{"gene":"NUP43","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2004,"finding":"NUP43 was identified as a new WD-repeat nucleoporin and member of the Nup107-160 complex, specific to higher eukaryotes. All constituents of the Nup107-160 complex, including NUP43, are targeted to kinetochores from prophase to anaphase of mitosis.","method":"Biochemical co-purification, GFP-tagging, RNAi knockdown, immunofluorescence microscopy","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal biochemical isolation, live-cell imaging, and functional knockdown across multiple nucleoporins; foundational paper with 223 citations","pmids":["15146057"],"is_preprint":false},{"year":2007,"finding":"The Nup107-160 complex (of which NUP43 is a constituent) interacts with CENP-F and the Ndc80 complex for kinetochore targeting; efficient depletion of the complex induces mitotic delay, impaired chromosome congression, reduced kinetochore tension, and kinetochore-microtubule attachment defects, and the complex is required for recruitment of Crm1 and RanGAP1-RanBP2 to kinetochores.","method":"siRNA knockdown of multiple Nup107-160 subunits including NUP43 components, co-immunoprecipitation, live-cell imaging, kinetochore tension assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — epistasis with multiple siRNAs, Co-IP for binding partners, quantitative kinetochore phenotyping; replicated context with 171 citations","pmids":["17363900"],"is_preprint":false},{"year":2014,"finding":"BioID proximity labeling demonstrated a direct interaction of NUP43 with NUP85 within the Nup107-160 subcomplex, refining the molecular architecture of this conserved NPC subcomplex.","method":"BioID (proximity-dependent biotin identification) in living cells, streptavidin affinity purification, mass spectrometry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — in vivo proximity labeling with the Nup107-160 complex used as a molecular ruler; strong mechanistic follow-up; 432 citations","pmids":["24927568"],"is_preprint":false},{"year":2017,"finding":"Morpholino-mediated knockdown of NUP43 in zebrafish caused cardiac abnormalities including pericardial edema and heart failure, identifying NUP43 as a candidate gene for cardiovascular disease.","method":"Morpholino knockdown in zebrafish embryos, whole exome sequencing (truncating variant identified in patient)","journal":"Circulation. Cardiovascular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo loss-of-function with defined cardiac phenotype, supported by human variant; single study","pmids":["28611029"],"is_preprint":false},{"year":2017,"finding":"Adenosine-to-inosine RNA editing of the NUP43 transcript occurs at constant levels between single mammalian cells, and editing is uncorrelated with nuclear localization or paraspeckle association of the transcript.","method":"inoFISH (single-molecule RNA FISH for edited transcripts), single-cell quantification","journal":"Nature methods","confidence":"Medium","confidence_rationale":"Tier 2 — direct single-cell imaging of edited transcripts; novel method with rigorous controls; single study","pmids":["28604724"],"is_preprint":false},{"year":2021,"finding":"NUP43 and SEH1 are dispensable for pluripotency in mouse embryonic stem cells but are required for normal cell growth rates, viability upon differentiation, and maintenance of proper NPC density. An N-terminally truncated NUP85 mutation (impairing interaction with SEH1) also reduces NPC density but does not affect proliferation or differentiation, indicating that Y-complex integrity rather than NPC number per se is critical for these processes.","method":"CRISPR/Cas9 genome editing in mouse ESCs, flow cytometry, immunofluorescence for NPC density, differentiation assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — clean genetic knockout with multiple orthogonal readouts (growth, differentiation, NPC density), mechanistic dissection via hypomorphic NUP85 allele","pmids":["34037234"],"is_preprint":false},{"year":2019,"finding":"NUP43 is a direct target gene of miR-409-5p; miR-409-5p negatively regulates NUP43 expression, and NUP43 knockdown inhibits CML cell proliferation and arrests the cell cycle in G0/G1, implicating NUP43 in cell cycle progression in leukemia cells.","method":"Dual-luciferase reporter assay (3′-UTR binding), qRT-PCR, Western blot, CCK-8 proliferation assay, flow cytometry cell cycle analysis","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 3 — luciferase 3′-UTR validation plus functional cellular phenotype; single lab, single study","pmids":["31646577"],"is_preprint":false},{"year":2020,"finding":"In gastric cancer cells, the lncRNA NCK1-AS1 acts as a sponge for miR-137, thereby upregulating NUP43 expression; elevated NUP43 promotes gastric cancer cell proliferation, migration, and invasion, and tumor growth in vivo.","method":"Luciferase reporter assay, RNA immunoprecipitation (RIP), siRNA knockdown, rescue experiments, xenograft mouse model","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 3 — multiple orthogonal methods (RIP, luciferase, rescue) establishing the ceRNA axis; single lab","pmids":["33116577"],"is_preprint":false},{"year":2024,"finding":"NUP43 promotes PD-L1 nuclear translocation in colorectal cancer by regulating the expression of the PD-L1 chaperone protein IPO5; nuclear PD-L1 then stimulates TM4SF1 expression, activates the JAK/STAT3 signaling pathway, and transcriptionally enhances PD-L1 expression, establishing a PD-L1–nPD-L1–PD-L1 feedback loop that promotes CRC progression and liver metastasis.","method":"CRISPR-Cas9 genome-wide screening combined with RNA-seq, loss-of-function experiments, rescue experiments, nuclear fractionation, western blot, in vivo metastasis models","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide CRISPR screen plus mechanistic