{"gene":"NUP98","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1999,"finding":"NUP98 and NUP96 are both generated by autoproteolytic cleavage of a 186-kDa precursor protein; proteolytic cleavage is required for correct targeting of both NUP98 and NUP96 to the nucleoplasmic side of the NPC, and a complex containing NUP96, NUP107, and Sec13-related proteins was identified as a conserved NPC subcomplex.","method":"Biochemical fractionation of rat liver nuclei, mutational analysis, immunoelectron microscopy, in vitro autoproteolytic cleavage assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, mutagenesis, and immunoelectron microscopy in a single rigorous study; evolutionary conservation confirmed with yeast Nup145p","pmids":["10087256"],"is_preprint":false},{"year":1997,"finding":"Nuclear injection of anti-Nup98 antibodies in Xenopus oocytes inhibits export of snRNAs, 5S RNA, large ribosomal RNAs, and mRNA, but not tRNA, and does not affect import of karyophilic proteins or snRNPs, establishing Nup98 as an essential component of multiple RNA export pathways but not protein import.","method":"Antibody injection into Xenopus laevis oocyte nucleus with functional RNA export assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vivo functional blocking experiment with monospecific antibodies, multiple RNA classes tested, clear positive and negative results","pmids":["9015297"],"is_preprint":false},{"year":2002,"finding":"Nup98 is found both at the nuclear pore complex and within the nucleus at a novel intranuclear structure termed the GLFG body; the GLFG domain of Nup98 is required for targeting to this structure; Nup98 is mobile and moves between these localizations; this mobility is dependent on ongoing transcription by RNA polymerases I and II.","method":"GFP-Nup98 live-cell imaging, FRAP (photobleaching), transcription inhibitor treatments, domain deletion analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — FRAP in living cells combined with domain mutagenesis and pharmacological transcription inhibition; multiple orthogonal methods","pmids":["11950939"],"is_preprint":false},{"year":2003,"finding":"Nup98 is localized on both the nuclear and cytoplasmic faces of the nuclear pore; the pore-targeting domain of Nup98 directly interacts with the cytoplasmic nucleoporin Nup88; the same site within Nup98 binds both Nup88 (cytoplasmic face) and Nup96 (nuclear face); autoproteolytic cleavage of the Nup98 C-terminus is required for both binding interactions.","method":"Immunofluorescence, immunoelectron microscopy, direct binding assays, point mutation blocking cleavage","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — immunoelectron microscopy plus direct binding assays plus mutagenesis; multiple orthogonal methods in one study","pmids":["12589057"],"is_preprint":false},{"year":2001,"finding":"Disruption of murine NUP98 (leaving NUP96 intact) causes inefficient assembly of cytoplasmic-face nucleoporins (NUP358, NUP214, NUP88, p62) into nuclear pores, with these nucleoporins instead associating with annulate lamellae; NUP98-deficient cells show impaired transport receptor-mediated docking and nuclear import of NLS and M9 signal-containing substrates, but not ribosomal protein L23a or U1A import.","method":"Gene targeting in mice, immunofluorescence, nuclear pore import assays with selective cargo classes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple biochemical and functional readouts; selective cargo import tested","pmids":["11248054"],"is_preprint":false},{"year":2005,"finding":"Rae1 and Nup98 form a complex with Cdh1-activated APC (APC-Cdh1) in early mitosis and specifically inhibit APC-Cdh1-mediated ubiquitination of securin; combined Rae1 and Nup98 haploinsufficiency in mice causes premature securin degradation, sister chromatid separation, and severe aneuploidy.","method":"Mouse haploinsufficiency genetics, co-immunoprecipitation of APC-Cdh1 complex, in vitro ubiquitination assay, flow cytometry for aneuploidy","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro ubiquitination assay plus genetic mouse model plus co-IP; multiple orthogonal methods establishing mechanistic inhibition of APC-Cdh1","pmids":["16355229"],"is_preprint":false},{"year":1999,"finding":"The NUP98-HOXA9 fusion protein's FG repeats act as potent transcriptional transactivation domains that physically and functionally interact with transcriptional coactivators CBP and p300; this FG-repeat-mediated transactivation is essential for transformation of NIH 3T3 cells.","method":"NIH 3T3 transformation assay, luciferase reporter transactivation assay, co-immunoprecipitation with CBP/p300, domain deletion/mutation analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP of endogenous CBP/p300 with FG repeats, functional transactivation assays, mutagenesis showing necessity; multiple orthogonal methods","pmids":["9858599"],"is_preprint":false},{"year":2003,"finding":"Nup98, Rae1/Gle2, and TAP form a ternary mRNA export complex; TAP binds with highest affinity to a specific region within the GLFG domain of Nup98 (not all FG repeats equally); Gle2/Rae1 binds Nup98 and TAP at adjacent but overlapping sites, and when Gle2 is bound to Nup98 it can no longer directly interact with TAP.","method":"In vitro binding assays (pulldown), domain mapping, competition binding experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assays with defined domains, single lab, multiple binding pairs tested","pmids":["12637516"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of human Rae1 in complex with the GLEBS motif of Nup98 at 1.65 Å resolution shows Rae1 forms a seven-bladed β-propeller; the C-terminal arm of the Nup98 GLEBS hairpin binds an invariant hydrophobic surface on the top face of Rae1; a tandem glutamate element in the C-terminal arm is critical for complex formation; the Rae1·Nup98 complex possesses single-stranded RNA-binding capability.","method":"X-ray crystallography (1.65 Å), mutagenesis, RNA-binding assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure plus mutagenesis validation plus RNA-binding functional assay in one study","pmids":["20498086"],"is_preprint":false},{"year":1999,"finding":"Nup98 participates in HIV-1 Rev-hCRM1-mediated nuclear export; Rev recruits Nup98 and Nup214 to the nucleolus; FG-repeat domains of Nup98 and Nup214 competitively inhibit Rev/RRE-mediated expression; upon actinomycin D treatment Nup98 (but not Nup214 or Nup153) translocates to the cytoplasm, demonstrating it can act as a soluble factor.","method":"Nucleolar recruitment assays, competitive inhibition reporter assays, immunofluorescence after actinomycin D treatment","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional competition assay plus localization experiments, single lab","pmids":["9847314"],"is_preprint":false},{"year":2001,"finding":"Nup98 associates with the intranuclear filamentous protein network of TPR; in vitro translated TPR binds in vitro translated Nup98, and via Nup98 also associates with Nup96; immunofluorescence shows colocalization of Nup98 and TPR including at perinucleolar sites.","method":"In vitro translation/binding assay, double-immunofluorescence microscopy, immunoelectron microscopy","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding reconstitution plus immunoelectron microscopy, single lab","pmids":["11248057"],"is_preprint":false},{"year":2003,"finding":"Sec13 stably interacts with Nup96 at the nuclear pore complex via its WD repeat region binding to the N-terminal region of Nup96; Sec13 shuttles between intranuclear sites and the cytoplasm; cotransfection of the Sec13-binding domain of Nup96 decreased the mobile pool of Sec13, confirming the interaction in vivo.","method":"Yeast two-hybrid, biochemical assays, immunofluorescence, confocal and immunoelectron microscopy, FRAP, in vivo competition cotransfection","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus biochemical pulldown plus FRAP plus in vivo competition; multiple orthogonal methods","pmids":["14517296"],"is_preprint":false},{"year":2010,"finding":"Nup98 functions as a cofactor for Crm1-mediated nuclear protein export; Nup98 physically and functionally interacts with Crm1 in a RanGTP-dependent manner through its N-terminal FG repeat region; this activity is modulated by RanBP3; cytoplasmic microinjection of anti-Nup98 antibody inhibits Crm1-dependent nuclear export.","method":"Leptomycin B treatment, co-immunoprecipitation (RanGTP-dependent), mutational analysis, microinjection of anti-Nup98 antibodies with nuclear export assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP demonstrating RanGTP dependence, mutagenesis of FG repeats, functional antibody inhibition assay, multiple orthogonal methods","pmids":["20375145"],"is_preprint":false},{"year":2007,"finding":"NUP98-NSD1 fusion protein binds genomic elements adjacent to HoxA7 and HoxA9, maintains H3K36 methylation and histone acetylation at these loci, and prevents EZH2-mediated transcriptional repression of the Hox-A locus; deletion of the NUP98 FG-repeat domain or inactivating mutations in the NSD1 H3K36 methyltransferase activity abrogated both Hox-A gene activation and myeloid progenitor immortalization.","method":"Chromatin immunoprecipitation (ChIP), mutagenesis of catalytic site and FG domain, in vitro immortalization assay, in vivo AML mouse model","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP demonstrating H3K36 methylation maintenance, catalytic site mutagenesis of NSD1, genetic domain deletions, in vivo mouse AML model; multiple orthogonal methods","pmids":["17589499"],"is_preprint":false},{"year":2016,"finding":"NUP98 fusion proteins (NUP98-HOXA9, NUP98-HOXD13, NUP98-NSD1, NUP98-PHF23, NUP98-TOP1) physically interact with the MLL1 and NSL histone-modifying complexes; NUP98-HOXA9 and MLL1 co-occupy Hox gene promoter regions on chromatin; MLL1 is required for proliferation of NUP98-HOXA9 cells and for NUP98-HOXA9-induced gene expression.","method":"Co-immunoprecipitation, ChIP-sequencing, MLL1 