{"gene":"ZWINT","run_date":"2026-04-28T23:00:24","timeline":{"discoveries":[{"year":2004,"finding":"ZWINT-1 (Zwint-1) is a component of the human Mis12 core complex at kinetochores; nine polypeptides bind to hMis12, including HEC1 and Zwint-1 as outer kinetochore proteins. Centromeric HP1 anchors the hMis12 complex which extends to outer Zwint-1 during mitosis.","method":"Co-immunoprecipitation, mass spectrometry, RNAi knockdown in HeLa cells, immunofluorescence","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with MS identification, functional validation by RNAi, replicated across S. pombe and human cells","pmids":["15502821"],"is_preprint":false},{"year":2004,"finding":"ZWINT-1 is required and sufficient for kinetochore localization of ZW10; Zwint-1 interacts with the N-terminal domain of ZW10. Depletion of Zwint-1 by siRNA abolishes ZW10 kinetochore localization, causes premature chromosome segregation, chromosome bridges, and abolishes the mitotic spindle checkpoint (cells fail to arrest in response to microtubule inhibitors). Zwint-1 is also required for stable kinetochore association of CENP-F and dynamitin but not BUB1.","method":"siRNA knockdown, immunofluorescence, co-immunoprecipitation, domain mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — siRNA with specific phenotypic readouts, Co-IP domain mapping, multiple orthogonal assays in a single study","pmids":["15485811"],"is_preprint":false},{"year":2004,"finding":"Inhibition of ZWINT-1 by antisense oligonucleotides causes centromere separation, chromosome aneuploidy, and micronuclei formation, phenocopying the Roberts syndrome cellular phenotype.","method":"Antisense oligonucleotide knockdown, atomic force microscopy, cytogenetic analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 — loss-of-function with defined cellular phenotype, single lab","pmids":["15094189"],"is_preprint":false},{"year":2006,"finding":"HEC1 (NDC80) directly interacts with ZWINT-1, and this interaction is required for the sequential recruitment of Zwint-1 and then ZW10 to kinetochores. Depletion of Hec1 impairs recruitment of both Zwint-1 and ZW10; depletion of Zwint-1 abrogates ZW10 kinetochore localization but not Hec1. The Hec1-Zwint-1-ZW10 complex forms specifically during M phase.","method":"Co-immunoprecipitation (M-phase specific), siRNA knockdown, immunofluorescence, domain interaction mapping","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, epistatic siRNA knockdown with defined localization phenotypes, multiple orthogonal methods","pmids":["16732327"],"is_preprint":false},{"year":2008,"finding":"ZWINT-1 is a binding partner of Rab3c GTPase; the interaction is determined by a unique residue in Rab3c and is distinct from the Rab3c-rabphilin3a interaction. SNAP25 binds to the same region in Zwint-1 as Rab3c, suggesting a role for Zwint-1 in presynaptic vesicle events. Rab3c and Zwint-1 colocalize extensively in primary hippocampal neurons.","method":"Yeast two-hybrid, co-immunoprecipitation, GST pulldown, immunofluorescence in primary neurons","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and pulldown with colocalization, single lab, moderate mechanistic follow-up","pmids":["18625218"],"is_preprint":false},{"year":2011,"finding":"Aurora B kinase phosphorylates ZWINT-1 at three novel sites (identified by tandem mass spectrometry). Aurora B phosphorylation of Zwint-1 is required for assembly of the RZZ (ROD-ZW10-Zwilch) complex and dynein at kinetochores. A triple-Ala (phospho-dead) Zwint-1 mutant blocks kinetochore assembly of RZZ-dependent proteins and impairs chromosome movement; a triple-Glu (phospho-mimetic) mutant renders cells resistant to Aurora B inhibition during prometaphase but prevents poleward streaming of dynein/dynactin/RZZ and SAC silencing at metaphase.","method":"In vitro kinase assay, tandem mass spectrometry, site-directed mutagenesis (Ala/Glu substitution), AurB inhibitor (ZM447439), kinase-dead construct, immunofluorescence","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with MS site identification, mutagenesis with functional rescue/dominant-negative phenotypes","pmids":["21775627"],"is_preprint":false},{"year":2011,"finding":"TERF/TRIM17 E3 ubiquitin ligase interacts with