocurcumin (THC) targets TRIP13 to disrupt the TRIP13/USP7/c-FLIP complex, leading to c-FLIP ubiquitination and extrinsic apoptosis induction.\",\n      \"method\": \"Click chemistry-based target fishing; CETSA; DARTS; SPR; Co-IP of TRIP13-USP7-c-FLIP; in vitro deubiquitination assay; confocal microscopy\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal target engagement methods plus Co-IP and deubiquitination reconstitution; single lab\",\n      \"pmids\": [\"39505147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIP13 interacts with YWHAE and disrupting the TRIP13/YWHAE complex by DCZ5417 inhibits the ERK/MAPK signaling axis; DCZ5417 inhibits TRIP13 ATPase activity directly.\",\n      \"method\": \"Molecular docking; pull-down; surface plasmon resonance; cellular thermal shift; ATPase assay; Co-IP of TRIP13-YWHAE; functional MM cell assays\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding methods plus ATPase inhibition assay plus Co-IP; single lab\",\n      \"pmids\": [\"38012658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIP13 promotes survival of KRAS(G12V)-expressing cells specifically through homologous recombination (HR); KRASG12V-expressing cells lacking TRIP13 acquire HR deficiency hallmarks (sensitivity to translesion synthesis inhibitors and PARP inhibitors), establishing TRIP13 as a KRAS-induced HR factor in pancreatic cancer.\",\n      \"method\": \"Genetic (siRNA/CRISPR) and pharmacological TRIP13 depletion in KRASG12V-expressing HPNE cells; HR reporter assays; DNA damage sensitivity assays; xenograft models\",\n      \"journal\": \"NAR cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological tools with multiple orthogonal functional readouts; single lab\",\n      \"pmids\": [\"40115747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIP13 interacts with EGFR and induces its phosphorylation and downstream pathway activation (EGFR signaling) in NSCLC gefitinib-resistant cells; TRIP13 also improves autophagy to desensitize gefitinib in NSCLC cells.\",\n      \"method\": \"Co-IP of TRIP13 with EGFR; immunofluorescence; Western blot of phospho-EGFR; autophagy assays; TRIP13 overexpression/knockdown in resistant cells\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus functional assays; single lab\",\n      \"pmids\": [\"36896765\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIP13 is a hexameric AAA+ ATPase that uses ATP hydrolysis to remodel HORMA-domain proteins by engaging their disordered N-termini through axial pore loops and unfolding their conformationally dynamic regions: with the adapter p31(comet), it converts active closed-MAD2 (C-MAD2) to inactive open-MAD2 (O-MAD2), thereby disassembling the Mitotic Checkpoint Complex (MCC) to silence the spindle assembly checkpoint; it similarly converts closed-REV7 to open-REV7, disassembling the REV7-Shieldin complex to promote homologous recombination over NHEJ; and in meiosis it removes HORMAD1/2 from synapsed chromosome axes to establish proper chromosome domain organization, crossover formation, and checkpoint signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TRIP13 is a hexameric AAA+ ATPase that remodels HORMA-domain proteins by threading their disordered N-termini through its central pore, converting them from closed/active to open/inactive conformations, thereby controlling the spindle assembly checkpoint, DNA damage repair pathway choice, and meiotic chromosome dynamics. Using the adapter p31(comet), TRIP13 converts closed MAD2 (C-MAD2) to open MAD2 (O-MAD2), disassembling the Mitotic Checkpoint Complex (MCC) to silence the spindle assembly checkpoint and permit anaphase onset; this activity, together with APC15-dependent Cdc20 degradation, constitutes the two essential routes for mitotic exit [PMID:25918846, PMID:29973720, PMID:30341343]. TRIP13 similarly converts closed REV7 to open REV7 via p31(comet), disassembling the REV7–Shieldin complex to promote homologous recombination over NHEJ and disassembling REV7–REV3 to suppress translesion synthesis [PMID:31915374, PMID:33597306]. In meiosis, TRIP13 localizes to the synaptonemal complex and telomeres, where it removes HORMAD1/HORMAD2 from synapsed axes through the same N-terminal threading mechanism, establishing proper chromosome domain organization and enabling crossover formation; biallelic TRIP13 loss-of-function mutations in humans cause severe chromosome missegregation due to spindle assembly checkpoint impairment [PMID:19851446, PMID:39207914, PMID:28553959].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing that TRIP13 functions in meiotic recombination downstream of strand invasion resolved its placement in the meiotic DSB repair pathway and revealed its requirement for completing recombination events.