genetic inactivation with proliferation and gene expression readouts","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP of multiple NUP98 fusions with MLL1/NSL, ChIP-seq co-occupancy, genetic loss-of-function with defined molecular and cellular phenotypes","pmids":["27889185"],"is_preprint":false},{"year":2013,"finding":"NUP98 associates with developmentally regulated genes in human embryonic stem cells at both the nuclear periphery (pore-embedded) and the nuclear interior (away from pores); overexpression of a dominant-negative NUP98 fragment decreases expression of NUP98-bound genes; two spatial modes of gene regulation are distinguished by gene activation state.","method":"Genome-wide ChIP-seq in human ESCs, dominant-negative NUP98 fragment overexpression with gene expression analysis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus functional dominant-negative experiment, single lab","pmids":["23468646"],"is_preprint":false},{"year":2017,"finding":"In hematopoietic cells, Nup98 binds predominantly to transcription start sites and recruits the Wdr82-Set1A/COMPASS complex, which is required for H3K4me3 deposition; depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and ablates H3K4me3 at adjacent promoters; expression of a leukemogenic NUP98 fusion protein causes mislocalization of H3K4me3 and up-regulation of associated genes.","method":"ChIP-seq, siRNA knockdown of Nup98 and Wdr82 with H3K4me3 and Set1A ChIP, co-immunoprecipitation","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq showing co-occupancy plus genetic depletion experiments demonstrating H3K4me3 loss plus co-IP; multiple orthogonal methods","pmids":["29269482"],"is_preprint":false},{"year":2012,"finding":"Nup98 regulates p21 mRNA levels by a posttranscriptional mechanism in which a complex containing Nup98 and the p21 mRNA 3'UTR protects p21 mRNA from degradation by the exosome; Nup98 is similarly required for expression of the p53 target 14-3-3σ; this function is distinct from NUP98 fusion oncoproteins' activities.","method":"Single-molecule mRNA analysis, conventional mRNA analysis, 3'UTR-Nup98 complex identification, siRNA knockdown, exosome activity assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — single-molecule mRNA analysis plus exosome degradation assay plus RIP (Nup98-3'UTR complex), multiple orthogonal methods identifying posttranscriptional mechanism","pmids":["23102701"],"is_preprint":false},{"year":2020,"finding":"SARS-CoV-2 Orf6 localizes to the nuclear pore complex and directly interacts with the Nup98-Rae1 complex via its C-terminal domain to impair docking of karyopherin/importin cargo complexes, blocking STAT1 and STAT2 nuclear translocation and suppressing interferon-stimulated gene induction; a Met58-to-Arg substitution in Orf6 abolishes binding to Nup98-Rae1 and eliminates its IFN antagonistic function.","method":"Co-immunoprecipitation, nuclear import assays for STAT1/STAT2, immunofluorescence, site-directed mutagenesis (M58R)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP demonstrating direct interaction, functional nuclear import assay, mutagenesis abolishing binding and function; multiple orthogonal methods in one study","pmids":["33097660"],"is_preprint":false},{"year":2021,"finding":"SARS-CoV-2 ORF6 blocks both nuclear import and mRNA nuclear export through interactions with Rae1 and Nup98 that map to the C-terminus of ORF6 (Met58); overexpression of Rae1 restores reporter gene expression in presence of ORF6; SARS-CoV-2 ORF6 more strongly co-purifies with Rae1 and Nup98 than SARS-CoV ORF6.","method":"Co-purification assays, reporter expression assays, nuclear poly(A) RNA accumulation assays, Rae1 overexpression rescue, M58 mutagenesis","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-purification with mutagenesis plus functional rescue by Rae1 overexpression plus mRNA nuclear retention assay; replicates and extends PMID 33097660","pmids":["33849972"],"is_preprint":false},{"year":2014,"finding":"Crystal structure at 3.15 Å of the VSV matrix protein M in complex with Rae1·Nup98 reveals M contacts the Rae1 β-propeller via a 'finger' (containing Met51) and 'thumb'; M protein occupies the nucleic acid-binding site of Rae1·Nup98 and competitively inhibits oligonucleotide binding to this complex; the finger peptide alone is sufficient to compete for nucleic acid binding.","method":"X-ray crystallography (3.15 Å), in vitro competition binding assay with oligonucleotides, synthetic peptide competition","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic resolution crystal structure plus in vitro nucleic-acid competition assay plus peptide validation; multiple orthogonal methods","pmids":["24927547"],"is_preprint":false},{"year":2012,"finding":"VSV M protein preferentially interacts with intermediate-molecular-weight Rae1-Nup98 complexes; silencing Rae1 reduces VSV's ability to inhibit host transcription but not nuclear mRNA accumulation or translation inhibition; M protein-Rae1-Nup98 complexes are associated with the chromatin fraction, consistent with a role in transcription inhibition.","method":"Size exclusion chromatography, sedimentation velocity analysis, siRNA knockdown, chromatin fractionation, transcription/translation reporter assays in VSV-infected cells","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromatography-based complex characterization plus functional siRNA knockdown with multiple readouts, single lab","pmids":["23028327"],"is_preprint":false},{"year":2017,"finding":"The DExH/D-box helicase DHX9 is an intranuclear binding partner of Nup98; the FG/GLFG region of Nup98 binds N- and C-terminal regions of DHX9 in an RNA-facilitated manner; Nup98 binding stimulates the ATPase activity of DHX9; Nup98 and DHX9 bind interdependently to similar gene loci and their transcripts.","method":"In vitro binding assays, ATPase activity assay, transcriptional reporter assay, co-occupancy analysis (ChIP/RNA-seq), RNA facilitation experiments","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ATPase stimulation assay plus RNA-facilitated binding assay plus transcriptional reporter plus genomic co-occupancy; multiple orthogonal methods","pmids":["28221134"],"is_preprint":false},{"year":2010,"finding":"Nup98-homeodomain fusion proteins dynamically interact with endogenous Nup98 during interphase, mislocalizing the intranuclear fraction of Nup98 without altering Nup98 levels at the NPC; during mitosis, the fusions localize entirely to kinetochores and chromosome arms (sites of APC/C activity) rather than interacting with endogenous Nup98.","method":"Live-cell fluorescence microscopy, cell cycle staging, co-localization with APC/C markers","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — fluorescence live-cell imaging at multiple cell cycle stages, single lab, no biochemical validation of interactions","pmids":["20237156"],"is_preprint":false},{"year":2013,"finding":"NUP98 fusion oncoproteins (but not wild-type NUP98) cause mitotic spindle defects and chromosome missegregation; NUP98 fusions physically interact with APC/C-Cdc20 and displace the BubR1 SAC component, causing premature securin degradation and spindle assembly checkpoint slippage; wild-type NUP98 stability is controlled by a PEST sequence absent in oncoproteins, whose deletion reproduces the aberrant SAC-interfering activity.","method":"Co-immunoprecipitation of APC/C-Cdc20, chromosome segregation assays (live imaging), PEST sequence deletion mutagenesis, securin degradation assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with APC/C-Cdc20 plus mutagenesis of PEST domain plus functional mitotic assays, single lab","pmids":["24371226"],"is_preprint":false},{"year":2011,"finding":"RAE1 knockdown disrupts proper chromosome segregation and ablates RAE1 but not HDAC1 expression/localization; rescue experiments confirm the RAE1-NUP98 complex orchestrates proper chromosome segregation; in NUP98-HOXA9-transfected cells, RAE1 protein is reduced and mislocalized, consistent with RAE1 contributing to NUP98-fusion-mediated leukemogenesis.","method":"siRNA knockdown, rescue experiments, immunofluorescence, chromosome segregation analysis, NUP98-HOXA9 transgenic mouse analysis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with rescue, consistent with mouse model data, single lab","pmids":["21467841"],"is_preprint":false},{"year":2016,"finding":"Nup98-HoxA9 is preferentially targeted to Hox cluster regions where Crm1 is prebound on chromatin; leptomycin B (Crm1 inhibitor) disassembles nuclear Nup98-HoxA9 dots, abolishes chromatin binding, and reverses Hox gene activation; Crm1 physically interacts with Nup98-HoxA9 to mediate its targeting to Hox loci.","method":"Genome-wide ChIP-seq, leptomycin B treatment, co-immunoprecipitation, immunofluorescence, gene expression analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq genome-wide binding analysis plus pharmacological Crm1 inhibition with loss of chromatin binding plus co-IP; multiple orthogonal methods","pmids":["26740045"],"is_preprint":false},{"year":2022,"finding":"NUP98-HOXA9 and related NUP98 fusion oncoproteins form nuclear condensates (liquid-liquid phase separation) via homotypic and heterotypic interactions; the intrinsically disordered FG-repeat region of NUP98 drives LLPS in vitro; condensate formation is required for aberrant transcriptional activity and transformation of hematopoietic stem/progenitor cells.","method":"In vitro LLPS assays, mutagenesis of FG repeats, nuclear condensate live imaging, hematopoietic transformation assays, transcriptional reporter assays","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of LLPS, mutagenesis demonstrating necessity, functional transformation assays with multiple NUP98 fusions; multiple orthogonal methods","pmids":["34903620"],"is_preprint":false},{"year":2022,"finding":"NUP98-NSD1 core interactome binding is largely dependent on its FG-repeat domains, which mediate formation of liquid-like phase-separated nuclear condensates; SMARCA5 (ISWI family member) is