ZWINT-1 via its coiled-coil domain and promotes proteasomal degradation of ZWINT-1; overexpression of TERF reduces ZWINT-1 protein levels and decreases cell proliferation.","method":"Yeast two-hybrid screening, co-immunoprecipitation, western blot, cell proliferation assay, siRNA knockdown","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP with functional overexpression/knockdown data, single lab","pmids":["22023800"],"is_preprint":false},{"year":2015,"finding":"ZWINT-1 is required for spindle assembly checkpoint function during oocyte meiosis I; Zwint-1 knockdown abrogates kinetochore recruitment of Mad2, leading to accelerated meiosis, chromosome misalignment, and aneuploidy. Aurora C kinase-mediated correction of erroneous kinetochore-microtubule attachment requires Zwint-1.","method":"siRNA knockdown in mouse oocytes, immunofluorescence, Aurora C kinase inhibition, washout rescue experiment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO/KD with defined meiotic phenotype and epistasis with Aurora C kinase, single lab","pmids":["26486467"],"is_preprint":false},{"year":2020,"finding":"APC/C-Cdc20 ubiquitinates ZWINT-1 in a D-box-dependent manner, promoting its proteasomal degradation during mitotic exit. Cdc20 overexpression decreases Zwint-1 levels (blocked by MG132); Cdc20 silencing causes Zwint-1 accumulation. A D-box-deleted Zwint-1 mutant (Zwint-1ΔD-box) does not interact with Cdc20 and is not degraded.","method":"In vivo ubiquitination assay, co-immunoprecipitation, site-directed mutagenesis (D-box deletion), MG132 proteasome inhibitor, cycloheximide chase, siRNA knockdown","journal":"Cell biochemistry and function","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo ubiquitination assay with mutagenesis and pharmacological validation, single lab","pmids":["31945194"],"is_preprint":false},{"year":2021,"finding":"ZWINT-1 interacts with p53 and promotes its ubiquitination and proteasomal degradation, thereby reducing p53/p21 signaling. This interaction was shown to be enhanced under hypoxia (via HIF1α-driven ZWINT upregulation), promoting pancreatic cancer cell proliferation.","method":"Co-immunoprecipitation, immunofluorescence, ubiquitination assay, ChIP (HIF1α on ZWINT promoter), CCK8/colony formation, luciferase reporter","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ubiquitination assay, ChIP, multiple functional readouts, single lab","pmids":["34900978"],"is_preprint":false}],"current_model":"ZWINT-1 is an outer kinetochore protein that acts downstream of HEC1/NDC80 and upstream of ZW10/RZZ in a sequential recruitment hierarchy; Aurora B kinase phosphorylates ZWINT-1 at multiple sites to promote RZZ complex and dynein assembly at kinetochores for spindle assembly checkpoint signaling, while its protein levels are regulated by APC/C-Cdc20–mediated ubiquitin-proteasomal degradation (via a D-box) and by TERF/TRIM17 E3 ligase activity."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing ZWINT-1 as an outer kinetochore component within the Mis12 complex network resolved where the protein sits in the centromere-to-kinetochore hierarchy and linked it to the ZW10 recruitment pathway.","evidence":"Co-IP/MS of hMis12-associated polypeptides in HeLa cells; siRNA depletion of ZWINT-1 abolished ZW10 kinetochore localization, caused premature segregation and SAC failure","pmids":["15502821","15485811"],"confidence":"High","gaps":["Direct binding interface between ZWINT-1 and ZW10 not structurally resolved","How ZWINT-1 couples to dynein/dynactin recruitment was unclear"]},{"year":2006,"claim":"Defining an HEC1→ZWINT-1→ZW10 sequential recruitment hierarchy during M phase established the epistatic order through which the outer kinetochore assembles checkpoint-competent signaling platforms.","evidence":"M-phase-specific reciprocal Co-IP; epistatic siRNA knockdown showing HEC1 depletion removes ZWINT-1 and ZW10, but ZWINT-1 depletion does not affect HEC1","pmids":["16732327"],"confidence":"High","gaps":["Whether ZWINT-1–ZW10 interaction is direct or bridged by Zwilch/ROD was unresolved","Regulation of the HEC1–ZWINT-1 interaction was unknown"]},{"year":2011,"claim":"Identifying Aurora B phosphorylation of ZWINT-1 at three sites as the switch for RZZ/dynein