{"gene":"DDX39B","run_date":"2026-06-09T23:54:41","timeline":{"discoveries":[{"year":2001,"finding":"UAP56 directly and specifically interacts with the mRNA export factor Aly/REF, and is present together with Aly in the spliced mRNP. Excess UAP56 acts as a dominant negative inhibitor of mRNA export and blocks recruitment of Aly to the spliced mRNP. A mutation in Aly that blocks its interaction with UAP56 prevents recruitment of Aly to the spliced mRNP, demonstrating that UAP56 recruits Aly to couple splicing and mRNA export.","method":"Co-immunoprecipitation, dominant-negative overexpression, mutational analysis in Xenopus oocyte and mammalian systems","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, dominant-negative functional assay, mutagenesis, replicated across multiple experimental systems","pmids":["11675789"],"is_preprint":false},{"year":2001,"finding":"The Drosophila UAP56 homolog HEL is essential for bulk mRNA export; depletion of HEL by RNAi causes nuclear accumulation of poly(A)+ RNA and inhibits global protein synthesis. Human UAP56 preferentially associates with spliced mRNAs carrying the exon junction complex in HeLa nuclear extracts.","method":"RNAi depletion in Drosophila Schneider cells, [35S]methionine incorporation, nuclear fractionation, co-immunoprecipitation","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with specific cellular phenotype (nuclear poly(A)+ accumulation), multiple orthogonal methods, independently consistent with other labs","pmids":["11696332"],"is_preprint":false},{"year":2001,"finding":"UAP56/RAF-2p48/NPI-5/BAT1 interacts directly with influenza virus nucleoprotein (NP) via the amino-terminal RNA-binding domain of NP; UAP56 binds free NP but not RNA-bound NP, and facilitates NP-RNA complex formation, thereby enhancing influenza virus RNA synthesis.","method":"Yeast two-hybrid, in vitro binding assays, biochemical RNA synthesis assay with purified RAF-2 fraction","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus in vitro binding and functional RNA synthesis assay, single lab","pmids":["11160689"],"is_preprint":false},{"year":2002,"finding":"In Chironomus tentans, HEL/UAP56 binds cotranscriptionally to the Balbiani ring pre-mRNA independently of intron location, accompanies the mRNP to the nuclear pore, and is released from the mRNP during translocation to the cytoplasm, before Aly/REF dissociation.","method":"Immunoelectron microscopy, in situ analysis of mRNP at nuclear pore","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in situ imaging with immunoelectron microscopy, single lab, clear spatiotemporal resolution","pmids":["12015125"],"is_preprint":false},{"year":2003,"finding":"RNAi depletion of UAP56 in C. elegans causes strong nuclear retention of mRNA (suppression of GFP reporter expression due to nuclear retention), and overexpression of UAP56 also causes rapid loss of GFP expression and lethality, establishing UAP56 as a key mRNA export factor in worms.","method":"RNAi in C. elegans, GFP reporter assay, fluorescence microscopy","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function and overexpression with defined mRNA export phenotype, single lab","pmids":["12810918"],"is_preprint":false},{"year":2004,"finding":"Crystal structure of human UAP56 was solved, revealing a unique spatial arrangement of two RecA-like helicase domains. ADP binding induces significant conformational changes in the ATP-binding pocket. Purified UAP56 is an active RNA-dependent ATPase. Structural analyses suggest a protein-RNA displacement model for UAP56/Sub2 function.","method":"X-ray crystallography (crystal structures of UAP56 alone, ADP-bound, and DECD→DEAD mutant); in vitro ATPase assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional ATPase validation and mutagenesis, replicated by second independent crystal structure study (PMID:15296731)","pmids":["15585580"],"is_preprint":false},{"year":2004,"finding":"Crystal structures of the N- and C-terminal domains of human UAP56 at 1.9 Å resolution revealed two RecA-like domains connected by a flexible linker, similar to eIF4A, with an NTP binding pocket occupied by citrate. The N-terminal domain reveals a dimer interface potentially important for UAP56 function.","method":"X-ray crystallography","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — independent crystal structure determination at high resolution, consistent with PMID:15585580","pmids":["15296731"],"is_preprint":false},{"year":2004,"finding":"Both UAP56 and its paralog URH49 interact with the mRNA export factor Aly and both can rescue loss of Sub2p in yeast, indicating functionally overlapping roles in splicing and mRNA export.","method":"Yeast complementation assay, co-immunoprecipitation","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast genetic rescue plus Co-IP, single lab","pmids":["15047853"],"is_preprint":false},{"year":2006,"finding":"Human cytomegalovirus pUL69 promotes cytoplasmic accumulation of unspliced RNA by directly interacting with UAP56 and URH49 via a 12-amino-acid N-terminal domain; both UAP56 interaction and nucleocytoplasmic shuttling of pUL69 are required for its mRNA export activity.","method":"Co-immunoprecipitation, deletion/mutation mapping, mRNA export assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction mapping plus functional mRNA export assay, single lab","pmids":["16478985"],"is_preprint":false},{"year":2006,"finding":"siRNA depletion of either UAP56 or URH49 alone in HeLa cells causes speckled nuclear accumulation of poly(A)+ RNA; combined depletion of both causes major reduction in reporter gene expression and cell death within 72 h, demonstrating essential but largely redundant functions in mRNA processing and export.","method":"siRNA knockdown, fluorescence in situ hybridization (FISH) for poly(A)+ RNA, reporter gene assay","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with orthogonal phenotypic readouts (FISH + reporter), single lab","pmids":["16949217"],"is_preprint":false},{"year":2007,"finding":"UAP56 promotes ATP-dependent loading of Aly/REF onto intronless mRNAs in vitro; ATP activates the RNA-binding activity of UAP56 itself, and ATP-bound UAP56 binds both RNA and Aly/REF simultaneously, stimulating UAP56's ATPase activity cooperatively. An ATP-binding-deficient UAP56 mutant specifically inhibits mRNA export in Xenopus oocytes.","method":"In vitro RNA binding assays, ATPase assays, Xenopus oocyte mRNA export assay with dominant-negative mutant","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of Aly loading with mechanistic mutagenesis and orthogonal Xenopus export assay, single lab","pmids":["17984224"],"is_preprint":false},{"year":2007,"finding":"UAP56 is an RNA-stimulated ATPase that can only hydrolyze ATP (not other NTPs) and is an ATP-dependent RNA helicase capable of unwinding substrates with 5' or 3' overhangs or blunt ends. Mutations in conserved helicase motifs I, II, and III abolish ATPase and/or helicase activity. U2AF65 and Aly do not influence UAP56's ATPase or helicase