identified as a condensate constituent that interacts with NUP98-NSD1 and is required for hematopoietic cell transformation; SMARCA5 inhibition impairs transformation without disrupting condensate formation itself.","method":"Affinity purification-mass spectrometry (AP-MS), FRAP, b-isoxazole condensate assay, siRNA/pharmacological SMARCA5 inhibition, proximity ligation assay, methylcellulose transformation assay","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — AP-MS interactome plus FRAP/condensate assays plus genetic and pharmacological loss-of-function with defined phenotype; multiple orthogonal methods","pmids":["35073946"],"is_preprint":false},{"year":2020,"finding":"NUP98 fusion proteins directly bind to CDK6 gene loci and are required for CDK6 transcription; CDK6 loss severely attenuates NUP98-fusion-driven leukemogenesis; NUP98-fusion AML is sensitive to pharmacologic CDK6 inhibition in vitro and in vivo.","method":"ChIP-seq (chromatin occupancy of NUP98 fusions), inducible fusion protein inactivation with transcriptome profiling, CDK6 genetic loss-of-function, CDK6 inhibitor treatment in mouse and in vivo models","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq plus inducible knockdown transcriptomics plus genetic CDK6 loss-of-function in multiple NUP98-fusion models in vivo; multiple orthogonal methods","pmids":["32344427"],"is_preprint":false},{"year":2017,"finding":"The second FG repeat domain of the NUP98 moiety of NUP98-HOXA9 is required for cell immortalization and leukemogenesis; NUP98-HOXA9 interacts with MLL via this FG repeat domain; in the absence of MLL, NUP98-HOXA9 fails to be recruited to the HOXA locus and HOXA gene expression is not induced.","method":"Domain deletion mutagenesis, co-immunoprecipitation (NUP98-HOXA9 with MLL), ChIP at HOXA locus, MLL conditional knockout in NUP98-HOXA9 cells","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP plus ChIP plus genetic MLL knockout with direct molecular readout; multiple orthogonal methods in one study","pmids":["28210005"],"is_preprint":false},{"year":2022,"finding":"Nup98's role in transcriptional memory in Drosophila is to stabilize the forward rate of conversion from low to high expressing transcriptional state; this memory establishment is independent of actual transcription during the initial exposure, as inhibiting transcription during initial ecdysone exposure does not prevent memory establishment.","method":"Single-molecule RNA FISH (smFISH), mathematical modeling, transcription inhibitor experiments, Drosophila cell system with ecdysone stimulation","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — smFISH plus mathematical modeling plus pharmacological transcription inhibition confirming model prediction; single lab in Drosophila model","pmids":["35289742"],"is_preprint":false},{"year":2025,"finding":"In NUP98-PHF23 fusion, the PHD domain targets condensates to H3K4me3/2-marked developmental genes, while the FG repeats determine condensate composition and gene activation; FG repeats are necessary and sufficient to partition specific transcriptional regulators (KMT2/MLL H3K4 methyltransferases, histone acetyltransferases, BRD4) into condensates; FG-repeat-tethered condensates initiate a feedforward loop of reading-and-writing active histone modifications.","method":"Mutagenesis, proteomics (condensate composition analysis), ChIP-seq (genomics), in vitro condensate reconstitution, tethering assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro condensate reconstitution plus mutagenesis plus proteomics plus ChIP-seq; multiple rigorous orthogonal methods in one study","pmids":["39922194"],"is_preprint":false},{"year":2025,"finding":"MYST family histone acetyltransferases KAT6A and KAT7 associate with NUP98 fusion oncoproteins on chromatin and within condensates; KAT6A/7 are molecular dependencies in NUP98-rearranged leukemia; KAT6A/7 inhibition decreases H3K23ac, displaces NUP98::HOXA9 from chromatin at the Meis1 locus, and drives myeloid differentiation.","method":"Co-immunoprecipitation/ChIP co-occupancy, genetic KAT6A/7 inactivation, pharmacological HAT inhibition, H3K23ac ChIP, xenograft mouse models","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP/co-occupancy plus genetic and pharmacological loss-of-function plus histone mark ChIP plus in vivo xenograft models; multiple orthogonal methods","pmids":["40536430"],"is_preprint":false},{"year":2014,"finding":"NUP98-PHF23 fusion binds H3K4me3-marked chromatin via the PHF23 PHD finger; disulfiram directly inhibits PHD-H3K4me3 binding and kills NUP98-PHF23 AML cells; NMR analysis confirms H3K4me3 binding by PHD fingers of PHF23, KDM5A, and BPTF at conserved sites, suggesting a common PHD-dependent chromatin-targeting mechanism for this class of NUP98 fusions.","method":"ChIP demonstrating H3K4me3 co-occupancy, NMR analysis of PHD-H3K4me3 interaction, disulfiram PHD-inhibition cell viability assay","journal":"Nature communications / Cancer discovery","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structural analysis plus ChIP-seq plus pharmacological inhibition with mechanistic read-out across multiple fusion proteins; multiple orthogonal methods","pmids":["32620764","24535671"],"is_preprint":false},{"year":2013,"finding":"Nup98 specifically regulates nuclear-to-cytoplasmic transport of galectin-3; Nup98 interacts with galectin-3 at the nuclear membrane and promotes galectin-3 cytoplasmic translocation; silencing Nup98 retains galectin-3 in the nucleus, retards cell growth, and suppresses β-catenin pathway target gene expression (cyclin D1, FRA-1).","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, cell growth assays, gene expression analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus siRNA knockdown with multiple readouts, single lab","pmids":["23541576"],"is_preprint":false},{"year":2006,"finding":"Nup96+/− mice with selectively low Nup96 levels display downregulated MHC I and MHC II, ICAM-1, and impaired IFN-alpha and gamma-mediated induction of these proteins, demonstrating Nup96 (the NUP98 precursor cleavage product) is specifically required for proper nuclear transport and expression of interferon-regulated proteins and immune function.","method":"Nup96+/- mouse genetics, interferon stimulation assays, MHC expression analysis, T cell functional assays, viral infection susceptibility","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo haploinsufficiency mouse model with multiple immunological functional readouts; replicated across multiple immune assays in vivo","pmids":["16546098"],"is_preprint":false}],"current_model":"NUP98 is a bifunctional nucleoporin: at the nuclear pore complex it facilitates multiple RNA export pathways (via its GLFG repeats docking export factors Rae1/Gle2 and TAP and acting as a Crm1 cofactor), assists in NPC assembly (autoproteolytic cleavage generating NUP96 and enabling cytoplasmic-face nucleoporin recruitment), and in mitosis forms a Rae1-Nup98 complex that inhibits APC/C-Cdh1-mediated securin ubiquitination to prevent premature anaphase; in the nuclear interior, mobile Nup98 recruits the Wdr82-Set1A/COMPASS complex to deposit H3K4me3 at active gene promoters, stimulates DHX9 helicase activity, protects specific mRNAs (p21) from exosomal degradation, and establishes transcriptional memory; in leukemia, NUP98 fusion oncoproteins exploit the FG-repeat transactivation domain to recruit CBP/p300, MLL1, KAT6A/KAT7, and other coactivators into phase-separated nuclear condensates targeted to developmental gene loci (via partner chromatin-reader domains such as PHF23-PHD binding H3K4me3), maintaining aberrant HOX/MEIS1 gene expression programs that drive leukemogenesis."},"narrative":{"mechanistic_narrative":"NUP98 is a bifunctional FG/GLFG-repeat nucleoporin that supports nucleocytoplasmic transport at the nuclear pore complex (NPC) while also acting in the nuclear interior to regulate gene expression [PMID:9015297, PMID:11950939]. NUP98 is co-translated with NUP96 as a 186-kDa precursor whose autoproteolytic cleavage is required to target both products to the nucleoplasmic face of the NPC and to nucleate a conserved NUP96-NUP107-Sec13 subcomplex [PMID:10087256, PMID:14517296]; the same cleavage-dependent C-terminal site mediates binding to both the cytoplasmic nucleoporin Nup88 and to Nup96, and loss of NUP98 impairs assembly of cytoplasmic-face nucleoporins and receptor-mediated import of selective cargoes [PMID:12589057, PMID:11248054]. At the pore, NUP98 enables export of multiple RNA classes [PMID:9015297], serving as a docking platform whose GLFG domain assembles a ternary mRNA-export complex with Rae1/Gle2 and TAP [PMID:12637516] and acting as a RanGTP-dependent cofactor for Crm1-mediated protein export through its N-terminal FG repeats [PMID:20375145]. The Rae1·NUP98 module forms a seven-bladed β-propeller heterocomplex with single-stranded RNA-binding capacity [PMID:20498086], and beyond transport this complex governs mitotic fidelity by inhibiting APC-Cdh1-mediated securin ubiquitination, preventing premature sister-chromatid separation and aneuploidy [PMID:16355229]. A mobile intranuclear pool of NUP98, dependent on ongoing transcription, associates with developmentally regulated genes and active promoters [PMID:11950939, PMID:23468646], where it recruits the Wdr82-Set1A/COMPASS complex to deposit H3K4me3 at transcription start sites [PMID:29269482], stimulates the ATPase activity of the DHX9 helicase at shared gene loci [PMID:28221134], and post-transcriptionally protects specific mRNAs such as p21 from exosomal degradation [PMID:23102701]. In leukemia, NUP98 fusion oncoproteins exploit the intrinsically disordered FG repeats to drive liquid-liquid phase separation into nuclear condensates that partition transcriptional coactivators—CBP/p300, MLL1/KMT2, the NSL complex, BRD4, and MYST acetyltransferases KAT6A/KAT7—and are targeted to developmental loci through partner chromatin-reader domains (e.g. the PHF23 PHD finger binding H3K4me3) and through prebound