follow-up; single lab, multiple orthogonal readouts","pmids":["38762481"],"is_preprint":false},{"year":2025,"finding":"NUP43 and NUP107, as members of the NPC Y-complex, localize to DNA double-strand break (DSB) sites in a manner interdependent with PHC2 (a PRC1 subunit); depletion of NUP43 disrupts DSB-induced transcriptional gene silencing, revealing a cooperative role between nucleoporins and Polycomb repressive complex 1 in DNA damage-induced transcriptional repression and genome stability.","method":"Interactome analysis (PHC2 pulldown), siRNA knockdown, ChIP/DSB localization assays, reporter-based transcriptional silencing assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — multiple complementary methods; interdependency between NUP43 and PHC2 at DSBs established; single study","pmids":["40440073"],"is_preprint":false},{"year":2025,"finding":"In Drosophila, Nup43 is essential for fertility in both sexes; in males, loss of Nup43 arrests spermiogenesis at the canoe stage, impairing nuclear elongation, nuclear shaping, and actin cone assembly during individualization complex formation. Myosin VI (jar) interacts physically with Nup43 and rescues actin cone assembly (but not sterility) in Nup43 null mutants, revealing a non-canonical role for Nup43 in actin-based sperm individualization.","method":"Drosophila null mutant generation, transgene rescue, co-immunoprecipitation (Nup43–Myosin VI interaction), fluorescence imaging of actin cones and nuclei","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genetic null + transgene rescue + Co-IP for binding partner; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.09.29.679220"],"is_preprint":true}],"current_model":"NUP43 is a WD-repeat nucleoporin and core member of the conserved Nup107-160/Y-complex of the nuclear pore complex; it directly interacts with NUP85, is required for proper NPC density, localizes to kinetochores during mitosis for proper chromosome segregation, and localizes to DNA double-strand break sites where it cooperates with Polycomb repressive complex 1 to promote transcriptional silencing; beyond its canonical NPC role, NUP43 regulates PD-L1 nuclear translocation via IPO5 and the JAK/STAT3 pathway in colorectal cancer, is targeted by miR-409-5p and the NCK1-AS1/miR-137 ceRNA axis to modulate cell proliferation, and plays a non-canonical role in actin cone assembly during Drosophila spermiogenesis through interaction with Myosin VI."},"narrative":{"teleology":[{"year":2004,"claim":"Identification of NUP43 as a new WD-repeat nucleoporin within the Nup107-160 complex and its mitotic targeting to kinetochores established the gene's dual nuclear pore and cell-division functions.","evidence":"Biochemical co-purification, GFP-tagging, RNAi, and immunofluorescence in human cells","pmids":["15146057"],"confidence":"High","gaps":["Direct binding partner within the Y-complex not yet mapped","Functional consequence of kinetochore targeting not determined"]},{"year":2007,"claim":"Defining the mitotic phenotype of Nup107-160 depletion — impaired chromosome congression, reduced kinetochore tension, and loss of Crm1/RanGAP1–RanBP2 recruitment — showed that the complex (including NUP43) is essential for kinetochore–microtubule attachment fidelity.","evidence":"siRNA knockdown of multiple Y-complex subunits, Co-IP, live-cell imaging, kinetochore tension assays","pmids":["17363900"],"confidence":"High","gaps":["Specific contribution of NUP43 versus other Y-complex subunits to kinetochore function not individually resolved","Mechanism by which the complex recruits Crm1 and RanBP2 unclear"]},{"year":2014,"claim":"BioID proximity labeling in living cells mapped a direct NUP43–NUP85 interaction, refining the molecular architecture of the Y-complex and positioning NUP43 within the subcomplex.","evidence":"BioID proximity-dependent biotinylation with mass spectrometry","pmids":["24927568"],"confidence":"High","gaps":["Structural details of the NUP43–NUP85 interface unresolved","Whether NUP43 contacts other Y-complex members beyond NUP85 not addressed"]},{"year":2017,"claim":"Morpholino knockdown in zebrafish linked NUP43 loss-of-function to cardiac defects, connecting Y-complex integrity to cardiovascular development in vivo.","evidence":"Morpholino knockdown in zebrafish embryos, corroborated by a truncating human variant from whole-exome sequencing","pmids":["28611029"],"confidence":"Medium","gaps":["Single morpholino study without genetic mutant confirmation","Mechanism connecting NPC function to cardiac morphogenesis unknown","Human variant causality not formally proven by segregation or rescue"]},{"year":2021,"claim":"CRISPR knockout in mouse ESCs showed NUP43 is dispensable for pluripotency but required for normal NPC density, growth rate, and viability upon differentiation, separating Y-complex integrity from NPC number in controlling cell fate.","evidence":"CRISPR/Cas9 knockout in mouse ESCs with flow cytometry, immunofluorescence for NPC density, and differentiation assays","pmids":["34037234"],"confidence":"High","gaps":["Whether NUP43 loss alters specific transport pathways during differentiation unknown","Contribution of reduced NPC density versus altered gene expression not separated"]},{"year":2024,"claim":"A genome-wide CRISPR screen in colorectal cancer uncovered a non-canonical role for NUP43 in promoting PD-L1 nuclear translocation via regulation of the karyopherin IPO5, establishing a PD-L1/nPD-L1/JAK-STAT3 feedback loop that drives metastasis.","evidence":"CRISPR-Cas9 screen combined with RNA-seq, nuclear fractionation, rescue experiments, and in vivo metastasis models in CRC cells","pmids":["38762481"],"confidence":"Medium","gaps":["Whether NUP43 regulates IPO5 transcriptionally or post-transcriptionally not resolved","Generalizability beyond colorectal cancer not