kinetochore assembly answered how the checkpoint recruitment cascade is activated and how its silencing requires dephosphorylation-dependent poleward streaming.","evidence":"In vitro kinase assay with MS site mapping; phospho-dead (3A) mutant blocked RZZ assembly, phospho-mimetic (3E) mutant sustained SAC and blocked dynein streaming","pmids":["21775627"],"confidence":"High","gaps":["Identity of the phosphatase(s) that reverse Aurora B phosphorylation on ZWINT-1 is unknown","Structural basis of phosphorylation-dependent RZZ binding not determined"]},{"year":2011,"claim":"Discovery that TRIM17 E3 ligase promotes ZWINT-1 proteasomal degradation via its coiled-coil domain established a first post-translational mechanism controlling ZWINT-1 protein abundance.","evidence":"Yeast two-hybrid, Co-IP, and overexpression/knockdown in cell proliferation assays","pmids":["22023800"],"confidence":"Medium","gaps":["Ubiquitination sites on ZWINT-1 targeted by TRIM17 not mapped","Cell-cycle timing of TRIM17-mediated degradation not established","Not independently confirmed by a second group"]},{"year":2015,"claim":"Demonstrating ZWINT-1's requirement for SAC function and Aurora C–mediated error correction in oocyte meiosis I extended its role beyond mitosis to female germ cell chromosome fidelity.","evidence":"siRNA in mouse oocytes; ZWINT-1 depletion abolished Mad2 kinetochore recruitment and caused aneuploidy; epistasis with Aurora C inhibition","pmids":["26486467"],"confidence":"Medium","gaps":["Whether Aurora C directly phosphorylates ZWINT-1 (analogous to Aurora B) was not tested","Relevance to human oocyte meiosis not confirmed"]},{"year":2020,"claim":"Identification of APC/C-Cdc20 as the E3 ligase that ubiquitinates ZWINT-1 through a D-box motif during mitotic exit provided the molecular timer for ZWINT-1 destruction and kinetochore disassembly.","evidence":"In vivo ubiquitination assay, D-box deletion mutant escapes Cdc20-mediated degradation; MG132 and cycloheximide chase experiments","pmids":["31945194"],"confidence":"Medium","gaps":["Specific lysine residues ubiquitinated by APC/C-Cdc20 not identified","Functional consequences of stabilized ZWINT-1 (D-box mutant) on subsequent cell cycles not characterized"]},{"year":2021,"claim":"Finding that ZWINT-1 promotes p53 ubiquitination and degradation under hypoxia revealed a non-kinetochore function linking ZWINT-1 overexpression to oncogenic proliferation via suppression of p53/p21 signaling.","evidence":"Co-IP, ubiquitination assay, ChIP showing HIF1α drives ZWINT transcription, functional proliferation assays in pancreatic cancer cells","pmids":["34900978"],"confidence":"Medium","gaps":["Whether ZWINT-1 acts as an E3 ligase adaptor or scaffold for p53 ubiquitination is unknown","Not independently replicated; mechanism may be indirect through kinetochore-independent pool","Physiological relevance beyond cancer cell lines not established"]},{"year":null,"claim":"A structural model of the ZWINT-1–RZZ interface, the identity of phosphatases counteracting Aurora B on ZWINT-1, and the in vivo significance of ZWINT-1's reported p53-regulatory function remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of ZWINT-1 in complex with RZZ or HEC1","No genetic mouse model assessing ZWINT-1 loss in vivo","Potential non-kinetochore functions (Rab3c/SNAP25 interaction in neurons) not mechanistically developed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3,5]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,1,3,5]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,3,5,7,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,8]}],"complexes":["Mis12 complex network","HEC1/NDC80 complex (associated)"],"partners":["NDC80","ZW10","AURKB","CDC20","TRIM17","RAB3C","TP53"],"other_free_text":[]},"mechanistic_narrative":"ZWINT-1 is an outer kinetochore protein essential for spindle assembly checkpoint (SAC) signaling and accurate chromosome segregation during mitosis and meiosis. It is recruited to kinetochores downstream of HEC1/NDC80 as part of the Mis12 complex network and is required for the subsequent kinetochore localization of ZW10, the RZZ complex, dynein/dynactin, CENP-F, and Mad2 [PMID:15502821, PMID:15485811, PMID:16732327]. Aurora B kinase phosphorylates ZWINT-1 at three sites to promote RZZ and dynein assembly at kinetochores, and phospho-mimetic mutations sustain SAC activity while blocking poleward streaming needed for checkpoint silencing [PMID:21775627]. ZWINT-1 protein levels are controlled by APC/C-Cdc20–mediated D-box-dependent ubiquitination during mitotic exit and by TRIM17 E3 ligase–directed proteasomal degradation [PMID:31945194, PMID:22023800]."