Crm1, sustaining aberrant HOX/MEIS1 and CDK6 transcriptional programs that drive transformation [PMID:9858599, PMID:17589499, PMID:27889185, PMID:26740045, PMID:34903620, PMID:32344427, PMID:39922194, PMID:40536430, PMID:32620764, PMID:24535671]. The Nup98-Rae1 complex is additionally hijacked by viral antagonists, including SARS-CoV-2 ORF6 and VSV matrix protein, to block host transport and immune gene induction [PMID:33097660, PMID:24927547].","teleology":[{"year":1997,"claim":"Established NUP98 as a functional requirement for RNA export rather than protein import, defining its core role at the pore.","evidence":"Anti-Nup98 antibody injection into Xenopus oocyte nuclei with class-specific RNA export and import assays","pmids":["9015297"],"confidence":"High","gaps":["Did not identify the molecular export factors NUP98 docks","tRNA export and protein import unaffected, leaving pathway selectivity unexplained"]},{"year":1999,"claim":"Resolved the biogenesis of NUP98 and NUP96 from a single precursor, showing autoproteolytic cleavage is required for correct NPC targeting and subcomplex assembly.","evidence":"Biochemical fractionation, mutagenesis, immunoEM, and in vitro autocleavage assays in rat liver nuclei","pmids":["10087256"],"confidence":"High","gaps":["Did not address the intranuclear transport-independent functions of NUP98","in vivo consequence of cleavage failure not tested"]},{"year":1999,"claim":"Identified the FG repeats as a transactivation domain in the NUP98-HOXA9 oncofusion, linking a transport motif to coactivator recruitment in transformation.","evidence":"NIH 3T3 transformation, luciferase transactivation, and co-IP with CBP/p300","pmids":["9858599"],"confidence":"High","gaps":["Did not establish chromatin targeting of the fusion","physiological vs oncogenic FG-repeat function not yet distinguished"]},{"year":2001,"claim":"Genetic disruption in mice demonstrated NUP98 is required for cytoplasmic-face nucleoporin assembly and selective cargo import, separating its roles from NUP96.","evidence":"Murine NUP98 gene targeting with immunofluorescence and selective cargo import assays","pmids":["11248054"],"confidence":"High","gaps":["Mechanism of cytoplasmic nucleoporin recruitment by NUP98 not resolved here"]},{"year":2003,"claim":"Mapped the GLFG-domain binding sites for the mRNA export machinery and the cleavage-dependent dual binding of NUP98 to Nup88 and Nup96.","evidence":"In vitro pulldown/competition binding and domain mapping; immunoEM and mutagenesis","pmids":["12637516","12589057"],"confidence":"Medium","gaps":["TAP-Rae1 binding overlap defined in vitro without in vivo export consequence","single-lab binding data"]},{"year":2005,"claim":"Defined a transport-independent mitotic function: the Rae1-NUP98 complex inhibits APC-Cdh1 to safeguard chromosome segregation.","evidence":"Mouse haploinsufficiency genetics, APC-Cdh1 co-IP, in vitro securin ubiquitination, and aneuploidy flow cytometry","pmids":["16355229"],"confidence":"High","gaps":["Structural basis of APC-Cdh1 inhibition not defined","how the same complex switches between transport and mitotic roles unknown"]},{"year":2010,"claim":"Provided atomic-resolution structure of the Rae1·NUP98 GLEBS complex and revealed its single-stranded RNA-binding activity, and separately defined NUP98 as a RanGTP-dependent Crm1 export cofactor.","evidence":"1.65 Å crystal structure with mutagenesis and RNA-binding assays; RanGTP-dependent co-IP, FG-repeat mutagenesis, and antibody export inhibition","pmids":["20498086","20375145"],"confidence":"High","gaps":["Functional RNA target of the Rae1·NUP98 RNA-binding surface not identified","RanBP3 modulation mechanism not detailed"]},{"year":2013,"claim":"Showed NUP98 binds developmental genes at both the pore and the nuclear interior and post-transcriptionally protects specific mRNAs, broadening its role to direct gene regulation.","evidence":"Genome-wide ChIP-seq in human ESCs with dominant-negative fragment; single-molecule mRNA analysis and exosome degradation assays for p21","pmids":["23468646","23102701"],"confidence":"High","gaps":["Mechanism distinguishing pore-tethered vs interior gene regulation incomplete","exosome-protection mechanism for mRNAs beyond p21/14-3-3σ not generalized"]},{"year":2016,"claim":"Established that NUP98 fusions are recruited to HOX loci via prebound Crm1 and physically engage MLL1/NSL complexes for aberrant transcription.","evidence":"Genome-wide ChIP-seq, leptomycin B Crm1 inhibition, and reciprocal co-IP of multiple fusions with MLL1/NSL","pmids":["26740045","27889185"],"confidence":"High","gaps":["Whether Crm1 recruits wild-type NUP98 to the same loci unresolved","biophysical nature of the chromatin 'dots' not yet defined"]},{"year":2017,"claim":"Defined the wild-type chromatin function of NUP98: recruitment of Wdr82-Set1A/COMPASS for H3K4me3 deposition and stimulation of the DHX9 helicase, and showed fusions mislocalize H3K4me3.","evidence":"ChIP-seq with Nup98/Wdr82 depletion and Set1A/H3K4me3 ChIP; in vitro ATPase stimulation and RNA-facilitated binding assays","pmids":["29269482","28221134"],"confidence":"High","gaps":["How transcription-dependent NUP98 mobility couples to COMPASS recruitment unclear","DHX9 substrate transcripts in vivo not enumerated"]},{"year":2022,"claim":"Showed FG-repeat-driven liquid-liquid phase separation is the organizing principle of NUP98-fusion oncogenesis, concentrating chromatin regulators including SMARCA5.","evidence":"In vitro LLPS reconstitution, FG-repeat mutagenesis, AP-MS, FRAP, and hematopoietic transformation assays","pmids":["34903620","35073946"],"confidence":"High","gaps":["Whether wild-type NUP98 phase behavior contributes to normal gene regulation untested","condensate composition rules across diverse fusions incomplete"]},{"year":2025,"claim":"Dissected the division of labor between fusion partner reader domains (targeting) and FG repeats (composition/activation), revealing a feedforward read-and-write loop and actionable MYST-HAT dependencies.","evidence":"In vitro condensate reconstitution, mutagenesis, condensate proteomics, ChIP-seq, and genetic/pharmacological KAT6A/7 loss-of-function with xenografts","pmids":["39922194","40536430"],"confidence":"High","gaps":["Generalizability of the read-write loop across all NUP98 fusion classes not fully mapped","therapeutic window of HAT and PHD inhibition not established here"]},{"year":null,"claim":"How NUP98's transport, mitotic, and chromatin-regulatory activities are integrated and switched in normal cells, and whether condensate-based regulation operates at endogenous NUP98, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model linking pore residence, intranuclear mobility, and gene activation","endogenous NUP98 phase behavior in normal hematopoiesis uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[8,20]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,16,32]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,12,22]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,12]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,15,16]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[2,22]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[16,26]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,4,12]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,7,17]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[16,22,32]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,24]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[13,16,32]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,13,27,29]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[18,36]}],"complexes":["NUP96-NUP107-Sec13 NPC subcomplex","Rae1-NUP98 complex","NUP98-Rae1-TAP mRNA export complex","Wdr82-Set1A/COMPASS complex"],"partners":["RAE1","NUP96","NUP88","TAP","CRM1","DHX9","TPR","SEC13"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P52948","full_name":"Nuclear pore complex protein Nup98-Nup96","aliases":[],"length_aa":1817,"mass_kda":197.6,"function":"Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance. NUP98 and NUP96 are involved in the bidirectional transport across the NPC (PubMed:33097660). May anchor NUP153 and TPR to the NPC. In cooperation with DHX9, plays a role in transcription and alternative splicing activation of a subset of genes (PubMed:28221134). Involved in the localization of DHX9 in discrete intranuclear foci (GLFG-body) (PubMed:28221134) (Microbial infection) Interacts with HIV-1 capsid protein P24 and nucleocapsid protein P7 and may thereby promote the integration of the virus in the host nucleus (in vitro) (PubMed:23523133). Binding affinity to HIV-1 CA-NC complexes bearing the capsid change Asn-74-Asp is reduced (in vitro) (PubMed:23523133)","subcellular_location":"Nucleus membrane","url":"https://www.uniprot.org/uniprotkb/P52948/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NUP98","classification":"Common 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MOTIF-CONTAINING PROTEIN G; IQCG","url":"https://www.omim.org/entry/612477"},{"mim_id":"612376","title":"ACUTE PROMYELOCYTIC LEUKEMIA; APL","url":"https://www.omim.org/entry/612376"},{"mim_id":"611749","title":"ZINC FINGER RANBP2-TYPE DOMAIN-CONTAINING PROTEIN 1; ZRANB1","url":"https://www.omim.org/entry/611749"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NUP98"},"hgnc":{"alias_symbol":["NUP96","Nup98-Nup96","Nup98-96","NUP196"],"prev_symbol":[]},"alphafold":{"accession":"P52948","domains":[{"cath_id":"3.30.1610.10","chopping":"742-889","consensus_level":"high","plddt":85.0178,"start":742,"end":889},{"cath_id":"-","chopping":"1643-1764_1777-1816","consensus_level":"medium","plddt":73.6725,"start":1643,"end":1816}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P52948","model_url":"https://alphafold.ebi.ac.uk/files/AF-P52948-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P52948-F1-predicted_aligned_error_v6.png","plddt_mean":55.