tested","Whether this function depends on Y-complex membership unclear"]},{"year":2025,"claim":"Discovery that NUP43 localizes to DNA double-strand break sites interdependently with PRC1 subunit PHC2 and is required for DSB-induced transcriptional silencing extended the gene's function to genome stability maintenance.","evidence":"PHC2 interactome pulldown, siRNA knockdown, ChIP-based DSB localization, and reporter-based transcriptional silencing assays","pmids":["40440073"],"confidence":"Medium","gaps":["Mechanism of NUP43 recruitment to DSBs not defined","Whether other Y-complex subunits co-localize at DSBs not fully addressed","Relationship between NPC-associated and DSB-associated NUP43 pools unclear"]},{"year":null,"claim":"Major open questions include: how NUP43 is partitioned among its NPC, kinetochore, and DSB-associated pools; whether the cancer-associated functions (PD-L1 translocation, proliferation control) are mechanistically linked to its Y-complex role; and whether the cardiac phenotype seen in zebrafish reflects a conserved developmental function in mammals.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of NUP43 in the context of the human Y-complex","Separation-of-function alleles distinguishing NPC from non-NPC roles not generated","No mammalian in vivo knockout model phenotyped comprehensively"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,5]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5,9]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[5,8]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[9]}],"complexes":["Nup107-160 complex (Y-complex)"],"partners":["NUP85","NUP107","SEH1L","CENP-F","PHC2","IPO5"],"other_free_text":[]},"mechanistic_narrative":"NUP43 is a WD-repeat nucleoporin and stable subunit of the Nup107-160 (Y-complex) of the nuclear pore complex, with roles spanning nucleocytoplasmic transport, mitotic chromosome segregation, and DNA damage-induced transcriptional silencing. Within the Y-complex it directly contacts NUP85 and is required for normal NPC density and cell viability upon differentiation, though it is dispensable for pluripotency in mouse embryonic stem cells [PMID:15146057, PMID:24927568, PMID:34037234]. During mitosis, NUP43 localizes to kinetochores where the Nup107-160 complex interacts with CENP-F and the Ndc80 complex to support chromosome congression, kinetochore–microtubule attachment, and recruitment of Crm1 and RanGAP1–RanBP2 [PMID:17363900]. At DNA double-strand breaks, NUP43 cooperates with Polycomb repressive complex 1 subunit PHC2 to enforce damage-induced transcriptional gene silencing, and in colorectal cancer it facilitates PD-L1 nuclear translocation through regulation of the karyopherin IPO5, feeding a JAK/STAT3-dependent PD-L1 amplification loop that promotes metastasis [PMID:40440073, PMID:38762481]."},"prefetch_data":{"uniprot":{"accession":"Q8NFH3","full_name":"Nucleoporin Nup43","aliases":["Nup107-160 subcomplex subunit Nup43","p42"],"length_aa":380,"mass_kda":42.2,"function":"Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC. The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation","subcellular_location":"Chromosome, centromere, kinetochore; Nucleus, nuclear pore complex","url":"https://www.uniprot.org/uniprotkb/Q8NFH3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NUP43","classification":"Common Essential","n_dependent_lines":1132,"n_total_lines":1208,"dependency_fraction":0.9370860927152318},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCT2","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NUP43","total_profiled":1310},"omim":[{"mim_id":"609264","title":"NUCLEOPORIN, 37-KD; NUP37","url":"https://www.omim.org/entry/609264"},{"mim_id":"609263","title":"SEH1-LIKE PROTEIN; SEH1L","url":"https://www.omim.org/entry/609263"},{"mim_id":"608141","title":"NUCLEOPORIN, 43-KD; NUP43","url":"https://www.omim.org/entry/608141"},{"mim_id":"607617","title":"NUCLEOPORIN, 107-KD; NUP107","url":"https://www.omim.org/entry/607617"},{"mim_id":"607614","title":"NUCLEOPORIN, 160-KD; NUP160","url":"https://www.omim.org/entry/607614"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NUP43"},"hgnc":{"alias_symbol":["bA350J20.1","FLJ13287"],"prev_symbol":[]},"alphafold":{"accession":"Q8NFH3","domains":[{"cath_id":"-","chopping":"12-110","consensus_level":"medium","plddt":88.1282,"start":12,"end":110}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFH3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFH3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFH3-F1-predicted_aligned_error_v6.png","plddt_mean":85.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUP43","jax_strain_url":"https://www.jax.org/strain/search?query=NUP43"},"sequence":{"accession":"Q8NFH3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NFH3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NFH3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFH3"}},"corpus_meta":[{"pmid":"24927568","id":"PMC_24927568","title":"Probing nuclear pore complex architecture with proximity-dependent biotinylation.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24927568","citation_count":432,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15146057","id":"PMC_15146057","title":"The entire Nup107-160 complex, including three new members, is targeted as one entity to kinetochores in mitosis.","date":"2004","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15146057","citation_count":223,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28611029","id":"PMC_28611029","title":"Whole Exome Sequencing Identifies Truncating Variants in Nuclear Envelope Genes in Patients With Cardiovascular Disease.","date":"2017","source":"Circulation. 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 \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NUP43 directly interacts with NUP85 within the Nup107-160 complex, as demonstrated by BioID proximity-dependent biotinylation in living human cells.