activity.","method":"In vitro ATPase assay, RNA helicase unwinding assay, site-directed mutagenesis of helicase motifs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with systematic mutagenesis, single lab, multiple orthogonal assays","pmids":["17562711"],"is_preprint":false},{"year":2007,"finding":"UAP56 is required for bulk mRNA export from nurse cell nuclei in Drosophila, and also functions in the cytoplasm for remodeling RNP complexes that dictate cytoplasmic mRNA localization; loss of UAP56 disrupts localization of gurken, bicoid, and oskar mRNAs and post-translational modification of Osk protein.","method":"Drosophila genetics (loss-of-function alleles), RNA FISH, grk RNA injection into oocyte cytoplasm","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with specific molecular phenotypes plus cytoplasmic injection experiment, single lab","pmids":["18237727"],"is_preprint":false},{"year":2008,"finding":"ATP binding (but not hydrolysis per se) by UAP56 is required for mRNA export; a point mutant unable to bind ATP fails to export mRNA but does not affect RNA splicing. UAP56 is concentrated in nuclear speckle domains and in equilibrium binding at speckles regulated by ATP, as measured by FRAP.","method":"Confocal microscopy, FRAP, ATP-binding point mutant, mRNA export assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP plus mutant-based functional dissection, single lab","pmids":["18411249"],"is_preprint":false},{"year":2010,"finding":"CIP29/SARNP was identified as a new component of the human TREX complex. UAP56 mediates an ATP-dependent interaction between the THO complex and both CIP29 and Aly. Using recombinant proteins, UAP56, Aly, and CIP29 form an ATP-dependent trimeric complex in which UAP56 bridges the CIP29–Aly interaction, establishing that TREX assembly is ATP-dependent.","method":"Proteomic analysis of immunopurified TREX, in vitro reconstitution with recombinant proteins from E. coli, ATP-dependence assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified recombinant proteins plus proteomic validation, multiple orthogonal methods, single lab","pmids":["20844015"],"is_preprint":false},{"year":2010,"finding":"UAP56 and its paralog URH49 form distinct mRNA export complexes: UAP56 forms the canonical human TREX complex, while URH49 forms a distinct URH49-CIP29 complex (AREX). The two helicases regulate different genome-wide sets of mRNAs. Depletion of UAP56 causes mitotic delay and sister chromatid cohesion defects, while URH49 depletion causes chromosome arm resolution defects and cytokinesis failure.","method":"Co-immunoprecipitation, siRNA depletion, genome-wide microarray, flow cytometry, live-cell imaging","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genome-wide target analysis, loss-of-function with distinct mitotic phenotypes, multiple orthogonal methods","pmids":["20573985"],"is_preprint":false},{"year":2011,"finding":"UAP56 is required to prevent accumulation of double-stranded RNA (dsRNA) during influenza A virus infection; siRNA depletion of UAP56 leads to rapid accumulation of dsRNA in the perinuclear region and robust activation of dsRNA-dependent PKR. UAP56 depletion also reduces nuclear export of M1 and HA viral mRNAs.","method":"siRNA knockdown, immunofluorescence for dsRNA, PKR activation assay, mRNA nuclear export assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with specific molecular readouts (dsRNA detection, PKR activation), single lab","pmids":["21680511"],"is_preprint":false},{"year":2011,"finding":"Interferon-induced antiviral protein MxA directly interacts with UAP56 and URH49 in vitro using purified recombinant proteins; MxA forms complexes with UAP56/URH49 in the perinuclear region of cells, and mouse Mx1 (nuclear) interacts with UAP56/URH49 in distinct nuclear dots.","method":"Co-immunoprecipitation, in vitro binding assay with purified recombinant proteins, immunofluorescence colocalization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro direct binding with recombinant proteins plus cellular Co-IP and colocalization, single lab","pmids":["21859714"],"is_preprint":false},{"year":2011,"finding":"Polo-like kinase 1 (Plk1) interacts with UAP56 and phosphorylates it both in vitro and in vivo; Plk1-dependent phosphorylation of UAP56 triggers its ubiquitination and proteasomal degradation, inversely correlating UAP56 and Plk1 protein levels during the cell cycle.","method":"Co-immunoprecipitation, in vitro kinase assay, proteasome inhibitor treatment, cell cycle analysis","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus cellular ubiquitination/degradation assay, single lab","pmids":["21637952"],"is_preprint":false},{"year":2011,"finding":"UAP56 exhibits a CRM1-independent nucleocytoplasmic shuttling activity; intranuclear localization requires UAP56 amino acids 81–381, REF interaction requires residues 51–428, and the shuttling activity maps to the C-terminus (aa 195–428). Human UAP56 shuttles independently of Rae1, unlike its S. pombe ortholog.","method":"Heterokaryon shuttling assay, deletion/truncation mutant mapping, co-immunoprecipitation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping with heterokaryon assay, single lab","pmids":["21799930"],"is_preprint":false},{"year":2012,"finding":"In Drosophila, UAP56 colocalizes with the piRNA cluster-associated HP1 variant Rhino in the nucleus; cluster transcripts immunoprecipitate with both UAP56 and Vasa. A charge-substitution mutation of a conserved surface residue in UAP56 disrupts colocalization with Rhino, germline piRNA production, transposon silencing, and perinuclear localization of Vasa, establishing UAP56 as a component of the nuclear phase of a piRNA processing compartment spanning the nuclear envelope.","method":"Immunofluorescence colocalization, RNA immunoprecipitation, piRNA sequencing, transposon silencing assay, UAP56 charge-substitution mutant analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (imaging, RIP, sequencing, genetic mutant), single lab but rigorous mechanistic dissection","pmids":["23141543"],"is_preprint":false},{"year":2016,"finding":"DDX39B (UAP56) directly binds FUT3 pre-mRNA and promotes its splicing and nuclear export in colorectal cancer cells; upregulation of FUT3 activates TGFβ signaling via fucosylation of TGFβR-I, driving EMT.","method":"RIP-seq, minigene splicing assay, nuclear/cytoplasmic RNA fractionation, RNA-seq, gain/loss-of-function assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-seq plus orthogonal minigene splicing and fractionation assays, single lab","pmids":["33436563"],"is_preprint":false},{"year":2016,"finding":"shRNA screen identified DDX39B as a regulator of AR-V7 splice variant mRNA expression in prostate cancer; simultaneous knockdown of DDX39B and its paralog DDX39A drastically and selectively downregulated AR-V7 mRNA in multiple AR-V7-positive cell lines.","method":"shRNA library screen, siRNA knockdown, RT-PCR","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — focused knockdown screen with RT-PCR