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUP98","jax_strain_url":"https://www.jax.org/strain/search?query=NUP98"},"sequence":{"accession":"P52948","fasta_url":"https://rest.uniprot.org/uniprotkb/P52948.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P52948/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P52948"}},"corpus_meta":[{"pmid":"33097660","id":"PMC_33097660","title":"SARS-CoV-2 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haematology","url":"https://pubmed.ncbi.nlm.nih.gov/37465857","citation_count":13,"is_preprint":false},{"pmid":"16174445","id":"PMC_16174445","title":"Deguelin regulates nuclear pore complex proteins Nup98 and Nup88 in U937 cells in vitro.","date":"2005","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/16174445","citation_count":13,"is_preprint":false},{"pmid":"39808803","id":"PMC_39808803","title":"Precision medicine for high-risk gene fusions in pediatric AML: a focus on KMT2A, NUP98, and GLIS2 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     \"method\": \"Biochemical fractionation of rat liver nuclei, mutational analysis, immunoelectron microscopy, in vitro autoproteolytic cleavage assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, mutagenesis, and immunoelectron microscopy in a single rigorous study; evolutionary conservation confirmed with yeast Nup145p\",\n      \"pmids\": [\"10087256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Nuclear injection of anti-Nup98 antibodies in Xenopus oocytes inhibits export of snRNAs, 5S RNA, large ribosomal RNAs, and mRNA, but not tRNA, and does not affect import of karyophilic proteins or snRNPs, establishing Nup98 as an essential component of multiple RNA export pathways but not protein import.\",\n      \"method\": \"Antibody injection into Xenopus laevis oocyte nucleus with functional RNA export assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vivo functional blocking experiment with monospecific antibodies, multiple RNA classes tested, clear positive and negative results\",\n      \"pmids\": [\"9015297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Nup98 is found both at the nuclear pore complex and within the nucleus at a novel intranuclear structure termed the GLFG body; the GLFG domain of Nup98 is required for targeting to this structure; Nup98 is mobile and moves between these localizations; this mobility is dependent on ongoing transcription by RNA polymerases I and II.\",\n      \"method\": \"GFP-Nup98 live-cell imaging, FRAP (photobleaching), transcription inhibitor treatments, domain deletion analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — FRAP in living cells combined with domain mutagenesis and pharmacological transcription inhibition; multiple orthogonal methods\",\n      \"pmids\": [\"11950939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Nup98 is localized on both the nuclear and cytoplasmic faces of the nuclear pore; the pore-targeting domain of Nup98 directly interacts with the cytoplasmic nucleoporin Nup88; the same site within Nup98 binds both Nup88 (cytoplasmic face) and Nup96 (nuclear face); autoproteolytic cleavage of the Nup98 C-terminus is required for both binding interactions.\",\n      \"method\": \"Immunofluorescence, immunoelectron microscopy, direct binding assays, point mutation blocking cleavage\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — immunoelectron microscopy plus direct binding assays plus mutagenesis; multiple orthogonal methods in one study\",\n      \"pmids\": [\"12589057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Disruption of murine NUP98 (leaving NUP96 intact) causes inefficient assembly of cytoplasmic-face nucleoporins (NUP358, NUP214, NUP88, p62) into nuclear pores, with these nucleoporins instead associating with annulate lamellae; NUP98-deficient cells show impaired transport receptor-mediated docking and nuclear import of NLS and M9 signal-containing substrates, but not ribosomal protein L23a or U1A import.\",\n      \"method\": \"Gene targeting in mice, immunofluorescence, nuclear pore import assays with selective cargo classes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple biochemical and functional readouts; selective cargo import tested\",\n      \"pmids\": [\"11248054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Rae1 and Nup98 form a complex with Cdh1-activated APC (APC-Cdh1) in early mitosis and specifically inhibit APC-Cdh1-mediated ubiquitination of securin; combined Rae1 and Nup98 haploinsufficiency in mice causes premature securin degradation, sister chromatid separation, and severe aneuploidy.\",\n      \"method\": \"Mouse haploinsufficiency genetics, co-immunoprecipitation of APC-Cdh1 complex, in vitro ubiquitination assay, flow cytometry for aneuploidy\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro ubiquitination assay plus genetic mouse model plus co-IP; multiple orthogonal methods establishing mechanistic inhibition of APC-Cdh1\",\n      \"pmids\": [\"16355229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The NUP98-HOXA9 fusion protein's FG repeats act as potent transcriptional transactivation domains that physically and functionally interact with transcriptional coactivators CBP and p300; this FG-repeat-mediated transactivation is essential for transformation of NIH 3T3 cells.\",\n      \"method\": \"NIH 3T3 transformation assay, luciferase reporter transactivation assay, co-immunoprecipitation with CBP/p300, domain deletion/mutation analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP of endogenous CBP/p300 with FG repeats, functional transactivation assays, mutagenesis showing necessity; multiple orthogonal methods\",\n      \"pmids\": [\"9858599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Nup98, Rae1/Gle2, and TAP form a ternary mRNA export complex; TAP binds with highest affinity to a specific region within the GLFG domain of Nup98 (not all FG repeats equally); Gle2/Rae1 binds Nup98 and TAP at adjacent but overlapping sites, and when Gle2 is bound to Nup98 it can no longer directly interact with TAP.\",\n      \"method\": \"In vitro binding assays (pulldown), domain mapping, competition binding experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assays with defined domains, single lab, multiple binding pairs tested\",\n      \"pmids\": [\"12637516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of human Rae1 in complex with the GLEBS motif of Nup98 at 1.65 Å resolution shows Rae1 forms a seven-bladed β-propeller; the C-terminal arm of the Nup98 GLEBS hairpin binds an invariant hydrophobic surface on the top face of Rae1; a tandem glutamate element in the C-terminal arm is critical for complex formation; the Rae1·Nup98 complex possesses single-stranded RNA-binding capability.\",\n      \"method\": \"X-ray crystallography (1.65 Å), mutagenesis, RNA-binding assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structure plus mutagenesis validation plus RNA-binding functional assay in one study\",\n      \"pmids\": [\"20498086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Nup98 participates in HIV-1 Rev-hCRM1-mediated nuclear export; Rev recruits Nup98 and Nup214 to the nucleolus; FG-repeat domains of Nup98 and Nup214 competitively inhibit Rev/RRE-mediated expression; upon actinomycin D treatment Nup98 (but not Nup214 or Nup153) translocates to the cytoplasm, demonstrating it can act as a soluble factor.\",\n      \"method\": \"Nucleolar recruitment assays, competitive inhibition reporter assays, immunofluorescence after actinomycin D treatment\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional competition assay plus localization experiments, single lab\",\n      \"pmids\": [\"9847314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Nup98 associates with the intranuclear filamentous protein network of TPR; in vitro translated TPR binds in vitro translated Nup98, and via Nup98 also associates with Nup96; immunofluorescence shows colocalization of Nup98 and TPR including at perinucleolar sites.\",\n      \"method\": \"In vitro translation/binding assay, double-immunofluorescence microscopy, immunoelectron microscopy\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding reconstitution plus immunoelectron microscopy, single lab\",\n      \"pmids\": [\"11248057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Sec13 stably interacts with Nup96 at the nuclear pore complex via its WD repeat region binding to the N-terminal region of Nup96; Sec13 shuttles between intranuclear sites and the cytoplasm; cotransfection of the Sec13-binding domain of Nup96 decreased the mobile pool of Sec13, confirming the interaction in vivo.\",\n      \"method\": \"Yeast two-hybrid, biochemical assays, immunofluorescence, confocal and immunoelectron microscopy, FRAP, in vivo competition cotransfection\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus biochemical pulldown plus FRAP plus in vivo competition; multiple orthogonal methods\",\n      \"pmids\": [\"14517296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Nup98 functions as a cofactor for Crm1-mediated nuclear protein export; Nup98 physically and functionally interacts with Crm1 in a RanGTP-dependent manner through its N-terminal FG repeat region; this activity is modulated by RanBP3; cytoplasmic microinjection of anti-Nup98 antibody inhibits Crm1-dependent nuclear export.\",\n      \"method\": \"Leptomycin B treatment, co-immunoprecipitation (RanGTP-dependent), mutational analysis, microinjection of anti-Nup98 antibodies with nuclear export assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP demonstrating RanGTP dependence, mutagenesis of FG repeats, functional antibody inhibition assay, multiple orthogonal methods\",\n      \"pmids\": [\"20375145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NUP98-NSD1 fusion protein binds genomic elements adjacent to HoxA7 and HoxA9, maintains H3K36 methylation and histone acetylation at these loci, and prevents EZH2-mediated transcriptional repression of the Hox-A locus; deletion of the NUP98 FG-repeat domain or inactivating mutations in the NSD1 H3K36 methyltransferase activity abrogated both Hox-A gene activation and myeloid progenitor immortalization.