},"prefetch_data":{"uniprot":{"accession":"O95229","full_name":"Outer kinetochore KNL1 complex subunit ZWINT","aliases":["ZW10 interactor","ZW10-interacting protein 1","Zwint-1"],"length_aa":277,"mass_kda":31.3,"function":"Acts as a component of the outer kinetochore KNL1 complex that serves as a docking point for spindle assembly checkpoint components and mediates microtubule-kinetochore interactions (PubMed:15094189, PubMed:15485811, PubMed:15824131, PubMed:16732327, PubMed:24530301, PubMed:27881301, PubMed:38459127, PubMed:38459128). Kinetochores, consisting of a centromere-associated inner segment and a microtubule-contacting outer segment, play a crucial role in chromosome segregation by mediating the physical connection between centromeric DNA and spindle microtubules (PubMed:15094189, PubMed:15485811, PubMed:16732327). The outer kinetochore is made up of the ten-subunit KMN network, comprising the MIS12, NDC80 and KNL1 complexes, and auxiliary microtubule-associated components; together they connect the outer kinetochore with the inner kinetochore, bind microtubules, and mediate interactions with mitotic checkpoint proteins that delay anaphase until chromosomes are bioriented on the spindle (PubMed:15094189, PubMed:15485811, PubMed:15824131, PubMed:16732327, PubMed:24530301, PubMed:38459127, PubMed:38459128). Targets the RZZ complex to the kinetochore at prometaphase (PubMed:15485811). Recruits MAD2L1 to the kinetochore, but is not required for BUB1B localization (By similarity). In addition to orienting mitotic chromosomes, it is also essential for alignment of homologous chromosomes during meiotic metaphase I (By similarity). In meiosis I, required to activate the spindle assembly checkpoint at unattached kinetochores to correct erroneous kinetochore-microtubule attachments (PubMed:15485811)","subcellular_location":"Nucleus; Chromosome, centromere, kinetochore","url":"https://www.uniprot.org/uniprotkb/O95229/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZWINT","classification":"Not Classified","n_dependent_lines":662,"n_total_lines":1208,"dependency_fraction":0.5480132450331126},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MIS12","stoichiometry":4.0},{"gene":"HSPA4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ZWINT","total_profiled":1310},"omim":[{"mim_id":"609178","title":"MIS12 KINETOCHORE COMPLEX COMPONENT; MIS12","url":"https://www.omim.org/entry/609178"},{"mim_id":"609177","title":"ZW10 INTERACTING KINETOCHORE PROTEIN; ZWINT","url":"https://www.omim.org/entry/609177"},{"mim_id":"609176","title":"POLYAMINE-MODULATED FACTOR 1; PMF1","url":"https://www.omim.org/entry/609176"},{"mim_id":"609175","title":"DSN1, MIS12 KINETOCHORE COMPLEX COMPONENT; DSN1","url":"https://www.omim.org/entry/609175"},{"mim_id":"609174","title":"NSL1, MIS12 KINETOCHORE COMPLEX COMPONENT; NSL1","url":"https://www.omim.org/entry/609174"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Nuclear bodies","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":39.2},{"tissue":"lymphoid tissue","ntpm":40.5}],"url":"https://www.proteinatlas.org/search/ZWINT"},"hgnc":{"alias_symbol":["KNTC2AP","SIP30","Zwint1"],"prev_symbol":[]},"alphafold":{"accession":"O95229","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95229","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95229-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95229-F1-predicted_aligned_error_v6.png","plddt_mean":78.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZWINT","jax_strain_url":"https://www.jax.org/strain/search?query=ZWINT"},"sequence":{"accession":"O95229","fasta_url":"https://rest.uniprot.org/uniprotkb/O95229.