\",\n      \"method\": \"BioID (proximity-dependent biotin identification) with NUP85 as bait, mass spectrometry identification of biotinylated proximate proteins\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — BioID proximity labeling in living cells, single lab but orthogonal to co-fractionation data\",\n      \"pmids\": [\"24927568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NUP43 (along with Seh1) is dispensable for pluripotency in mouse embryonic stem cells but is required for normal cell growth rates, viability upon differentiation, and maintenance of proper NPC density; N-terminally truncated Nup85 (which impairs Seh1 interaction) reduces NPC density but does not affect proliferation or differentiation, indicating that Y-complex integrity rather than NPC number is critical for these processes.\",\n      \"method\": \"Genome editing (CRISPR) in mouse embryonic stem cells, growth assays, differentiation assays, NPC density quantification\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotypes using orthogonal readouts (growth, differentiation, NPC density), multiple genetic conditions tested\",\n      \"pmids\": [\"34037234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Morpholino-mediated knockdown of NUP43 in zebrafish causes cardiac abnormalities including pericardial edema and heart failure, implicating NUP43 in cardiac development.\",\n      \"method\": \"Morpholino knockdown in zebrafish embryos with morphological readout (pericardial edema, heart failure)\",\n      \"journal\": \"Circulation. Cardiovascular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function in vivo model with defined cardiac phenotype\",\n      \"pmids\": [\"28611029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUP43 promotes PD-L1 nuclear translocation in colorectal cancer cells by regulating expression of the PD-L1 chaperone IPO5; nuclear PD-L1 then stimulates TM4SF1 expression, activates the JAK/STAT3 pathway, and transcriptionally upregulates PD-L1, establishing a PD-L1–nPD-L1–PD-L1 feedback loop that promotes tumor progression and liver metastasis.\",\n      \"method\": \"CRISPR-Cas9 genome-wide screening, RNA-seq, NUP43 knockdown/overexpression, IPO5 regulation assays, JAK/STAT3 pathway analysis, in vitro and in vivo tumor models\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen followed by mechanistic pathway validation with multiple orthogonal approaches in one lab\",\n      \"pmids\": [\"38762481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NUP43 and NUP107 (members of the NPC Y-complex) localize to DNA double-strand break (DSB) sites, cooperate with PRC1 subunit PHC2 in DSB-induced transcriptional silencing, and their presence at DSB regions is interdependent with PHC2 localization.\",\n      \"method\": \"Interactome analysis of PHC2, nucleoporin depletion, ChIP/localization at DSB sites, epistasis between nucleoporins and PRC1 components\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal localization and depletion experiments with functional silencing readout, single lab\",\n      \"pmids\": [\"40440073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Drosophila, Nup43 is required for male and female fertility; in males, loss of Nup43 arrests spermiogenesis at the canoe stage with defects in nuclear elongation/shaping and actin cone assembly during individualization complex formation; Myosin VI (jar) physically interacts with Nup43 and rescues actin cone assembly but not overall sterility, revealing a non-canonical role for Nup43 in actin-based spermiogenesis.\",\n      \"method\": \"Nup43 null mutant analysis, transgene rescue, Co-IP/interaction assay with Myosin VI, actin cone assembly assays in Drosophila testes\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — null mutant with transgene rescue and protein interaction, but preprint/not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.29.679220\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miRNA-409-5p directly targets the 3'-UTR of NUP43 mRNA (validated by dual-luciferase reporter assay) and negatively regulates NUP43 expression; NUP43 knockdown in CML cells inhibits proliferation and arrests cell cycle in G0/G1, with reduced PCNA, c-Myc, and cyclin D1 levels.\",\n      \"method\": \"Dual-luciferase reporter assay, miRNA mimic/inhibitor transfection, cell proliferation and cell cycle assays, Western blot\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — luciferase validation of miRNA-mRNA interaction plus functional KD phenotype, single lab\",\n      \"pmids\": [\"31646577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LncRNA NCK1-AS1 acts as a sponge for miR-137, thereby upregulating NUP43 expression in gastric cancer cells; this NCK1-AS1/miR-137/NUP43 axis promotes cancer cell proliferation, migration, and invasion.\",\n      \"method\": \"Luciferase reporter assay, RNA immunoprecipitation, rescue experiments, siRNA knockdown, in vivo tumor model\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — luciferase and RIP validation of ceRNA mechanism, rescue experiments, single lab\",\n      \"pmids\": [\"33116577\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP43 is an integral structural component of the Nup107-160 (Y-complex) subcomplex of the nuclear pore complex, directly interacting with NUP85, and is required for NPC density maintenance, cell growth, and differentiation; the complex localizes to kinetochores during mitosis; NUP43 also cooperates with Polycomb PRC1 components at DNA double-strand break sites to promote transcriptional silencing; it regulates PD-L1 nuclear translocation via IPO5 to activate a JAK/STAT3-driven feedback loop in cancer cells; and in Drosophila it plays a non-canonical role in actin cone assembly during spermiogenesis via interaction with Myosin VI.