\",\n      \"evidence\": \"Trip13-null mouse spermatocytes with retained recombination markers; epistasis with Spo11, Dmc1, Mei1, Rec8\",\n      \"pmids\": [\"17696610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular substrate of TRIP13 in meiosis unknown\", \"Whether TRIP13 acts catalytically or structurally was unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying HORMAD1/HORMAD2 as targets of TRIP13-dependent removal from synapsed axes established that TRIP13 remodels HORMA-domain proteins in vivo, linking its ATPase activity to chromosome domain organization during meiosis.\",\n      \"evidence\": \"Trip13 mutant mice; immunofluorescence showing persistent HORMADs on synapsed chromosomes\",\n      \"pmids\": [\"19851446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical mechanism of HORMAD removal not yet reconstituted\", \"Whether TRIP13 acts directly on HORMADs or through intermediaries was unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating graded meiotic phenotypes with different Trip13 alleles revealed that TRIP13 is required for synaptonemal complex integrity, sex chromosome synapsis, and normal crossover number/distribution, broadening its meiotic role beyond HORMAD removal.\",\n      \"evidence\": \"Multiple Trip13 hypomorph and severe alleles in mice; cytological analysis of SC, MLH1/MLH3 foci, chiasmata\",\n      \"pmids\": [\"20711356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRIP13 dosage translates to distinct meiotic outcomes was mechanistically unexplained\", \"Whether TRIP13 acts on recombination intermediates directly remained open\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two independent groups demonstrated that TRIP13 and p31(comet) catalytically disassemble the MCC through ATP hydrolysis, establishing TRIP13 as a direct SAC-silencing enzyme and connecting its AAA+ ATPase activity to mitotic checkpoint control.\",\n      \"evidence\": \"In vitro MCC disassembly from HeLa extracts; biochemical fractionation identifying TRIP13; TRIP13 knockdown delaying anaphase; kinetochore immunofluorescence\",\n      \"pmids\": [\"25012665\", \"25092294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TRIP13-MCC interaction unknown\", \"Whether TRIP13 acts on free MCC vs. APC/C-bound MCC was unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Cryo-EM of the TRIP13 ortholog PCH-2 and reconstituted MAD2 conformational conversion established that TRIP13 is a hexameric unfoldase resembling ClpX that converts C-MAD2 to O-MAD2 using p31(comet) as an adapter, providing the first structural and biochemical framework for its remodeling mechanism.\",\n      \"evidence\": \"Cryo-EM of C. elegans PCH-2; in vitro MAD2 conversion assay with purified human TRIP13 and p31(comet)\",\n      \"pmids\": [\"25918846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human TRIP13 structure not yet determined\", \"How the N-terminus of MAD2 is engaged was unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Crystal structures of human TRIP13 and crosslinking-MS/NMR studies revealed that TRIP13 engages the disordered MAD2 N-terminus through axial pore loops and causes local unfolding of the MAD2 C-terminal region without disrupting the folded core, defining the mechanism as N-terminal threading; the same mechanism was shown to operate on HORMAD1 in meiosis.\",\n      \"evidence\": \"X-ray crystallography of human TRIP13; NMR of MAD2 conformational change; crosslinking-MS; MAD2 and HORMAD1 N-terminal truncation mutants in vitro and in vivo\",\n      \"pmids\": [\"29208896\", \"28659378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full substrate-engaged complex structure not yet available\", \"TRIP13 selectivity for free vs. APC/C-bound MCC only partly addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that biallelic TRIP13 loss-of-function mutations cause severe SAC impairment and chromosome missegregation in human patients established TRIP13 as a disease gene and confirmed its essential SAC role in humans.\",\n      \"evidence\": \"Exome sequencing of patients; functional rescue of SAC and segregation fidelity in patient-derived cells\",\n      \"pmids\": [\"28553959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full clinical spectrum of TRIP13 deficiency not delineated\", \"Relative contribution of meiotic vs. mitotic defects to patient phenotype unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Cryo-EM structures of the TRIP13–p31(comet)–C-MAD2–CDC20 complex revealed the complete substrate-engaged architecture: p31(comet) positions the MAD2 N-terminus into the TRIP13 pore, and sequential ATP-driven translocation unwinds the αA helix to destabilize C-MAD2, providing an atomic-resolution mechanism for HORMA-domain remodeling.\",\n      \"evidence\": \"Cryo-EM of the quaternary complex; molecular modeling of translocation cycle\",\n      \"pmids\": [\"29973720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Real-time dynamics of translocation not observed\", \"Whether all six protomers fire sequentially was inferred, not directly shown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Acute depletion experiments demonstrated that TRIP13 is required both to maintain the O-MAD2 pool needed for checkpoint activation and for catalytic MCC disassembly for checkpoint silencing, resolving the apparent paradox that TRIP13 functions in both SAC activation and inactivation; combining TRIP13 loss with APC15 loss caused permanent mitotic arrest.