readout, no biochemical mechanistic follow-up, single lab","pmids":["28025139"],"is_preprint":false},{"year":2017,"finding":"UAP56 forms a complex with trimeric NP of influenza virus (not monomeric NP); two trimeric NP molecules are connected by UAP56 in the complex. UAP56 stimulates trimeric NP formation from monomeric NP and facilitates viral RNP formation by transferring trimeric NP to viral RNA, also preventing excess NP binding to RNA.","method":"Gel filtration, atomic force microscopy, co-immunoprecipitation, in vitro NP oligomerization assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with AFM structural analysis plus functional assays, single lab","pmids":["29070793"],"is_preprint":false},{"year":2018,"finding":"DDX39B overexpression promotes global translation by upregulating pre-ribosomal RNA levels, regulating both the stability and synthesis of pre-rRNA.","method":"Overexpression, ribosomal RNA stability assays, translation assays","journal":"RNA biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression-based functional analysis, single lab, limited mechanistic detail in abstract","pmids":["30176153"],"is_preprint":false},{"year":2020,"finding":"UAP56/DDX39B is a cotranscriptional RNA-DNA helicase that unwinds R loops genome-wide; its depletion causes R-loop accumulation, R-loop-mediated genome instability, and replication fork stalling. Overexpression of UAP56 suppresses R loops and genome instability induced by depletion of five different unrelated factors. UAP56 localizes to active chromatin.","method":"siRNA depletion, R-loop detection (S9.6 antibody), DNA damage assays, replication fork assay (DNA fiber), RNA-DNA helicase activity assay in vitro, ChIP-seq","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro helicase activity demonstrated plus genome-wide R-loop mapping, overexpression suppression of five independent perturbations, multiple orthogonal methods","pmids":["32439635"],"is_preprint":false},{"year":2020,"finding":"DDX39B inhibits NF-κB activity by inhibiting p65 phosphorylation; mechanistically, DDX39B interacts with the pattern recognition receptor LGP2 in a pathway requiring cellular response to cytoplasmic dsRNA. DDX39B protein abundance is regulated by site-specific sumoylation (mediated by SUMO E3 ligase PIASx-β) that promotes its poly-ubiquitination and degradation.","method":"Streptavidin-agarose pull-down with κB DNA probes, RNAi, CRISPR/Cas9, NF-κB reporter assay, Co-IP for LGP2 interaction, sumoylation and ubiquitination assays","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including pull-down, RNAi, CRISPR, and PTM assays, single lab","pmids":["32209106"],"is_preprint":false},{"year":2020,"finding":"DDX39B binds to and stabilizes BRCA1 mRNA; DDX39B depletion reduces BRCA1 levels, impairs ssDNA formation and RAD51 accumulation at DSBs, and sensitizes ovarian cancer cells to platinum/PARPi. DDX39B-deficient mice show embryonic lethality reminiscent of BRCA1 knockout.","method":"RIP (RNA immunoprecipitation), siRNA knockdown, CRISPR knockout, DNA repair assays (RPA/RAD51 foci), mRNA stability assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus functional DNA repair assays and mouse phenotype, single lab","pmids":["32989256"],"is_preprint":false},{"year":2020,"finding":"UAP56 interacts with influenza A virus NP at two sites: the canonical UAP56 core (two RecA domains) and a previously unidentified N-terminal extension (NTE); the NTE recognizes the nucleic acid binding region of NP and binding of UAP56-NTE and RNA to NP is mutually exclusive.","method":"In vitro binding assays with recombinant proteins, domain mapping, competition binding assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with recombinant proteins and domain mapping, single lab","pmids":["32085897"],"is_preprint":false},{"year":2022,"finding":"DDX39B directly binds the first exon of CDK6 and CCND1 pre-mRNAs (confirmed by RIP-seq) and promotes their splicing; CDK6/CCND1 are downstream effectors mediating DDX39B-driven G1/S cell cycle progression in colorectal cancer cells.","method":"RIP-seq, minigene splicing assay (RT-PCR/gel electrophoresis), flow cytometry, rescue experiments","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-seq plus orthogonal splicing assay and rescue experiment, single lab","pmids":["35046400"],"is_preprint":false},{"year":2022,"finding":"RETSAT interacts with DDX39B at replication forks; RETSAT detains DDX39B on forks to resolve R-loops via DDX39B's helicase activity, preventing fork damage and CHK1-initiated apoptosis.","method":"iPOND combined with mass spectrometry, co-immunoprecipitation, DNA fiber assay","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Low","confidence_rationale":"Tier 3 / Weak — iPOND/MS interaction discovery plus Co-IP, limited direct mechanistic reconstitution, single lab","pmids":["36109793"],"is_preprint":false},{"year":2023,"finding":"Crystal structure of a Tho1/SARNP–DDX39B/RNA complex was determined, revealing that SARNP/Tho1 engages DDX39B through tandem DDX39B-interacting motifs forming a high-order multivalent complex. Human SARNP can engage up to five DDX39B molecules. The SARNP/DDX39B/RNA high-order complex is evolutionarily conserved and affects export of GC-rich mRNAs.","method":"X-ray crystallography, co-immunoprecipitation, RNA-seq from SARNP knockdown cells","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation by RNA-seq from knockdown and biochemical binding assays, single lab","pmids":["37578863"],"is_preprint":false},{"year":2023,"finding":"DDX39B controls FOXP3 pre-mRNA splicing; DDX39B knockdown leads to loss of immune-regulatory and gain of immune-effector expression signatures. FOXP3 introns have C-rich/U-poor polypyrimidine tracts that confer exquisite sensitivity to DDX39B levels.","method":"siRNA knockdown, splicing assays, transcriptomics (RNA-seq), T regulatory cell functional assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with splicing and transcriptomic readouts, defined molecular mechanism (C-rich/U-poor py tracts), single lab","pmids":["37261960"],"is_preprint":false},{"year":2023,"finding":"DDX39B directly interacts with SREBP1 protein; DDX39B deficiency promotes FBXW7-mediated ubiquitination and degradation of SREBP1, reducing SREBP1 nuclear translocation and activation, resulting in decreased lipid accumulation in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, immunofluorescence for nuclear translocation, luciferase transcriptional activity assay, ubiquitination assay","journal":"Cellular oncology (Dordrecht, Netherlands)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP plus indirect pathway assays, single lab, no biochemical reconstitution of the interaction","pmids":["37052853"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of TREX-2.1/DDX39B and TREX-2/DDX39B complexes were determined. A novel nuclear complex TREX-2.1 (LENG8, PCID2, DSS1) was identified that facilitates release of DDX39B from mRNP; TREX-2.1 and TREX-2 share a conserved 'trigger loop' in LENG8 and GANP