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95229/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95229"}},"corpus_meta":[{"pmid":"15502821","id":"PMC_15502821","title":"A conserved Mis12 centromere complex is linked to heterochromatic HP1 and outer kinetochore protein Zwint-1.","date":"2004","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15502821","citation_count":222,"is_preprint":false},{"pmid":"15485811","id":"PMC_15485811","title":"Human Zwint-1 specifies localization of Zeste White 10 to kinetochores and is essential for mitotic checkpoint signaling.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15485811","citation_count":108,"is_preprint":false},{"pmid":"16732327","id":"PMC_16732327","title":"Hec1 sequentially recruits Zwint-1 and ZW10 to kinetochores for faithful chromosome segregation and spindle checkpoint control.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16732327","citation_count":55,"is_preprint":false},{"pmid":"22023800","id":"PMC_22023800","title":"Terf/TRIM17 stimulates degradation of kinetochore protein ZWINT and regulates cell proliferation.","date":"2011","source":"Journal of 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development and maintenance of peripheral nerve injury-induced neuropathic pain.","date":"2009","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/19748740","citation_count":24,"is_preprint":false},{"pmid":"12068081","id":"PMC_12068081","title":"Identification of a novel SNAP25 interacting protein (SIP30).","date":"2002","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12068081","citation_count":21,"is_preprint":false},{"pmid":"32323832","id":"PMC_32323832","title":"ZWINT: A potential therapeutic biomarker in patients with glioblastoma correlates with cell proliferation and invasion.","date":"2020","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/32323832","citation_count":19,"is_preprint":false},{"pmid":"33819373","id":"PMC_33819373","title":"KIFC1 regulates ZWINT to promote tumor progression and spheroid formation in colorectal cancer.","date":"2021","source":"Pathology 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andrology and urology","url":"https://pubmed.ncbi.nlm.nih.gov/41809788","citation_count":0,"is_preprint":false},{"pmid":"41911658","id":"PMC_41911658","title":"The RNA-binding protein ALYREF promotes mitochondrial dysfunction and ferroptosis in CD4+ helper T cells in chronic obstructive pulmonary disease and non-small cell lung cancer by enhancing ZWINT mRNA stability.","date":"2026","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41911658","citation_count":0,"is_preprint":false},{"pmid":"41378098","id":"PMC_41378098","title":"Radiotherapy and precision medicine's role in molecular alterations during chromosomal division: The influence of MB, TP53, CENPA, BUB1B, MAD2L1, ZWINT expression and noncoding RNAs in oral cancer.","date":"2025","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/41378098","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15691,"output_tokens":2605,"usd":0.043074},"stage2":{"model":"claude-opus-4-6","input_tokens":5924,"output_tokens":2212,"usd":0.12738},"total_usd":0.170454,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"ZWINT-1 (Zwint-1) is a component of the human Mis12 core complex at kinetochores; nine polypeptides bind to hMis12, including HEC1 and Zwint-1 as outer kinetochore proteins. Centromeric HP1 anchors the hMis12 complex which extends to outer Zwint-1 during mitosis.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, RNAi knockdown in HeLa cells, immunofluorescence\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with MS identification, functional validation by RNAi, replicated across S. pombe and human cells\",\n      \"pmids\": [\"15502821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ZWINT-1 is required and sufficient for kinetochore localization of ZW10; Zwint-1 interacts with the N-terminal domain of ZW10. Depletion of Zwint-1 by siRNA abolishes ZW10 kinetochore localization, causes premature chromosome segregation, chromosome bridges, and abolishes the mitotic spindle checkpoint (cells fail to arrest in response to microtubule inhibitors). Zwint-1 is also required for stable kinetochore association of CENP-F and dynamitin but not BUB1.