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"NUP43 was identified as a new WD-repeat nucleoporin and member of the Nup107-160 complex, specific to higher eukaryotes. All constituents of the Nup107-160 complex, including NUP43, are targeted to kinetochores from prophase to anaphase of mitosis.\",\n      \"method\": \"Biochemical co-purification, GFP-tagging, RNAi knockdown, immunofluorescence microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal biochemical isolation, live-cell imaging, and functional knockdown across multiple nucleoporins; foundational paper with 223 citations\",\n      \"pmids\": [\"15146057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The Nup107-160 complex (of which NUP43 is a constituent) interacts with CENP-F and the Ndc80 complex for kinetochore targeting; efficient depletion of the complex induces mitotic delay, impaired chromosome congression, reduced kinetochore tension, and kinetochore-microtubule attachment defects, and the complex is required for recruitment of Crm1 and RanGAP1-RanBP2 to kinetochores.\",\n      \"method\": \"siRNA knockdown of multiple Nup107-160 subunits including NUP43 components, co-immunoprecipitation, live-cell imaging, kinetochore tension assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with multiple siRNAs, Co-IP for binding partners, quantitative kinetochore phenotyping; replicated context with 171 citations\",\n      \"pmids\": [\"17363900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BioID proximity labeling demonstrated a direct interaction of NUP43 with NUP85 within the Nup107-160 subcomplex, refining the molecular architecture of this conserved NPC subcomplex.\",\n      \"method\": \"BioID (proximity-dependent biotin identification) in living cells, streptavidin affinity purification, mass spectrometry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo proximity labeling with the Nup107-160 complex used as a molecular ruler; strong mechanistic follow-up; 432 citations\",\n      \"pmids\": [\"24927568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Morpholino-mediated knockdown of NUP43 in zebrafish caused cardiac abnormalities including pericardial edema and heart failure, identifying NUP43 as a candidate gene for cardiovascular disease.\",\n      \"method\": \"Morpholino knockdown in zebrafish embryos, whole exome sequencing (truncating variant identified in patient)\",\n      \"journal\": \"Circulation. Cardiovascular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with defined cardiac phenotype, supported by human variant; single study\",\n      \"pmids\": [\"28611029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Adenosine-to-inosine RNA editing of the NUP43 transcript occurs at constant levels between single mammalian cells, and editing is uncorrelated with nuclear localization or paraspeckle association of the transcript.\",\n      \"method\": \"inoFISH (single-molecule RNA FISH for edited transcripts), single-cell quantification\",\n      \"journal\": \"Nature methods\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct single-cell imaging of edited transcripts; novel method with rigorous controls; single study\",\n      \"pmids\": [\"28604724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NUP43 and SEH1 are dispensable for pluripotency in mouse embryonic stem cells but are required for normal cell growth rates, viability upon differentiation, and maintenance of proper NPC density. An N-terminally truncated NUP85 mutation (impairing interaction with SEH1) also reduces NPC density but does not affect proliferation or differentiation, indicating that Y-complex integrity rather than NPC number per se is critical for these processes.\",\n      \"method\": \"CRISPR/Cas9 genome editing in mouse ESCs, flow cytometry, immunofluorescence for NPC density, differentiation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic knockout with multiple orthogonal readouts (growth, differentiation, NPC density), mechanistic dissection via hypomorphic NUP85 allele\",\n      \"pmids\": [\"34037234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NUP43 is a direct target gene of miR-409-5p; miR-409-5p negatively regulates NUP43 expression, and NUP43 knockdown inhibits CML cell proliferation and arrests the cell cycle in G0/G1, implicating NUP43 in cell cycle progression in leukemia cells.\",\n      \"method\": \"Dual-luciferase reporter assay (3′-UTR binding), qRT-PCR, Western blot, CCK-8 proliferation assay, flow cytometry cell cycle analysis\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — luciferase 3′-UTR validation plus functional cellular phenotype; single lab, single study\",\n      \"pmids\": [\"31646577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In gastric cancer cells, the lncRNA NCK1-AS1 acts as a sponge for miR-137, thereby upregulating NUP43 expression; elevated NUP43 promotes gastric cancer cell proliferation, migration, and invasion, and tumor growth in vivo.\",\n      \"method\": \"Luciferase reporter assay, RNA immunoprecipitation (RIP), siRNA knockdown, rescue experiments, xenograft mouse model\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — multiple orthogonal methods (RIP, luciferase, rescue) establishing the ceRNA axis; single lab\",\n      \"pmids\": [\"33116577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUP43 promotes PD-L1 nuclear translocation in colorectal cancer by regulating the expression of the PD-L1 chaperone protein IPO5; nuclear PD-L1 then stimulates TM4SF1 expression, activates the JAK/STAT3 signaling pathway, and transcriptionally enhances PD-L1 expression, establishing a PD-L1–nPD-L1–PD-L1 feedback loop that promotes CRC progression and liver metastasis.