subunits respectively that is critical for DDX39B regulation. LENG8 knockdown alters nucleocytoplasmic ratio of GC-rich mRNAs.","method":"Cryo-EM structure determination, co-immunoprecipitation, siRNA knockdown, RNA-seq","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structures of two complexes with functional validation by knockdown and RNA-seq, single lab","pmids":["40595470"],"is_preprint":false},{"year":2024,"finding":"DDX39B promotes FOXP3 intron splicing at the pre-spliceosome assembly step; FOXP3 introns have C-rich/U-poor polypyrimidine tracts that reduce U2AF2 affinity and alter U2AF2 conformation, causing deficient recruitment of DDX39B to commitment complexes and inefficient CC-to-pre-spliceosome conversion.","method":"In vitro splicing/commitment complex assembly assays, RNA-protein binding assays, mutagenesis of polypyrimidine tracts","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro spliceosome assembly assays with mechanistic dissection, single lab","pmids":["38575347"],"is_preprint":false},{"year":2024,"finding":"DDX39A and DDX39B have significant redundancy in splicing targets but also unique targets; DDX39A cannot complement DDX39B-dependent splicing of IL7R exon 6. Cassette exons uniquely dependent on DDX39B have U-poor/C-rich polypyrimidine tracts in the upstream intron, which is required for DDX39B dependency.","method":"siRNA knockdown, RNA-seq, minigene splicing assay, polypyrimidine tract mutagenesis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic knockdown with RNA-seq and functional mutagenesis of cis-elements, single lab","pmids":["38801080"],"is_preprint":false},{"year":2024,"finding":"The structural basis of functional divergence between UAP56 and URH49 was established by comparing crystal structures and chimeric mutant analysis; unique structural features at the terminal regions of each helicase contribute to formation of distinct apo-TREX and apo-AREX complexes. Additional apo-AREX components physically and functionally associated with URH49 were identified.","method":"X-ray crystallography (UAP56 and URH49 structures), chimeric mutant analysis, co-immunoprecipitation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures plus chimeric mutant functional analysis and Co-IP, multiple orthogonal methods, single lab","pmids":["38225262"],"is_preprint":false},{"year":2024,"finding":"DDX39B directly binds GPX4 pre-mRNA and promotes its splicing and cytoplasmic export; inhibition of DDX39B ATPase activity by CCT018159 represses GPX4 pre-mRNA splicing and export, sensitizing HCC cells to sorafenib-induced ferroptosis.","method":"RIP, nuclear/cytoplasmic fractionation, chemical inhibitor (CCT018159) of ATPase activity, splicing assay","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus fractionation and pharmacological inhibition with functional readout, single lab","pmids":["38701867"],"is_preprint":false},{"year":2024,"finding":"The terminal regions of UAP56 are indispensable for TREX complex formation; a specific C-terminal amino acid of UAP56 is critical for complex formation, and its alanine substitution impairs complex formation and subsequently mRNA processing and export activity.","method":"Co-immunoprecipitation with deletion mutants, alanine substitution mutagenesis, mRNA export assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP-based domain mapping with single amino acid mutant, single lab, limited mechanistic depth","pmids":["38377942"],"is_preprint":false},{"year":2025,"finding":"De novo missense variants in DDX39B (e.g., p.Gly92Asp) and a splicing variant (c.433-1G>T) impair interaction with other TREX complex members in vitro; patient blood transcriptomics shows elevated aberrant splicing events; Drosophila and zebrafish models confirm loss-of-function effects on development.","method":"In vitro overexpression Co-IP for TREX interaction, blood transcriptomics, Drosophila transgenic overexpression lethality assay, zebrafish morpholino knockdown with mRNA rescue","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple model systems with orthogonal readouts, in vitro interaction studies, but variant effects are complex and partially variant-specific","pmids":["39918047"],"is_preprint":false},{"year":2025,"finding":"DDX39B undergoes TRIM28-mediated K63-linked ubiquitination at Lys241, Lys384, and Lys398 via interaction through Pro322; this ubiquitination stabilizes DDX39B protein. Stabilized DDX39B directly binds ECAD and promotes its lysosomal degradation by recruiting Src and Hakai, independent of DDX39B's RNA helicase activity, activating β-catenin signaling.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, immunofluorescence, functional metastasis assays","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutational mapping of ubiquitination sites plus functional assays, single lab","pmids":["40664668"],"is_preprint":false},{"year":2025,"finding":"DDX39B functions as a global repressor of A-to-I RNA editing by preventing double-stranded RNA accumulation through its helicase activity; DDX39B depletion significantly enhances A-to-I RNA editing efficiency genome-wide.","method":"CRISPR-based genetic screen (CREDITS/scCREDIT-seq), RNA editing transcriptomics, mechanistic follow-up with DDX39B knockdown","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-scale CRISPR screen with mechanistic follow-up, single lab","pmids":["40652511"],"is_preprint":false},{"year":2025,"finding":"The PAXT complex harbors a TREX-2-like LENG8-PCID2-SEM1 (LENG8-PS) module structurally and functionally equivalent to the GANP-PCID2-SEM1 trimer of TREX-2; this module releases pA+ RNAs from UAP56 for nuclear exosome-mediated decay. The nuclear fate of pA+ RNPs is governed by competition between nucleoplasmic PAXT and NPC-associated TREX-2, both interpreting RNA-bound UAP56 as a signal for either RNA decay or export, respectively.","method":"Structural analysis (cryo-EM/mutagenesis), RNA-seq, interaction/pulldown assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — structural and mutagenesis data plus transcriptomics, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.09.16.676470"],"is_preprint":true},{"year":2026,"finding":"Loss of UAP56 in Drosophila c4da sensory neurons causes dendrite and presynapse pruning defects during metamorphosis; this is linked to impaired ecdysone-induced expression of the actin-severing enzyme Mical and to actin accumulation at pruning presynapses, demonstrating a role for UAP56-dependent mRNA export in actin regulation during neuronal remodeling.","method":"Drosophila genetics (loss-of-function), immunofluorescence, live imaging, mRNA expression analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with specific molecular and cellular readouts (Mical expression, actin accumulation, pruning defect), single lab","pmids":["41958408"],"is_preprint":false}],"current_model":"DDX39B/UAP56 is a conserved ATP-dependent DEAD-box RNA helicase whose crystal/cryo-EM structures reveal two RecA-like domains that undergo ADP-induced conformational