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, co-immunoprecipitation, domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA with specific phenotypic readouts, Co-IP domain mapping, multiple orthogonal assays in a single study\",\n      \"pmids\": [\"15485811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Inhibition of ZWINT-1 by antisense oligonucleotides causes centromere separation, chromosome aneuploidy, and micronuclei formation, phenocopying the Roberts syndrome cellular phenotype.\",\n      \"method\": \"Antisense oligonucleotide knockdown, atomic force microscopy, cytogenetic analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — loss-of-function with defined cellular phenotype, single lab\",\n      \"pmids\": [\"15094189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HEC1 (NDC80) directly interacts with ZWINT-1, and this interaction is required for the sequential recruitment of Zwint-1 and then ZW10 to kinetochores. Depletion of Hec1 impairs recruitment of both Zwint-1 and ZW10; depletion of Zwint-1 abrogates ZW10 kinetochore localization but not Hec1. The Hec1-Zwint-1-ZW10 complex forms specifically during M phase.\",\n      \"method\": \"Co-immunoprecipitation (M-phase specific), siRNA knockdown, immunofluorescence, domain interaction mapping\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, epistatic siRNA knockdown with defined localization phenotypes, multiple orthogonal methods\",\n      \"pmids\": [\"16732327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ZWINT-1 is a binding partner of Rab3c GTPase; the interaction is determined by a unique residue in Rab3c and is distinct from the Rab3c-rabphilin3a interaction. SNAP25 binds to the same region in Zwint-1 as Rab3c, suggesting a role for Zwint-1 in presynaptic vesicle events. Rab3c and Zwint-1 colocalize extensively in primary hippocampal neurons.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, GST pulldown, immunofluorescence in primary neurons\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and pulldown with colocalization, single lab, moderate mechanistic follow-up\",\n      \"pmids\": [\"18625218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Aurora B kinase phosphorylates ZWINT-1 at three novel sites (identified by tandem mass spectrometry). Aurora B phosphorylation of Zwint-1 is required for assembly of the RZZ (ROD-ZW10-Zwilch) complex and dynein at kinetochores. A triple-Ala (phospho-dead) Zwint-1 mutant blocks kinetochore assembly of RZZ-dependent proteins and impairs chromosome movement; a triple-Glu (phospho-mimetic) mutant renders cells resistant to Aurora B inhibition during prometaphase but prevents poleward streaming of dynein/dynactin/RZZ and SAC silencing at metaphase.\",\n      \"method\": \"In vitro kinase assay, tandem mass spectrometry, site-directed mutagenesis (Ala/Glu substitution), AurB inhibitor (ZM447439), kinase-dead construct, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with MS site identification, mutagenesis with functional rescue/dominant-negative phenotypes\",\n      \"pmids\": [\"21775627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TERF/TRIM17 E3 ubiquitin ligase interacts with ZWINT-1 via its coiled-coil domain and promotes proteasomal degradation of ZWINT-1; overexpression of TERF reduces ZWINT-1 protein levels and decreases cell proliferation.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, western blot, cell proliferation assay, siRNA knockdown\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with functional overexpression/knockdown data, single lab\",\n      \"pmids\": [\"22023800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ZWINT-1 is required for spindle assembly checkpoint function during oocyte meiosis I; Zwint-1 knockdown abrogates kinetochore recruitment of Mad2, leading to accelerated meiosis, chromosome misalignment, and aneuploidy. Aurora C kinase-mediated correction of erroneous kinetochore-microtubule attachment requires Zwint-1.\",\n      \"method\": \"siRNA knockdown in mouse oocytes, immunofluorescence, Aurora C kinase inhibition, washout rescue experiment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/KD with defined meiotic phenotype and epistasis with Aurora C kinase, single lab\",\n      \"pmids\": [\"26486467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"APC/C-Cdc20 ubiquitinates ZWINT-1 in a D-box-dependent manner, promoting its proteasomal degradation during mitotic exit. Cdc20 overexpression decreases Zwint-1 levels (blocked by MG132); Cdc20 silencing causes Zwint-1 accumulation. A D-box-deleted Zwint-1 mutant (Zwint-1ΔD-box) does not interact with Cdc20 and is not degraded.