\",\n      \"evidence\": \"Degron-mediated acute TRIP13 depletion combined with APC15 knockout; mitotic timing and MCC measurements\",\n      \"pmids\": [\"30341343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative balance between O-MAD2 generation and MCC disassembly rates not modeled\", \"Whether TRIP13 is rate-limiting for SAC activation in normal cells unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extending TRIP13's substrate repertoire beyond MAD2, biochemical and cellular studies showed that TRIP13 converts closed REV7 to open REV7 via p31(comet), disassembling the REV7–Shieldin complex to promote HDR and disassembling REV7–REV3 to suppress translesion synthesis, establishing TRIP13 as a general HORMA-domain remodeler controlling DNA repair pathway choice.\",\n      \"evidence\": \"REV7 conformational change assays; Co-IP of TRIP13–REV7–Shieldin; HDR/NHEJ reporters; PARP inhibitor resistance in BRCA1-deficient cells\",\n      \"pmids\": [\"31915374\", \"33051298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TRIP13–REV7 engagement not yet determined at this point\", \"Relative kinetics of REV7 vs. MAD2 remodeling unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Crystal and cryo-EM structures of the SHLD2–SHLD3–REV7–TRIP13 complex revealed that the C-REV7 N-terminus inserts into the TRIP13 central channel analogously to MAD2, and ATP hydrolysis drives rotatory pulling to disassemble Shieldin, providing the structural basis for TRIP13's role in DNA repair pathway choice.\",\n      \"evidence\": \"X-ray crystallography of SHLD3–REV7 and SHLD2–SHLD3–REV7; cryo-EM of ATPγS-bound TRIP13–Shieldin complex\",\n      \"pmids\": [\"33597306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of full Shieldin disassembly cycle not captured\", \"Whether additional co-factors regulate TRIP13–Shieldin interaction in vivo unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"TRIP13 was shown to enhance USP7-mediated deubiquitination of oncoproteins (NEK2) and tumor suppressors (p53, PTEN), and TRIP13 overexpression accelerated B cell tumorigenesis in transgenic mice, revealing a non-HORMA-domain function in ubiquitin pathway regulation with oncogenic consequences.\",\n      \"evidence\": \"Co-IP of USP7 with substrates; ubiquitination assays; TRIP13 transgenic mouse tumor model; USP7 inhibitor rescue\",\n      \"pmids\": [\"34061780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIP13 ATPase activity is required for USP7 enhancement not determined\", \"Mechanism by which TRIP13 enhances USP7–substrate association is unclear\", \"Whether this function operates through HORMA-domain remodeling or an independent mechanism is unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Direct localization of endogenous TRIP13 to the synaptonemal complex and telomeres throughout meiotic prophase I, independent of axial element proteins, together with dosage-sensitive meiotic defects in heterozygotes, refined understanding of where and when TRIP13 acts during meiosis.\",\n      \"evidence\": \"FLAG-tagged TRIP13 knockin mice; live imaging and immunofluorescence; Trip13+/− phenotypic analysis\",\n      \"pmids\": [\"39207914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Telomeric function of TRIP13 is unexplained mechanistically\", \"Identity of TRIP13 recruitment factors at SC and telomeres unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of TRIP13's telomeric function, whether TRIP13's enhancement of USP7 deubiquitination requires its ATPase or HORMA-domain remodeling activity, quantitative modeling of how TRIP13 balances O-MAD2 generation with MCC disassembly in living cells, and whether additional non-HORMA substrates exist.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Telomeric mechanism unknown\", \"USP7 interaction mechanism unresolved\", \"No comprehensive substrate profiling beyond HORMA-domain proteins\", \"In vivo quantitative flux through TRIP13-dependent pathways not measured\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3, 5, 7, 8, 9, 10, 11, 14]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 7, 8, 9, 11, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 11, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 2, 18]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 5, 7, 9, 10, 16, 19]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4, 11, 12, 27, 31]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 1, 2, 8, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 7, 8, 9, 14, 15]}\n    ],\n    \"complexes\": [\n      \"TRIP13 hexamer\",\n      \"TRIP13–p31(comet)–C-MAD2 complex\",\n      \"TRIP13–p31(comet)–REV7–Shieldin complex\"\n    ],\n    \"partners\": [\n      \"MAD2L1\",\n      \"MAD2L2\",\n      \"MAD1L1BP (p31comet/MAD2L1BP)\",\n      \"CDC20\",\n      \"USP7\",\n      \"SHLD3\",\n      \"SHLD2\",\n      \"EGFR\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}