changes; it functions as an RNA-stimulated ATPase and ATP-dependent RNA-DNA helicase that: (1) recruits the mRNA export adaptor Aly/REF onto both spliced and intronless mRNAs in an ATP-dependent manner, bridging splicing and export by assembling the TREX complex (UAP56–Aly–CIP29/SARNP–THO) and coupling to the NPC-associated TREX-2 for mRNP release; (2) promotes pre-spliceosome assembly, particularly on introns with C-rich/U-poor polypyrimidine tracts such as those in FOXP3 and IL7R; (3) cotranscriptionally unwinds harmful R-loops genome-wide to prevent transcription-replication conflicts; (4) represses A-to-I RNA editing by preventing dsRNA accumulation; (5) participates in piRNA biogenesis by coupling nuclear cluster transcripts to perinuclear nuage; (6) acts as a molecular chaperone for influenza NP to facilitate viral RNP assembly; and (7) is post-translationally regulated by Plk1-mediated phosphorylation (triggering proteasomal degradation) and PIASx-β-mediated sumoylation-dependent ubiquitination, with its protein abundance and complex formation critically dependent on specific C-terminal residues."},"narrative":{"mechanistic_narrative":"DDX39B/UAP56 is a conserved DEAD-box ATP-dependent RNA helicase that couples nuclear mRNA biogenesis to export and safeguards genome integrity by resolving aberrant nucleic acid structures [PMID:11675789, PMID:15585580, PMID:32439635]. Crystal and cryo-EM structures reveal two RecA-like helicase domains that undergo ADP-induced conformational changes, supporting an RNA-stimulated ATPase that hydrolyzes only ATP and an ATP-dependent helicase that unwinds RNA duplexes with diverse end structures [PMID:15585580, PMID:15296731, PMID:17562711]. Through ATP-dependent loading of the export adaptor Aly/REF onto both spliced and intronless mRNAs, DDX39B bridges splicing and export by nucleating the human TREX complex, in which it directly links Aly and CIP29/SARNP; loss of DDX39B causes nuclear retention of poly(A)+ RNA and is essential across metazoa [PMID:11675789, PMID:11696332, PMID:17984224, PMID:20844015]. SARNP engages DDX39B through tandem motifs to build a high-order multivalent mRNP, and release of DDX39B from the export-competent mRNP is governed at the nuclear pore by TREX-2 and the related TREX-2.1 (LENG8-PCID2-DSS1) complex, which together direct GC-rich transcripts toward export [PMID:37578863, PMID:40595470]. Beyond export, DDX39B promotes pre-spliceosome assembly on introns bearing C-rich/U-poor polypyrimidine tracts—such as those in FOXP3 and IL7R—conferring substrate-specific dependence not shared with its paralog DDX39A [PMID:37261960, PMID:38575347, PMID:38801080]. As a cotranscriptional RNA-DNA helicase it unwinds R-loops genome-wide to prevent transcription-replication conflicts and replication fork stalling, and it represses A-to-I RNA editing by limiting double-stranded RNA accumulation [PMID:32439635, PMID:40652511]. DDX39B is post-translationally controlled by Plk1-dependent phosphorylation and PIASx-β-mediated sumoylation that trigger its ubiquitination and degradation, while its abundance and TREX assembly depend on specific terminal residues [PMID:21637952, PMID:32209106, PMID:38377942]. In addition to its cellular roles, DDX39B acts as a chaperone for influenza nucleoprotein, promoting trimeric NP formation and viral RNP assembly [PMID:29070793, PMID:32085897]. De novo DDX39B variants that impair TREX interaction cause aberrant splicing and developmental defects in patients and animal models, linking the gene to a neurodevelopmental disorder [PMID:39918047].","teleology":[{"year":2001,"claim":"Established how splicing is mechanistically coupled to mRNA export by showing DDX39B recruits the export adaptor Aly/REF onto spliced mRNPs.","evidence":"Reciprocal Co-IP, dominant-negative overexpression, and interaction-blocking mutagenesis in Xenopus and mammalian systems","pmids":["11675789"],"confidence":"High","gaps":["ATP-dependence of Aly recruitment not yet resolved at this stage","Intronless mRNA handling not addressed"]},{"year":2001,"claim":"Defined DDX39B as an essential bulk mRNA export factor, linking its loss to global nuclear poly(A)+ RNA retention.","evidence":"RNAi depletion in Drosophila with nuclear fractionation, protein synthesis measurement, and human spliced-mRNP association","pmids":["11696332"],"confidence":"High","gaps":["Molecular mechanism of release at the pore not addressed","Helicase activity not yet biochemically demonstrated"]},{"year":2001,"claim":"Identified DDX39B as an influenza NP-interacting host factor that promotes NP-RNA complex formation, revealing a viral-hijacking function.","evidence":"Yeast two-hybrid, in vitro binding, and biochemical viral RNA synthesis assays","pmids":["11160689"],"confidence":"Medium","gaps":["Structural basis of NP recognition unresolved at this stage","Single-lab finding"]},{"year":2004,"claim":"Provided the structural framework: two RecA-like helicase domains with an ADP-responsive nucleotide pocket and validated RNA-dependent ATPase activity.","evidence":"X-ray crystallography of apo, ADP-bound, and mutant forms plus in vitro ATPase assays, replicated by an independent structure","pmids":["15585580","15296731"],"confidence":"High","gaps":["Conformational cycle on RNA substrate not captured","Coupling of structure to TREX assembly not yet shown"]},{"year":2007,"claim":"Resolved the enzymology: DDX39B is an ATP-specific RNA-stimulated ATPase and ATP-dependent helicase whose activity drives Aly loading onto RNA.","evidence":"In vitro ATPase, RNA helicase unwinding, and Aly-loading assays with helicase-motif mutagenesis and Xenopus export assay","pmids":["17562711","17984224"],"confidence":"High","gaps":["Whether ATP hydrolysis versus binding suffices for export not fully separated here","In vivo substrate selectivity unaddressed"]},{"year":2010,"claim":"Demonstrated that TREX assembly is ATP-dependent and DDX39B bridges Aly and CIP29/SARNP, defining the architecture of the export-competent mRNP nucleator.","evidence":"Proteomics of immunopurified TREX and in vitro reconstitution with recombinant proteins","pmids":["20844015"],"confidence":"High","gaps":["Stoichiometry of the complex not yet defined","How TREX engages the NPC unresolved"]},{"year":2010,"claim":"Distinguished DDX39B from its paralog by showing it nucleates the canonical TREX complex with distinct genome-wide targets and mitotic functions.","evidence":"Reciprocal Co-IP, siRNA depletion, genome-wide microarray, flow cytometry, and live-cell imaging","pmids":["20573985"],"confidence":"High","gaps":["Structural determinants of paralog divergence not yet defined","Mechanism linking export to cohesion unclear"]},{"year":2020,"claim":"Revealed a genome-protective role: DDX39B is a cotranscriptional RNA-DNA helicase that unwinds R-loops to prevent transcription-replication conflicts.","evidence":"siRNA depletion, S9.6 R-loop detection, DNA fiber assays, in vitro RNA-DNA helicase assay, and ChIP-seq","pmids":["32439635"],"confidence":"High","gaps":["Recruitment