\",\n      \"method\": \"CRISPR-Cas9 genome-wide screening combined with RNA-seq, loss-of-function experiments, rescue experiments, nuclear fractionation, western blot, in vivo metastasis models\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide CRISPR screen plus mechanistic follow-up; single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"38762481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NUP43 and NUP107, as members of the NPC Y-complex, localize to DNA double-strand break (DSB) sites in a manner interdependent with PHC2 (a PRC1 subunit); depletion of NUP43 disrupts DSB-induced transcriptional gene silencing, revealing a cooperative role between nucleoporins and Polycomb repressive complex 1 in DNA damage-induced transcriptional repression and genome stability.\",\n      \"method\": \"Interactome analysis (PHC2 pulldown), siRNA knockdown, ChIP/DSB localization assays, reporter-based transcriptional silencing assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple complementary methods; interdependency between NUP43 and PHC2 at DSBs established; single study\",\n      \"pmids\": [\"40440073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Drosophila, Nup43 is essential for fertility in both sexes; in males, loss of Nup43 arrests spermiogenesis at the canoe stage, impairing nuclear elongation, nuclear shaping, and actin cone assembly during individualization complex formation. Myosin VI (jar) interacts physically with Nup43 and rescues actin cone assembly (but not sterility) in Nup43 null mutants, revealing a non-canonical role for Nup43 in actin-based sperm individualization.\",\n      \"method\": \"Drosophila null mutant generation, transgene rescue, co-immunoprecipitation (Nup43–Myosin VI interaction), fluorescence imaging of actin cones and nuclei\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic null + transgene rescue + Co-IP for binding partner; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.29.679220\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NUP43 is a WD-repeat nucleoporin and core member of the conserved Nup107-160/Y-complex of the nuclear pore complex; it directly interacts with NUP85, is required for proper NPC density, localizes to kinetochores during mitosis for proper chromosome segregation, and localizes to DNA double-strand break sites where it cooperates with Polycomb repressive complex 1 to promote transcriptional silencing; beyond its canonical NPC role, NUP43 regulates PD-L1 nuclear translocation via IPO5 and the JAK/STAT3 pathway in colorectal cancer, is targeted by miR-409-5p and the NCK1-AS1/miR-137 ceRNA axis to modulate cell proliferation, and plays a non-canonical role in actin cone assembly during Drosophila spermiogenesis through interaction with Myosin VI.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NUP43 is a structural subunit of the Nup107-160 (Y-complex) of the nuclear pore complex that functions in nuclear envelope architecture, mitotic kinetochore organization, DNA damage-associated transcriptional silencing, and cell proliferation. Within the Y-complex, NUP43 directly interacts with NUP85 and localizes to kinetochores from prophase to anaphase; genetic ablation in mouse embryonic stem cells demonstrates that NUP43 is dispensable for pluripotency but required for normal cell growth, viability upon differentiation, and maintenance of NPC density [PMID:15146057, PMID:24927568, PMID:34037234]. At DNA double-strand breaks, NUP43 cooperates with the PRC1 subunit PHC2 to enforce DSB-induced transcriptional silencing, with interdependent recruitment of nucleoporins and Polycomb components to damage sites [PMID:40440073]. NUP43 also regulates PD-L1 nuclear translocation through control of the nuclear import receptor IPO5, activating a JAK/STAT3-driven feedback loop that promotes colorectal cancer progression [PMID:38762481].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of NUP43 as a novel Y-complex subunit resolved how the Nup107-160 complex is composed in vertebrates and established that the entire complex relocates to kinetochores during mitosis, linking NPC biology to chromosome segregation.\",\n      \"evidence\": \"Biochemical co-fractionation, GFP live imaging of tagged nucleoporins, antibody localization, and RNAi in human cells\",\n      \"pmids\": [\"15146057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding partner of NUP43 within the Y-complex was not determined\",\n        \"Functional consequence of NUP43 loss on NPC assembly or cell viability was not tested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that NUP43 directly interacts with NUP85 via proximity labeling in living cells defined NUP43's position within the Y-complex architecture.\",\n      \"evidence\": \"BioID proximity-dependent biotinylation with NUP85 as bait followed by mass spectrometry in human cells\",\n      \"pmids\": [\"24927568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"BioID reports proximity rather than direct binding; no orthogonal binary interaction assay was performed\",\n        \"Structural basis of the NUP43-NUP85 interface was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Knockdown of NUP43 in zebrafish revealed a requirement in cardiac development, extending the gene's roles beyond NPC/kinetochore function to organogenesis.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish embryos with morphological assessment of cardiac phenotype\",\n      \"pmids\": [\"28611029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Morpholino off-target effects were not fully excluded by genetic rescue\",\n        \"Molecular mechanism linking NUP43 loss to cardiac defects was not elucidated\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Validation of NUP43 as a direct target of miR-409-5p, whose knockdown arrests CML cells in G0/G1, established NUP43 as a cell-cycle-promoting factor in leukemia.