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), mutagenesis of catalytic site and FG domain, in vitro immortalization assay, in vivo AML mouse model\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP demonstrating H3K36 methylation maintenance, catalytic site mutagenesis of NSD1, genetic domain deletions, in vivo mouse AML model; multiple orthogonal methods\",\n      \"pmids\": [\"17589499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NUP98 fusion proteins (NUP98-HOXA9, NUP98-HOXD13, NUP98-NSD1, NUP98-PHF23, NUP98-TOP1) physically interact with the MLL1 and NSL histone-modifying complexes; NUP98-HOXA9 and MLL1 co-occupy Hox gene promoter regions on chromatin; MLL1 is required for proliferation of NUP98-HOXA9 cells and for NUP98-HOXA9-induced gene expression.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-sequencing, MLL1 genetic inactivation with proliferation and gene expression readouts\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP of multiple NUP98 fusions with MLL1/NSL, ChIP-seq co-occupancy, genetic loss-of-function with defined molecular and cellular phenotypes\",\n      \"pmids\": [\"27889185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NUP98 associates with developmentally regulated genes in human embryonic stem cells at both the nuclear periphery (pore-embedded) and the nuclear interior (away from pores); overexpression of a dominant-negative NUP98 fragment decreases expression of NUP98-bound genes; two spatial modes of gene regulation are distinguished by gene activation state.\",\n      \"method\": \"Genome-wide ChIP-seq in human ESCs, dominant-negative NUP98 fragment overexpression with gene expression analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus functional dominant-negative experiment, single lab\",\n      \"pmids\": [\"23468646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In hematopoietic cells, Nup98 binds predominantly to transcription start sites and recruits the Wdr82-Set1A/COMPASS complex, which is required for H3K4me3 deposition; depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and ablates H3K4me3 at adjacent promoters; expression of a leukemogenic NUP98 fusion protein causes mislocalization of H3K4me3 and up-regulation of associated genes.\",\n      \"method\": \"ChIP-seq, siRNA knockdown of Nup98 and Wdr82 with H3K4me3 and Set1A ChIP, co-immunoprecipitation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq showing co-occupancy plus genetic depletion experiments demonstrating H3K4me3 loss plus co-IP; multiple orthogonal methods\",\n      \"pmids\": [\"29269482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nup98 regulates p21 mRNA levels by a posttranscriptional mechanism in which a complex containing Nup98 and the p21 mRNA 3'UTR protects p21 mRNA from degradation by the exosome; Nup98 is similarly required for expression of the p53 target 14-3-3σ; this function is distinct from NUP98 fusion oncoproteins' activities.\",\n      \"method\": \"Single-molecule mRNA analysis, conventional mRNA analysis, 3'UTR-Nup98 complex identification, siRNA knockdown, exosome activity assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — single-molecule mRNA analysis plus exosome degradation assay plus RIP (Nup98-3'UTR complex), multiple orthogonal methods identifying posttranscriptional mechanism\",\n      \"pmids\": [\"23102701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SARS-CoV-2 Orf6 localizes to the nuclear pore complex and directly interacts with the Nup98-Rae1 complex via its C-terminal domain to impair docking of karyopherin/importin cargo complexes, blocking STAT1 and STAT2 nuclear translocation and suppressing interferon-stimulated gene induction; a Met58-to-Arg substitution in Orf6 abolishes binding to Nup98-Rae1 and eliminates its IFN antagonistic function.\",\n      \"method\": \"Co-immunoprecipitation, nuclear import assays for STAT1/STAT2, immunofluorescence, site-directed mutagenesis (M58R)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP demonstrating direct interaction, functional nuclear import assay, mutagenesis abolishing binding and function; multiple orthogonal methods in one study\",\n      \"pmids\": [\"33097660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SARS-CoV-2 ORF6 blocks both nuclear import and mRNA nuclear export through interactions with Rae1 and Nup98 that map to the C-terminus of ORF6 (Met58); overexpression of Rae1 restores reporter gene expression in presence of ORF6; SARS-CoV-2 ORF6 more strongly co-purifies with Rae1 and Nup98 than SARS-CoV ORF6.\",\n      \"method\": \"Co-purification assays, reporter expression assays, nuclear poly(A) RNA accumulation assays, Rae1 overexpression rescue, M58 mutagenesis\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-purification with mutagenesis plus functional rescue by Rae1 overexpression plus mRNA nuclear retention assay; replicates and extends PMID 33097660\",\n      \"pmids\": [\"33849972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure at 3.15 Å of the VSV matrix protein M in complex with Rae1·Nup98 reveals M contacts the Rae1 β-propeller via a 'finger' (containing Met51) and 'thumb'; M protein occupies the nucleic acid-binding site of Rae1·Nup98 and competitively inhibits oligonucleotide binding to this complex; the finger peptide alone is sufficient to compete for nucleic acid binding.\",\n      \"method\": \"X-ray crystallography (3.15 Å), in vitro competition binding assay with oligonucleotides, synthetic peptide competition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic resolution crystal structure plus in vitro nucleic-acid competition assay plus peptide validation; multiple orthogonal methods\",\n      \"pmids\": [\"24927547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"VSV M protein preferentially interacts with intermediate-molecular-weight Rae1-Nup98 complexes; silencing Rae1 reduces VSV's ability to inhibit host transcription but not nuclear mRNA accumulation or translation inhibition; M protein-Rae1-Nup98 complexes are associated with the chromatin fraction, consistent with a role in transcription inhibition.\",\n      \"method\": \"Size exclusion chromatography, sedimentation velocity analysis, siRNA knockdown, chromatin fractionation, transcription/translation reporter assays in VSV-infected cells\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromatography-based complex characterization plus functional siRNA knockdown with multiple readouts, single lab\",\n      \"pmids\": [\"23028327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The DExH/D-box helicase DHX9 is an intranuclear binding partner of Nup98; the FG/GLFG region of Nup98 binds N- and C-terminal regions of DHX9 in an RNA-facilitated manner; Nup98 binding stimulates the ATPase activity of DHX9; Nup98 and DHX9 bind interdependently to similar gene loci and their transcripts.\",\n      \"method\": \"In vitro binding assays, ATPase activity assay, transcriptional reporter assay, co-occupancy analysis (ChIP/RNA-seq), RNA facilitation experiments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ATPase stimulation assay plus RNA-facilitated binding assay plus transcriptional reporter plus genomic co-occupancy; multiple orthogonal methods\",\n      \"pmids\": [\"28221134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Nup98-homeodomain fusion proteins dynamically interact with endogenous Nup98 during interphase, mislocalizing the intranuclear fraction of Nup98 without altering Nup98 levels at the NPC; during mitosis, the fusions localize entirely to kinetochores and chromosome arms (sites of APC/C activity) rather than interacting with endogenous Nup98.\",\n      \"method\": \"Live-cell fluorescence microscopy, cell cycle staging, co-localization with APC/C markers\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — fluorescence live-cell imaging at multiple cell cycle stages, single lab, no biochemical validation of interactions\",\n      \"pmids\": [\"20237156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NUP98 fusion oncoproteins (but not wild-type NUP98) cause mitotic spindle defects and chromosome missegregation; NUP98 fusions physically interact with APC/C-Cdc20 and displace the BubR1 SAC component, causing premature securin degradation and spindle assembly checkpoint slippage; wild-type NUP98 stability is controlled by a PEST sequence absent in oncoproteins, whose deletion reproduces the aberrant SAC-interfering activity.\",\n      \"method\": \"Co-immunoprecipitation of APC/C-Cdc20, chromosome segregation assays (live imaging), PEST sequence deletion mutagenesis, securin degradation assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with APC/C-Cdc20 plus mutagenesis of PEST domain plus functional mitotic assays, single lab\",\n      \"pmids\": [\"24371226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RAE1 knockdown disrupts proper chromosome segregation and ablates RAE1 but not HDAC1 expression/localization; rescue experiments confirm the RAE1-NUP98 complex orchestrates proper chromosome segregation; in NUP98-HOXA9-transfected cells, RAE1 protein is reduced and mislocalized, consistent with RAE1 contributing to NUP98-fusion-mediated leukemogenesis.\",\n      \"method\": \"siRNA knockdown, rescue experiments, immunofluorescence, chromosome segregation analysis, NUP98-HOXA9 transgenic mouse analysis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with rescue, consistent with mouse model data, single lab\",\n      \"pmids\": [\"21467841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Nup98-HoxA9 is preferentially targeted to Hox cluster regions where Crm1 is prebound on chromatin; leptomycin B (Crm1 inhibitor) disassembles nuclear Nup98-HoxA9 dots, abolishes chromatin binding, and reverses Hox gene activation; Crm1 physically interacts with Nup98-HoxA9 to mediate its targeting to Hox loci.