to specific R-loop-prone loci not fully mapped","Relationship between export and R-loop functions unresolved"]},{"year":2023,"claim":"Established substrate-specific splicing control: DDX39B promotes pre-spliceosome assembly on introns with C-rich/U-poor polypyrimidine tracts such as FOXP3.","evidence":"siRNA knockdown, in vitro commitment-complex assembly assays, polypyrimidine-tract mutagenesis, and Treg transcriptomics","pmids":["37261960","38575347","38801080"],"confidence":"Medium","gaps":["How U2AF2 conformation gates DDX39B recruitment mechanistically incomplete","Generality across the transcriptome partially defined"]},{"year":2023,"claim":"Defined the multivalent SARNP-DDX39B mRNP architecture and its role in GC-rich mRNA export.","evidence":"X-ray crystallography of a Tho1/SARNP-DDX39B/RNA complex, Co-IP, and RNA-seq from knockdown","pmids":["37578863"],"confidence":"High","gaps":["Functional consequence of variable DDX39B occupancy not resolved","Disassembly mechanism not defined here"]},{"year":2024,"claim":"Identified the nuclear machinery that releases DDX39B from mRNP, showing TREX-2 and a new TREX-2.1 complex control export of GC-rich transcripts via a conserved trigger loop.","evidence":"Cryo-EM of TREX-2/DDX39B and TREX-2.1/DDX39B complexes, Co-IP, knockdown, and RNA-seq","pmids":["40595470"],"confidence":"High","gaps":["In vivo competition between release pathways not fully quantified","Trigger-loop catalytic mechanism partially defined"]},{"year":2025,"claim":"Connected DDX39B to human disease by showing de novo variants impair TREX interaction and cause developmental defects.","evidence":"In vitro Co-IP of variants, patient blood transcriptomics, and Drosophila/zebrafish models","pmids":["39918047"],"confidence":"Medium","gaps":["Variant effects are partly variant-specific and complex","Tissue-specific disease mechanism not resolved"]},{"year":2025,"claim":"Expanded RNA fate control: DDX39B-bound RNA is interpreted by competing PAXT (decay) and TREX-2 (export) machineries, and DDX39B represses A-to-I editing by limiting dsRNA.","evidence":"Structural/mutagenesis and RNA-seq analyses (one preprint); CRISPR editing screen with knockdown follow-up","pmids":["40652511"],"confidence":"Medium","gaps":["Determinants steering RNA toward decay versus export not fully defined","PAXT-competition model from preprint awaits peer review"]},{"year":null,"claim":"How DDX39B's distinct functions—export, splicing, R-loop resolution, editing repression, and helicase-independent roles—are spatially and temporally partitioned within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model coordinating multiple activities","Determinants of substrate and pathway choice undefined","In vivo regulation by PTMs across functions not unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[5,10,11]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[10,11,25]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[11,25]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,10,14]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[5,11,25]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[13,19]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[25]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,13,19]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,14,31,34]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[32,35,36]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[25,27]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,10]}],"complexes":["TREX","TREX-2","TREX-2.1"],"partners":["ALYREF","SARNP","DDX39A","PLK1","LENG8","PCID2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13838","full_name":"Spliceosome RNA helicase DDX39B","aliases":["56 kDa U2AF65-associated protein","ATP-dependent RNA helicase p47","DEAD box protein UAP56","HLA-B-associated transcript 1 protein"],"length_aa":428,"mass_kda":49.0,"function":"Involved in nuclear export of spliced and unspliced mRNA (PubMed:15833825, PubMed:15998806, PubMed:17190602). Component of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and specifically associates with spliced mRNA and not with unspliced pre-mRNA (PubMed:15833825, PubMed:15998806, PubMed:17190602). The TREX complex is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NXF1 pathway (PubMed:15833825, PubMed:15998806, PubMed:17190602). The THOC1-THOC2-THOC3 core complex alone is sufficient to promote ATPase activity of DDX39B; in the complex THOC2 is the only component that directly interacts with DDX39B (PubMed:33191911). Associates with SARNP/CIP29, which facilitates RNA binding of DDX39B and likely plays a role in mRNA export (PubMed:37578863). May undergo several rounds of ATP hydrolysis during assembly of TREX to drive subsequent loading of components such as ALYREF/THOC4 and CHTOP onto mRNA. Also associates with pre-mRNA independent of ALYREF/THOC4. Involved in the nuclear export of intronless mRNA; the ATP-bound form is proposed to recruit export adapter ALYREF/THOC4 to intronless mRNA; its ATPase activity is cooperatively stimulated by RNA and ALYREF/THOC4 and ATP hydrolysis is thought to trigger the dissociation from RNA to allow the association of ALYREF/THOC4 and the NXF1-NXT1 heterodimer. Involved in transcription elongation and genome stability Splice factor that is required for the first ATP-dependent step in spliceosome assembly and for the interaction of U2 snRNP with the branchpoint. Has both RNA-stimulated ATP binding/hydrolysis activity and ATP-dependent RNA unwinding activity. Even with the stimulation of RNA, the ATPase activity is weak. Can only hydrolyze ATP but not other NTPs. The RNA stimulation of ATPase activity does not have a strong preference for the sequence and length of the RNA. However, ssRNA stimulates the ATPase activity much more strongly than dsRNA. Can unwind 5' or 3' overhangs or blunt end RNA duplexes in vitro. The ATPase and helicase activities are not influenced by U2AF2; the effect of ALYREF/THOC4 is reported conflictingly with [PubMed:23299939] reporting a stimulatory effect (Microbial infection) The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production","subcellular_location":"Nucleus; Nucleus speckle; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q13838/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/DDX39B","classification":"Common Essential","n_dependent_lines":816,"n_total_lines":1208,"dependency_fraction":0.6754966887417219},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000198563","cell_line_id":"CID001752","localizations":[{"compartment":"chromatin","grade":3}],"interactors":[{"gene":"RTCB","stoichiometry":10.0},{"gene":"ERH","stoichiometry":4.0},{"gene":"ALYREF","stoichiometry":4.0},{"gene":"SNRPB","stoichiometry":4.0},{"gene":"TOP1","stoichiometry":4.0},{"gene":"ATG13","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"CDC40","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001752","total_profiled":1310},"omim":[{"mim_id":"619906","title":"DExD-BOX HELICASE 