\",\n      \"evidence\": \"Dual-luciferase reporter assay, miRNA mimic/inhibitor transfection, cell cycle and proliferation assays in CML cells\",\n      \"pmids\": [\"31646577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab observation without independent replication\",\n        \"Whether NUP43's proliferative role acts through NPC-dependent or NPC-independent mechanisms was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery of the lncRNA NCK1-AS1/miR-137/NUP43 ceRNA axis in gastric cancer demonstrated that NUP43 expression is regulated by competing endogenous RNA networks to promote tumor cell proliferation and invasion.\",\n      \"evidence\": \"Luciferase reporter assay, RNA immunoprecipitation, rescue experiments, and in vivo tumor models in gastric cancer cells\",\n      \"pmids\": [\"33116577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream effectors of NUP43 overexpression in gastric cancer were not identified\",\n        \"Specificity of the axis to gastric cancer versus other tumor types was not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CRISPR knockout in mouse ES cells resolved a longstanding question about Y-complex subunit dispensability, showing NUP43 is not needed for pluripotency but is essential for growth, differentiation viability, and NPC density — and that Y-complex integrity, rather than NPC number per se, is the critical variable.\",\n      \"evidence\": \"CRISPR-mediated NUP43 and Seh1 knockout in mouse ES cells with growth, differentiation, and NPC density quantification\",\n      \"pmids\": [\"34037234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether NUP43 loss affects specific gene transport or chromatin organization was not examined\",\n        \"Tissue-specific consequences of NUP43 loss in vivo in mammals remain untested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Genome-wide CRISPR screening identified NUP43 as a regulator of PD-L1 nuclear translocation via IPO5, revealing a non-canonical nucleoporin function in immune evasion signaling through a JAK/STAT3 feedback loop in colorectal cancer.\",\n      \"evidence\": \"CRISPR-Cas9 genome-wide screen, RNA-seq, NUP43 knockdown/overexpression, IPO5 regulation, and in vivo tumor/metastasis models\",\n      \"pmids\": [\"38762481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether NUP43 regulates IPO5 transcriptionally or post-transcriptionally was not fully dissected\",\n        \"Generalizability of the NUP43-PD-L1 axis to other cancer types was not tested\",\n        \"Whether this function depends on NUP43's incorporation into the NPC was not determined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Localization of NUP43 to DNA double-strand break sites and its interdependent recruitment with PRC1 subunit PHC2 established an NPC-independent chromatin-regulatory role for Y-complex nucleoporins in DSB-induced transcriptional silencing.\",\n      \"evidence\": \"PHC2 interactome analysis, nucleoporin depletion, ChIP at DSB sites, and transcriptional silencing assays in human cells\",\n      \"pmids\": [\"40440073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether NUP43 acts at DSBs as part of the intact Y-complex or independently was not resolved\",\n        \"The signal that recruits NUP43 to DSB sites is unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A Drosophila Nup43 null mutant revealed a non-canonical requirement in spermiogenesis for nuclear shaping and actin cone assembly, with Myosin VI (jar) as a physical interactor that partially rescues the actin phenotype.\",\n      \"evidence\": \"Null mutant analysis, transgene rescue, co-immunoprecipitation with Myosin VI, actin cone assays in Drosophila testes (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.29.679220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint not yet peer-reviewed\",\n        \"How NUP43 interfaces with the actin machinery mechanistically is undefined\",\n        \"Conservation of this spermiogenesis role in mammals is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether NUP43's emerging NPC-independent functions (DSB silencing, PD-L1 nuclear import regulation, actin-based spermiogenesis) operate through the intact Y-complex or through a separate soluble pool, and no high-resolution structural model of NUP43 within the human Y-complex has been reported.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No atomic-resolution structure of NUP43 in the human Y-complex context\",\n        \"NPC-dependent versus NPC-independent pools of NUP43 have not been biochemically separated\",\n        \"In vivo mammalian phenotyping of NUP43 loss is lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"Nup107-160 complex (Y-complex)\"\n    ],\n    \"partners\": [\n      \"NUP85\",\n      \"NUP107\",\n      \"NUP37\",\n      \"SEH1L\",\n      \"PHC2\",\n      \"IPO5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"NUP43 is a WD-repeat nucleoporin and stable subunit of the Nup107-160 (Y-complex) of the nuclear pore complex, with roles spanning nucleocytoplasmic transport, mitotic chromosome segregation, and DNA damage-induced transcriptional silencing. Within the Y-complex it directly contacts NUP85 and is required for normal NPC density and cell viability upon differentiation, though it is dispensable for pluripotency in mouse embryonic stem cells [PMID:15146057, PMID:24927568, PMID:34037234]. During mitosis, NUP43 localizes to kinetochores where the Nup107-160 complex interacts with CENP-F and the Ndc80 complex to support chromosome congression, kinetochore–microtubule attachment, and recruitment of Crm1 and RanGAP1–RanBP2 [PMID:17363900]. At DNA double-strand breaks, NUP43 cooperates with Polycomb repressive complex 1 subunit PHC2 to enforce damage-induced transcriptional gene silencing, and in colorectal cancer it facilitates PD-L1 nuclear translocation through regulation of the karyopherin IPO5, feeding a JAK/STAT3-dependent PD-L1 amplification loop that promotes metastasis [PMID:40440073, PMID:38762481].