\",\n      \"method\": \"Genome-wide ChIP-seq, leptomycin B treatment, co-immunoprecipitation, immunofluorescence, gene expression analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq genome-wide binding analysis plus pharmacological Crm1 inhibition with loss of chromatin binding plus co-IP; multiple orthogonal methods\",\n      \"pmids\": [\"26740045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NUP98-HOXA9 and related NUP98 fusion oncoproteins form nuclear condensates (liquid-liquid phase separation) via homotypic and heterotypic interactions; the intrinsically disordered FG-repeat region of NUP98 drives LLPS in vitro; condensate formation is required for aberrant transcriptional activity and transformation of hematopoietic stem/progenitor cells.\",\n      \"method\": \"In vitro LLPS assays, mutagenesis of FG repeats, nuclear condensate live imaging, hematopoietic transformation assays, transcriptional reporter assays\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of LLPS, mutagenesis demonstrating necessity, functional transformation assays with multiple NUP98 fusions; multiple orthogonal methods\",\n      \"pmids\": [\"34903620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NUP98-NSD1 core interactome binding is largely dependent on its FG-repeat domains, which mediate formation of liquid-like phase-separated nuclear condensates; SMARCA5 (ISWI family member) is identified as a condensate constituent that interacts with NUP98-NSD1 and is required for hematopoietic cell transformation; SMARCA5 inhibition impairs transformation without disrupting condensate formation itself.\",\n      \"method\": \"Affinity purification-mass spectrometry (AP-MS), FRAP, b-isoxazole condensate assay, siRNA/pharmacological SMARCA5 inhibition, proximity ligation assay, methylcellulose transformation assay\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — AP-MS interactome plus FRAP/condensate assays plus genetic and pharmacological loss-of-function with defined phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"35073946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NUP98 fusion proteins directly bind to CDK6 gene loci and are required for CDK6 transcription; CDK6 loss severely attenuates NUP98-fusion-driven leukemogenesis; NUP98-fusion AML is sensitive to pharmacologic CDK6 inhibition in vitro and in vivo.\",\n      \"method\": \"ChIP-seq (chromatin occupancy of NUP98 fusions), inducible fusion protein inactivation with transcriptome profiling, CDK6 genetic loss-of-function, CDK6 inhibitor treatment in mouse and in vivo models\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq plus inducible knockdown transcriptomics plus genetic CDK6 loss-of-function in multiple NUP98-fusion models in vivo; multiple orthogonal methods\",\n      \"pmids\": [\"32344427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The second FG repeat domain of the NUP98 moiety of NUP98-HOXA9 is required for cell immortalization and leukemogenesis; NUP98-HOXA9 interacts with MLL via this FG repeat domain; in the absence of MLL, NUP98-HOXA9 fails to be recruited to the HOXA locus and HOXA gene expression is not induced.\",\n      \"method\": \"Domain deletion mutagenesis, co-immunoprecipitation (NUP98-HOXA9 with MLL), ChIP at HOXA locus, MLL conditional knockout in NUP98-HOXA9 cells\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP plus ChIP plus genetic MLL knockout with direct molecular readout; multiple orthogonal methods in one study\",\n      \"pmids\": [\"28210005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nup98's role in transcriptional memory in Drosophila is to stabilize the forward rate of conversion from low to high expressing transcriptional state; this memory establishment is independent of actual transcription during the initial exposure, as inhibiting transcription during initial ecdysone exposure does not prevent memory establishment.\",\n      \"method\": \"Single-molecule RNA FISH (smFISH), mathematical modeling, transcription inhibitor experiments, Drosophila cell system with ecdysone stimulation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — smFISH plus mathematical modeling plus pharmacological transcription inhibition confirming model prediction; single lab in Drosophila model\",\n      \"pmids\": [\"35289742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In NUP98-PHF23 fusion, the PHD domain targets condensates to H3K4me3/2-marked developmental genes, while the FG repeats determine condensate composition and gene activation; FG repeats are necessary and sufficient to partition specific transcriptional regulators (KMT2/MLL H3K4 methyltransferases, histone acetyltransferases, BRD4) into condensates; FG-repeat-tethered condensates initiate a feedforward loop of reading-and-writing active histone modifications.\",\n      \"method\": \"Mutagenesis, proteomics (condensate composition analysis), ChIP-seq (genomics), in vitro condensate reconstitution, tethering assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro condensate reconstitution plus mutagenesis plus proteomics plus ChIP-seq; multiple rigorous orthogonal methods in one study\",\n      \"pmids\": [\"39922194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYST family histone acetyltransferases KAT6A and KAT7 associate with NUP98 fusion oncoproteins on chromatin and within condensates; KAT6A/7 are molecular dependencies in NUP98-rearranged leukemia; KAT6A/7 inhibition decreases H3K23ac, displaces NUP98::HOXA9 from chromatin at the Meis1 locus, and drives myeloid differentiation.\",\n      \"method\": \"Co-immunoprecipitation/ChIP co-occupancy, genetic KAT6A/7 inactivation, pharmacological HAT inhibition, H3K23ac ChIP, xenograft mouse models\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP/co-occupancy plus genetic and pharmacological loss-of-function plus histone mark ChIP plus in vivo xenograft models; multiple orthogonal methods\",\n      \"pmids\": [\"40536430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NUP98-PHF23 fusion binds H3K4me3-marked chromatin via the PHF23 PHD finger; disulfiram directly inhibits PHD-H3K4me3 binding and kills NUP98-PHF23 AML cells; NMR analysis confirms H3K4me3 binding by PHD fingers of PHF23, KDM5A, and BPTF at conserved sites, suggesting a common PHD-dependent chromatin-targeting mechanism for this class of NUP98 fusions.\",\n      \"method\": \"ChIP demonstrating H3K4me3 co-occupancy, NMR analysis of PHD-H3K4me3 interaction, disulfiram PHD-inhibition cell viability assay\",\n      \"journal\": \"Nature communications / Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structural analysis plus ChIP-seq plus pharmacological inhibition with mechanistic read-out across multiple fusion proteins; multiple orthogonal methods\",\n      \"pmids\": [\"32620764\", \"24535671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Nup98 specifically regulates nuclear-to-cytoplasmic transport of galectin-3; Nup98 interacts with galectin-3 at the nuclear membrane and promotes galectin-3 cytoplasmic translocation; silencing Nup98 retains galectin-3 in the nucleus, retards cell growth, and suppresses β-catenin pathway target gene expression (cyclin D1, FRA-1).\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, cell growth assays, gene expression analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus siRNA knockdown with multiple readouts, single lab\",\n      \"pmids\": [\"23541576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Nup96+/− mice with selectively low Nup96 levels display downregulated MHC I and MHC II, ICAM-1, and impaired IFN-alpha and gamma-mediated induction of these proteins, demonstrating Nup96 (the NUP98 precursor cleavage product) is specifically required for proper nuclear transport and expression of interferon-regulated proteins and immune function.\",\n      \"method\": \"Nup96+/- mouse genetics, interferon stimulation assays, MHC expression analysis, T cell functional assays, viral infection susceptibility\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo haploinsufficiency mouse model with multiple immunological functional readouts; replicated across multiple immune assays in vivo\",\n      \"pmids\": [\"16546098\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP98 is a bifunctional nucleoporin: at the nuclear pore complex it facilitates multiple RNA export pathways (via its GLFG repeats docking export factors Rae1/Gle2 and TAP and acting as a Crm1 cofactor), assists in NPC assembly (autoproteolytic cleavage generating NUP96 and enabling cytoplasmic-face nucleoporin recruitment), and in mitosis forms a Rae1-Nup98 complex that inhibits APC/C-Cdh1-mediated securin ubiquitination to prevent premature anaphase; in the nuclear interior, mobile Nup98 recruits the Wdr82-Set1A/COMPASS complex to deposit H3K4me3 at active gene promoters, stimulates DHX9 helicase activity, protects specific mRNAs (p21) from exosomal degradation, and establishes transcriptional memory; in leukemia, NUP98 fusion oncoproteins exploit the FG-repeat transactivation domain to recruit CBP/p300, MLL1, KAT6A/KAT7, and other coactivators into phase-separated nuclear condensates targeted to developmental gene loci (via partner chromatin-reader domains such as PHF23-PHD binding H3K4me3), maintaining aberrant HOX/MEIS1 gene expression programs that drive leukemogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NUP98 is a bifunctional FG/GLFG-repeat nucleoporin that supports nucleocytoplasmic transport at the nuclear pore complex (NPC) while also acting in the nuclear interior to regulate gene expression [#1, #2]. NUP98 is co-translated with NUP96 as a 186-kDa precursor whose autoproteolytic cleavage is required to target both products to the nucleoplasmic face of the NPC and to nucleate a conserved NUP96-NUP107-Sec13 subcomplex [#0, #11]; the same cleavage-dependent C-terminal site mediates binding to both the cytoplasmic nucleoporin Nup88 and to Nup96, and loss of NUP98 impairs assembly of cytoplasmic-face nucleoporins and receptor-mediated import of selective cargoes [#3, #4]. At the pore, NUP98 enables export of multiple RNA classes [#1], serving as a docking platform whose GLFG domain assembles a ternary mRNA-export complex with Rae1/Gle2 and TAP [#7] and acting as a RanGTP-dependent cofactor for Crm1-mediated protein export through its N-terminal FG repeats [#12]. The Rae1·NUP98 module forms a seven-bladed β-propeller heterocomplex with single-stranded RNA-binding capacity [#8], and beyond transport this complex governs mitotic fidelity by inhibiting APC-Cdh1-mediated securin ubiquitination, preventing premature sister-chromatid separation and aneuploidy [#5]. A mobile intranuclear pool of NUP98, dependent on ongoing transcription, associates with developmentally regulated genes and active promoters [#2, #15], where it recruits the Wdr82-Set1A/COMPASS complex to deposit H3K4me3 at transcription start sites [#16], stimulates the ATPase activity of the DHX9 helicase at shared gene loci [#22], and post-transcriptionally protects specific mRNAs such as p21 from exosomal degradation [#17]. In leukemia, NUP98 fusion oncoproteins exploit the intrinsically disordered FG repeats to drive liquid-liquid phase separation into nuclear condensates that partition transcriptional coactivators—CBP/p300, MLL1/KMT2, the NSL complex, BRD4, and MYST acetyltransferases KAT6A/KAT7—and are targeted to developmental loci through partner chromatin-reader domains (e.g. the PHF23 PHD finger binding H3K4me3) and through prebound Crm1, sustaining aberrant HOX/MEIS1 and CDK6 transcriptional programs that drive transformation [#6, #13, #14, #26, #27, #29, #32, #33, #34]. The Nup98-Rae1 complex is additionally hijacked by viral antagonists, including SARS-CoV-2 ORF6 and VSV matrix protein, to block host transport and immune gene induction [#18, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established NUP98 as a functional requirement for RNA export rather than protein import, defining its core role at the pore.\",\n      \"evidence\": \"Anti-Nup98 antibody injection into Xenopus oocyte nuclei with class-specific RNA export and import assays\",\n      \"pmids\": [\"9015297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the molecular export factors NUP98 docks\", \"tRNA export and protein import unaffected, leaving pathway selectivity unexplained\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved the biogenesis of NUP98 and NUP96 from a single precursor, showing autoproteolytic cleavage is required for correct NPC targeting and subcomplex assembly.\",\n      \"evidence\": \"Biochemical fractionation, mutagenesis, immunoEM, and in vitro autocleavage assays in rat liver nuclei\",\n      \"pmids\": [\"10087256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address the intranuclear transport-independent functions of NUP98\", \"in vivo consequence of cleavage failure not tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified the FG repeats as a transactivation domain in the NUP98-HOXA9 oncofusion, linking a transport motif to coactivator recruitment in transformation.\",\n      \"evidence\": \"NIH 3T3 transformation, luciferase transactivation, and co-IP with CBP/p300\",\n      \"pmids\": [\"9858599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish chromatin targeting of the fusion\", \"physiological vs oncogenic FG-repeat function not yet distinguished\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Genetic disruption in mice demonstrated NUP98 is required for cytoplasmic-face nucleoporin assembly and selective cargo import, separating its roles from NUP96.\",\n      \"evidence\": \"Murine NUP98 gene targeting with immunofluorescence and selective cargo import assays\",\n      \"pmids\": [\"11248054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of cytoplasmic nucleoporin recruitment by NUP98 not resolved here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapped the GLFG-domain binding sites for the mRNA export machinery and the cleavage-dependent dual binding of NUP98 to Nup88 and Nup96.\",\n      \"evidence\": \"In vitro pulldown/competition binding and domain mapping; immunoEM and mutagenesis\",\n      \"pmids\": [\"12637516\", \"12589057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TAP-Rae1 binding overlap defined in vitro without in vivo export consequence\", \"single-lab binding data\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined a transport-independent mitotic function: the Rae1-NUP98 complex inhibits APC-Cdh1 to safeguard chromosome segregation.\",\n      \"evidence\": \"Mouse haploinsufficiency genetics, APC-Cdh1 co-IP, in vitro securin ubiquitination, and aneuploidy flow cytometry\",\n      \"pmids\": [\"16355229\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of APC-Cdh1 inhibition not defined\", \"how the same complex switches between transport and mitotic roles unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided atomic-resolution structure of the Rae1·NUP98 GLEBS complex and revealed its single-stranded RNA-binding activity, and separately defined NUP98 as a RanGTP-dependent Crm1 export cofactor.\",\n      \"evidence\": \"1.65 Å crystal structure with mutagenesis and RNA-binding assays; RanGTP-dependent co-IP, FG-repeat mutagenesis, and antibody export inhibition\",\n      \"pmids\": [\"20498086\", \"20375145\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional RNA target of the Rae1·NUP98 RNA-binding surface not identified\", \"RanBP3 modulation mechanism not detailed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed NUP98 binds developmental genes at both the pore and the nuclear interior and post-transcriptionally protects specific mRNAs, broadening its role to direct gene regulation.\",\n      \"evidence\": \"Genome-wide ChIP-seq in human ESCs with dominant-negative fragment; single-molecule mRNA analysis and exosome degradation assays for p21\",\n      \"pmids\": [\"23468646\", \"23102701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing pore-tethered vs interior gene regulation incomplete\", \"exosome-protection mechanism for mRNAs beyond p21/14-3-3σ not generalized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that NUP98 fusions are recruited to HOX loci via prebound Crm1 and physically engage MLL1/NSL complexes for aberrant transcription.\",\n      \"evidence\": \"Genome-wide ChIP-seq, leptomycin B Crm1 inhibition, and reciprocal co-IP of multiple fusions with MLL1/NSL\",\n      \"pmids\": [\"26740045\", \"27889185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Crm1 recruits wild-type NUP98 to the same loci unresolved\", \"biophysical nature of the chromatin 'dots' not yet defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the wild-type chromatin function of NUP98: recruitment of Wdr82-Set1A/COMPASS for H3K4me3 deposition and stimulation of the DHX9 helicase, and showed fusions mislocalize H3K4me3.\",\n      \"evidence\": \"ChIP-seq with Nup98/Wdr82 depletion and Set1A/H3K4me3 ChIP; in vitro ATPase stimulation and RNA-facilitated binding assays\",\n      \"pmids\": [\"29269482\", \"28221134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How transcription-dependent NUP98 mobility couples to COMPASS recruitment unclear\", \"DHX9 substrate transcripts in vivo not enumerated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed FG-repeat-driven liquid-liquid phase separation is the organizing principle of NUP98-fusion oncogenesis, concentrating chromatin regulators including SMARCA5.\",\n      \"evidence\": \"In vitro LLPS reconstitution, FG-repeat mutagenesis, AP-MS, FRAP, and hematopoietic transformation assays\",\n      \"pmids\": [\"34903620\", \"35073946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether wild-type NUP98 phase behavior contributes to normal gene regulation untested\", \"condensate composition rules across diverse fusions incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Dissected the division of labor between fusion partner reader domains (targeting) and FG repeats (composition/activation), revealing a feedforward read-and-write loop and actionable MYST-HAT dependencies.\",\n      \"evidence\": \"In vitro condensate reconstitution, mutagenesis, condensate proteomics, ChIP-seq, and genetic/pharmacological KAT6A/7 loss-of-function with xenografts\",\n      \"pmids\": [\"39922194\", \"40536430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability of the read-write loop across all NUP98 fusion classes not fully mapped\", \"therapeutic window of HAT and PHD inhibition not established here\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NUP98's transport, mitotic, and chromatin-regulatory activities are integrated and switched in normal cells, and whether condensate-based regulation operates at endogenous NUP98, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model linking pore residence, intranuclear mobility, and gene activation\", \"endogenous NUP98 phase behavior in normal hematopoiesis uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [8, 20]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 16, 32]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 12, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 15, 16]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [2, 22]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [16, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 4, 12]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 7, 17]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [16, 22, 32]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 24]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [13, 16, 32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 13, 27, 29]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [18, 36]}\n    ],\n    \"complexes\": [\n      \"NUP96-NUP107-Sec13 NPC subcomplex\",\n      \"Rae1-NUP98 complex\",\n      \"NUP98-Rae1-TAP mRNA export complex\",\n      \"Wdr82-Set1A/COMPASS complex\"\n    ],\n    \"partners\": [\n      \"RAE1\",\n      \"NUP96\",\n      \"NUP88\",\n      \"TAP\",\n      \"CRM1\",\n      \"DHX9\",\n      \"TPR\",\n      \"SEC13\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}