39A; DDX39A","url":"https://www.omim.org/entry/619906"},{"mim_id":"616933","title":"FORTY-TWO-THREE DOMAIN-CONTAINING PROTEIN 1; FYTTD1","url":"https://www.omim.org/entry/616933"},{"mim_id":"615403","title":"THO COMPLEX, SUBUNIT 6; THOC6","url":"https://www.omim.org/entry/615403"},{"mim_id":"612733","title":"THO COMPLEX, SUBUNIT 5; THOC5","url":"https://www.omim.org/entry/612733"},{"mim_id":"611965","title":"THO COMPLEX, SUBUNIT 7; THOC7","url":"https://www.omim.org/entry/611965"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear speckles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DDX39B"},"hgnc":{"alias_symbol":["D6S81E","Uap56"],"prev_symbol":["BAT1"]},"alphafold":{"accession":"Q13838","domains":[{"cath_id":"3.40.50.300","chopping":"47-252","consensus_level":"high","plddt":94.067,"start":47,"end":252},{"cath_id":"3.40.50.300","chopping":"255-421","consensus_level":"high","plddt":88.7244,"start":255,"end":421}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13838","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13838-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13838-F1-predicted_aligned_error_v6.png","plddt_mean":84.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DDX39B","jax_strain_url":"https://www.jax.org/strain/search?query=DDX39B"},"sequence":{"accession":"Q13838","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13838.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13838/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13838"}},"corpus_meta":[{"pmid":"11675789","id":"PMC_11675789","title":"Pre-mRNA 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2001,\n      \"finding\": \"UAP56 directly and specifically interacts with the mRNA export factor Aly/REF, and is present together with Aly in the spliced mRNP. Excess UAP56 acts as a dominant negative inhibitor of mRNA export and blocks recruitment of Aly to the spliced mRNP. A mutation in Aly that blocks its interaction with UAP56 prevents recruitment of Aly to the spliced mRNP, demonstrating that UAP56 recruits Aly to couple splicing and mRNA export.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative overexpression, mutational analysis in Xenopus oocyte and mammalian systems\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, dominant-negative functional assay, mutagenesis, replicated across multiple experimental systems\",\n      \"pmids\": [\"11675789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The Drosophila UAP56 homolog HEL is essential for bulk mRNA export; depletion of HEL by RNAi causes nuclear accumulation of poly(A)+ RNA and inhibits global protein synthesis. Human UAP56 preferentially associates with spliced mRNAs carrying the exon junction complex in HeLa nuclear extracts.\",\n      \"method\": \"RNAi depletion in Drosophila Schneider cells, [35S]methionine incorporation, nuclear fractionation, co-immunoprecipitation\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with specific cellular phenotype (nuclear poly(A)+ accumulation), multiple orthogonal methods, independently consistent with other labs\",\n      \"pmids\": [\"11696332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"UAP56/RAF-2p48/NPI-5/BAT1 interacts directly with influenza virus nucleoprotein (NP) via the amino-terminal RNA-binding domain of NP; UAP56 binds free NP but not RNA-bound NP, and facilitates NP-RNA complex formation, thereby enhancing influenza virus RNA synthesis.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assays, biochemical RNA synthesis assay with purified RAF-2 fraction\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus in vitro binding and functional RNA synthesis assay, single lab\",\n      \"pmids\": [\"11160689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In Chironomus tentans, HEL/UAP56 binds cotranscriptionally to the Balbiani ring pre-mRNA independently of intron location, accompanies the mRNP to the nuclear pore, and is released from the mRNP during translocation to the cytoplasm, before Aly/REF dissociation.\",\n      \"method\": \"Immunoelectron microscopy, in situ analysis of mRNP at nuclear pore\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in situ imaging with immunoelectron microscopy, single lab, clear spatiotemporal resolution\",\n      \"pmids\": [\"12015125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RNAi depletion of UAP56 in C. elegans causes strong nuclear retention of mRNA (suppression of GFP reporter expression due to nuclear retention), and overexpression of UAP56 also causes rapid loss of GFP expression and lethality, establishing UAP56 as a key mRNA export factor in worms.\",\n      \"method\": \"RNAi in C. elegans, GFP reporter assay, fluorescence microscopy\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function and overexpression with defined mRNA export phenotype, single lab\",\n      \"pmids\": [\"12810918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Crystal structure of human UAP56 was solved, revealing a unique spatial arrangement of two RecA-like helicase domains. ADP binding induces significant conformational changes in the ATP-binding pocket. Purified UAP56 is an active RNA-dependent ATPase. Structural analyses suggest a protein-RNA displacement model for UAP56/Sub2 function.\",\n      \"method\": \"X-ray crystallography (crystal structures of UAP56 alone, ADP-bound, and DECD→DEAD mutant); in vitro ATPase assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional ATPase validation and mutagenesis, replicated by second independent crystal structure study (PMID:15296731)\",\n      \"pmids\": [\"15585580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Crystal structures of the N- and C-terminal domains of human UAP56 at 1.9 Å resolution revealed two RecA-like domains connected by a flexible linker, similar to eIF4A, with an NTP binding pocket occupied by citrate. The N-terminal domain reveals a dimer interface potentially important for UAP56 function.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — independent crystal structure determination at high resolution, consistent with PMID:15585580\",\n      \"pmids\": [\"15296731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Both UAP56 and its paralog URH49 interact with the mRNA export factor Aly and both can rescue loss of Sub2p in yeast, indicating functionally overlapping roles in splicing and mRNA export.\",\n      \"method\": \"Yeast complementation assay, co-immunoprecipitation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast genetic rescue plus Co-IP, single lab\",\n      \"pmids\": [\"15047853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human cytomegalovirus pUL69 promotes cytoplasmic accumulation of unspliced RNA by directly interacting with UAP56 and URH49 via a 12-amino-acid N-terminal domain; both UAP56 interaction and nucleocytoplasmic shuttling of pUL69 are required for its mRNA export activity.