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of NUP43 as a new WD-repeat nucleoporin within the Nup107-160 complex and its mitotic targeting to kinetochores established the gene's dual nuclear pore and cell-division functions.\",\n      \"evidence\": \"Biochemical co-purification, GFP-tagging, RNAi, and immunofluorescence in human cells\",\n      \"pmids\": [\"15146057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding partner within the Y-complex not yet mapped\",\n        \"Functional consequence of kinetochore targeting not determined\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defining the mitotic phenotype of Nup107-160 depletion — impaired chromosome congression, reduced kinetochore tension, and loss of Crm1/RanGAP1–RanBP2 recruitment — showed that the complex (including NUP43) is essential for kinetochore–microtubule attachment fidelity.\",\n      \"evidence\": \"siRNA knockdown of multiple Y-complex subunits, Co-IP, live-cell imaging, kinetochore tension assays\",\n      \"pmids\": [\"17363900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific contribution of NUP43 versus other Y-complex subunits to kinetochore function not individually resolved\",\n        \"Mechanism by which the complex recruits Crm1 and RanBP2 unclear\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"BioID proximity labeling in living cells mapped a direct NUP43–NUP85 interaction, refining the molecular architecture of the Y-complex and positioning NUP43 within the subcomplex.\",\n      \"evidence\": \"BioID proximity-dependent biotinylation with mass spectrometry\",\n      \"pmids\": [\"24927568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural details of the NUP43–NUP85 interface unresolved\",\n        \"Whether NUP43 contacts other Y-complex members beyond NUP85 not addressed\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Morpholino knockdown in zebrafish linked NUP43 loss-of-function to cardiac defects, connecting Y-complex integrity to cardiovascular development in vivo.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish embryos, corroborated by a truncating human variant from whole-exome sequencing\",\n      \"pmids\": [\"28611029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single morpholino study without genetic mutant confirmation\",\n        \"Mechanism connecting NPC function to cardiac morphogenesis unknown\",\n        \"Human variant causality not formally proven by segregation or rescue\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CRISPR knockout in mouse ESCs showed NUP43 is dispensable for pluripotency but required for normal NPC density, growth rate, and viability upon differentiation, separating Y-complex integrity from NPC number in controlling cell fate.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in mouse ESCs with flow cytometry, immunofluorescence for NPC density, and differentiation assays\",\n      \"pmids\": [\"34037234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether NUP43 loss alters specific transport pathways during differentiation unknown\",\n        \"Contribution of reduced NPC density versus altered gene expression not separated\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A genome-wide CRISPR screen in colorectal cancer uncovered a non-canonical role for NUP43 in promoting PD-L1 nuclear translocation via regulation of the karyopherin IPO5, establishing a PD-L1/nPD-L1/JAK-STAT3 feedback loop that drives metastasis.\",\n      \"evidence\": \"CRISPR-Cas9 screen combined with RNA-seq, nuclear fractionation, rescue experiments, and in vivo metastasis models in CRC cells\",\n      \"pmids\": [\"38762481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether NUP43 regulates IPO5 transcriptionally or post-transcriptionally not resolved\",\n        \"Generalizability beyond colorectal cancer not tested\",\n        \"Whether this function depends on Y-complex membership unclear\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that NUP43 localizes to DNA double-strand break sites interdependently with PRC1 subunit PHC2 and is required for DSB-induced transcriptional silencing extended the gene's function to genome stability maintenance.\",\n      \"evidence\": \"PHC2 interactome pulldown, siRNA knockdown, ChIP-based DSB localization, and reporter-based transcriptional silencing assays\",\n      \"pmids\": [\"40440073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of NUP43 recruitment to DSBs not defined\",\n        \"Whether other Y-complex subunits co-localize at DSBs not fully addressed\",\n        \"Relationship between NPC-associated and DSB-associated NUP43 pools unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include: how NUP43 is partitioned among its NPC, kinetochore, and DSB-associated pools; whether the cancer-associated functions (PD-L1 translocation, proliferation control) are mechanistically linked to its Y-complex role; and whether the cardiac phenotype seen in zebrafish reflects a conserved developmental function in mammals.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of NUP43 in the context of the human Y-complex\",\n        \"Separation-of-function alleles distinguishing NPC from non-NPC roles not generated\",\n        \"No mammalian in vivo knockout model phenotyped comprehensively\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\n      \"Nup107-160 complex (Y-complex)\"\n    ],\n    \"partners\": [\n      \"NUP85\",\n      \"NUP107\",\n      \"SEH1L\",\n      \"CENP-F\",\n      \"PHC2\",\n      \"IPO5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}