\",\n      \"method\": \"In vivo ubiquitination assay, co-immunoprecipitation, site-directed mutagenesis (D-box deletion), MG132 proteasome inhibitor, cycloheximide chase, siRNA knockdown\",\n      \"journal\": \"Cell biochemistry and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo ubiquitination assay with mutagenesis and pharmacological validation, single lab\",\n      \"pmids\": [\"31945194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZWINT-1 interacts with p53 and promotes its ubiquitination and proteasomal degradation, thereby reducing p53/p21 signaling. This interaction was shown to be enhanced under hypoxia (via HIF1α-driven ZWINT upregulation), promoting pancreatic cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, ubiquitination assay, ChIP (HIF1α on ZWINT promoter), CCK8/colony formation, luciferase reporter\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination assay, ChIP, multiple functional readouts, single lab\",\n      \"pmids\": [\"34900978\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZWINT-1 is an outer kinetochore protein that acts downstream of HEC1/NDC80 and upstream of ZW10/RZZ in a sequential recruitment hierarchy; Aurora B kinase phosphorylates ZWINT-1 at multiple sites to promote RZZ complex and dynein assembly at kinetochores for spindle assembly checkpoint signaling, while its protein levels are regulated by APC/C-Cdc20–mediated ubiquitin-proteasomal degradation (via a D-box) and by TERF/TRIM17 E3 ligase activity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ZWINT-1 is an outer kinetochore protein essential for spindle assembly checkpoint (SAC) signaling and accurate chromosome segregation during mitosis and meiosis. It is recruited to kinetochores downstream of HEC1/NDC80 as part of the Mis12 complex network and is required for the subsequent kinetochore localization of ZW10, the RZZ complex, dynein/dynactin, CENP-F, and Mad2 [PMID:15502821, PMID:15485811, PMID:16732327]. Aurora B kinase phosphorylates ZWINT-1 at three sites to promote RZZ and dynein assembly at kinetochores, and phospho-mimetic mutations sustain SAC activity while blocking poleward streaming needed for checkpoint silencing [PMID:21775627]. ZWINT-1 protein levels are controlled by APC/C-Cdc20–mediated D-box-dependent ubiquitination during mitotic exit and by TRIM17 E3 ligase–directed proteasomal degradation [PMID:31945194, PMID:22023800].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing ZWINT-1 as an outer kinetochore component within the Mis12 complex network resolved where the protein sits in the centromere-to-kinetochore hierarchy and linked it to the ZW10 recruitment pathway.\",\n      \"evidence\": \"Co-IP/MS of hMis12-associated polypeptides in HeLa cells; siRNA depletion of ZWINT-1 abolished ZW10 kinetochore localization, caused premature segregation and SAC failure\",\n      \"pmids\": [\"15502821\", \"15485811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding interface between ZWINT-1 and ZW10 not structurally resolved\",\n        \"How ZWINT-1 couples to dynein/dynactin recruitment was unclear\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defining an HEC1→ZWINT-1→ZW10 sequential recruitment hierarchy during M phase established the epistatic order through which the outer kinetochore assembles checkpoint-competent signaling platforms.\",\n      \"evidence\": \"M-phase-specific reciprocal Co-IP; epistatic siRNA knockdown showing HEC1 depletion removes ZWINT-1 and ZW10, but ZWINT-1 depletion does not affect HEC1\",\n      \"pmids\": [\"16732327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ZWINT-1–ZW10 interaction is direct or bridged by Zwilch/ROD was unresolved\",\n        \"Regulation of the HEC1–ZWINT-1 interaction was unknown\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying Aurora B phosphorylation of ZWINT-1 at three sites as the switch for RZZ/dynein kinetochore assembly answered how the checkpoint recruitment cascade is activated and how its silencing requires dephosphorylation-dependent poleward streaming.\",\n      \"evidence\": \"In vitro kinase assay with MS site mapping; phospho-dead (3A) mutant blocked RZZ assembly, phospho-mimetic (3E) mutant sustained SAC and blocked dynein streaming\",\n      \"pmids\": [\"21775627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the phosphatase(s) that reverse Aurora B phosphorylation on ZWINT-1 is unknown\",\n        \"Structural basis of phosphorylation-dependent RZZ binding not determined\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that TRIM17 E3 ligase promotes ZWINT-1 proteasomal degradation via its coiled-coil domain established a first post-translational mechanism controlling ZWINT-1 protein abundance.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, and overexpression/knockdown in cell proliferation assays\",\n      \"pmids\": [\"22023800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ubiquitination sites on ZWINT-1 targeted by TRIM17 not mapped\",\n        \"Cell-cycle timing of TRIM17-mediated degradation not established\",\n        \"Not independently confirmed by a second group\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrating ZWINT-1's requirement for SAC function and Aurora C–mediated error correction in oocyte meiosis I extended its role beyond mitosis to female germ cell chromosome fidelity.\",\n      \"evidence\": \"siRNA in mouse oocytes; ZWINT-1 depletion abolished Mad2 kinetochore recruitment and caused aneuploidy; epistasis with Aurora C inhibition\",\n      \"pmids\": [\"26486467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether Aurora C directly phosphorylates ZWINT-1 (analogous to Aurora B) was not tested\",\n        \"Relevance to human oocyte meiosis not confirmed\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of APC/C-Cdc20 as the E3 ligase that ubiquitinates ZWINT-1 through a D-box motif during mitotic exit provided the molecular timer for ZWINT-1 destruction and kinetochore disassembly.\",\n      \"evidence\": \"In vivo ubiquitination assay, D-box deletion mutant escapes Cdc20-mediated degradation; MG132 and cycloheximide chase experiments\",\n      \"pmids\": [\"31945194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific lysine residues ubiquitinated by APC/C-Cdc20 not identified\",\n        \"Functional consequences of stabilized ZWINT-1 (D-box mutant) on subsequent cell cycles not characterized\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Finding that ZWINT-1 promotes p53 ubiquitination and degradation under hypoxia revealed a non-kinetochore function linking ZWINT-1 overexpression to oncogenic proliferation via suppression of p53/p21 signaling.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, ChIP showing HIF1α drives ZWINT transcription, functional proliferation assays in pancreatic cancer cells\",\n      \"pmids\": [\"34900978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ZWINT-1 acts as an E3 ligase adaptor or scaffold for p53 ubiquitination is unknown\",\n        \"Not independently replicated; mechanism may be indirect through kinetochore-independent pool\",\n        \"Physiological relevance beyond cancer cell lines not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A structural model of the ZWINT-1–RZZ interface, the identity of phosphatases counteracting Aurora B on ZWINT-1, and the in vivo significance of ZWINT-1's reported p53-regulatory function remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of ZWINT-1 in complex with RZZ or HEC1\",\n        \"No genetic mouse model assessing ZWINT-1 loss in vivo\",\n        \"Potential non-kinetochore functions (Rab3c/SNAP25 interaction in neurons) not mechanistically developed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1, 3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 3, 5, 7, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"complexes\": [\n      \"Mis12 complex network\",\n      \"HEC1/NDC80 complex (associated)\"\n    ],\n    \"partners\": [\n      \"NDC80\",\n      \"ZW10\",\n      \"AURKB\",\n      \"CDC20\",\n      \"TRIM17\",\n      \"RAB3C\",\n      \"TP53\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}