\",\n      \"method\": \"Co-immunoprecipitation, deletion/mutation mapping, mRNA export assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction mapping plus functional mRNA export assay, single lab\",\n      \"pmids\": [\"16478985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"siRNA depletion of either UAP56 or URH49 alone in HeLa cells causes speckled nuclear accumulation of poly(A)+ RNA; combined depletion of both causes major reduction in reporter gene expression and cell death within 72 h, demonstrating essential but largely redundant functions in mRNA processing and export.\",\n      \"method\": \"siRNA knockdown, fluorescence in situ hybridization (FISH) for poly(A)+ RNA, reporter gene assay\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with orthogonal phenotypic readouts (FISH + reporter), single lab\",\n      \"pmids\": [\"16949217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UAP56 promotes ATP-dependent loading of Aly/REF onto intronless mRNAs in vitro; ATP activates the RNA-binding activity of UAP56 itself, and ATP-bound UAP56 binds both RNA and Aly/REF simultaneously, stimulating UAP56's ATPase activity cooperatively. An ATP-binding-deficient UAP56 mutant specifically inhibits mRNA export in Xenopus oocytes.\",\n      \"method\": \"In vitro RNA binding assays, ATPase assays, Xenopus oocyte mRNA export assay with dominant-negative mutant\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of Aly loading with mechanistic mutagenesis and orthogonal Xenopus export assay, single lab\",\n      \"pmids\": [\"17984224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UAP56 is an RNA-stimulated ATPase that can only hydrolyze ATP (not other NTPs) and is an ATP-dependent RNA helicase capable of unwinding substrates with 5' or 3' overhangs or blunt ends. Mutations in conserved helicase motifs I, II, and III abolish ATPase and/or helicase activity. U2AF65 and Aly do not influence UAP56's ATPase or helicase activity.\",\n      \"method\": \"In vitro ATPase assay, RNA helicase unwinding assay, site-directed mutagenesis of helicase motifs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with systematic mutagenesis, single lab, multiple orthogonal assays\",\n      \"pmids\": [\"17562711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UAP56 is required for bulk mRNA export from nurse cell nuclei in Drosophila, and also functions in the cytoplasm for remodeling RNP complexes that dictate cytoplasmic mRNA localization; loss of UAP56 disrupts localization of gurken, bicoid, and oskar mRNAs and post-translational modification of Osk protein.\",\n      \"method\": \"Drosophila genetics (loss-of-function alleles), RNA FISH, grk RNA injection into oocyte cytoplasm\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with specific molecular phenotypes plus cytoplasmic injection experiment, single lab\",\n      \"pmids\": [\"18237727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ATP binding (but not hydrolysis per se) by UAP56 is required for mRNA export; a point mutant unable to bind ATP fails to export mRNA but does not affect RNA splicing. UAP56 is concentrated in nuclear speckle domains and in equilibrium binding at speckles regulated by ATP, as measured by FRAP.\",\n      \"method\": \"Confocal microscopy, FRAP, ATP-binding point mutant, mRNA export assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP plus mutant-based functional dissection, single lab\",\n      \"pmids\": [\"18411249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CIP29/SARNP was identified as a new component of the human TREX complex. UAP56 mediates an ATP-dependent interaction between the THO complex and both CIP29 and Aly. Using recombinant proteins, UAP56, Aly, and CIP29 form an ATP-dependent trimeric complex in which UAP56 bridges the CIP29–Aly interaction, establishing that TREX assembly is ATP-dependent.\",\n      \"method\": \"Proteomic analysis of immunopurified TREX, in vitro reconstitution with recombinant proteins from E. coli, ATP-dependence assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified recombinant proteins plus proteomic validation, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"20844015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UAP56 and its paralog URH49 form distinct mRNA export complexes: UAP56 forms the canonical human TREX complex, while URH49 forms a distinct URH49-CIP29 complex (AREX). The two helicases regulate different genome-wide sets of mRNAs. Depletion of UAP56 causes mitotic delay and sister chromatid cohesion defects, while URH49 depletion causes chromosome arm resolution defects and cytokinesis failure.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion, genome-wide microarray, flow cytometry, live-cell imaging\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genome-wide target analysis, loss-of-function with distinct mitotic phenotypes, multiple orthogonal methods\",\n      \"pmids\": [\"20573985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"UAP56 is required to prevent accumulation of double-stranded RNA (dsRNA) during influenza A virus infection; siRNA depletion of UAP56 leads to rapid accumulation of dsRNA in the perinuclear region and robust activation of dsRNA-dependent PKR. UAP56 depletion also reduces nuclear export of M1 and HA viral mRNAs.\",\n      \"method\": \"siRNA knockdown, immunofluorescence for dsRNA, PKR activation assay, mRNA nuclear export assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with specific molecular readouts (dsRNA detection, PKR activation), single lab\",\n      \"pmids\": [\"21680511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Interferon-induced antiviral protein MxA directly interacts with UAP56 and URH49 in vitro using purified recombinant proteins; MxA forms complexes with UAP56/URH49 in the perinuclear region of cells, and mouse Mx1 (nuclear) interacts with UAP56/URH49 in distinct nuclear dots.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay with purified recombinant proteins, immunofluorescence colocalization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro direct binding with recombinant proteins plus cellular Co-IP and colocalization, single lab\",\n      \"pmids\": [\"21859714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Polo-like kinase 1 (Plk1) interacts with UAP56 and phosphorylates it both in vitro and in vivo; Plk1-dependent phosphorylation of UAP56 triggers its ubiquitination and proteasomal degradation, inversely correlating UAP56 and Plk1 protein levels during the cell cycle.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, proteasome inhibitor treatment, cell cycle analysis\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus cellular ubiquitination/degradation assay, single lab\",\n      \"pmids\": [\"21637952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"UAP56 exhibits a CRM1-independent nucleocytoplasmic shuttling activity; intranuclear localization requires UAP56 amino acids 81–381, REF interaction requires residues 51–428, and the shuttling activity maps to the C-terminus (aa 195–428). Human UAP56 shuttles independently of Rae1, unlike its S. pombe ortholog.\",\n      \"method\": \"Heterokaryon shuttling assay, deletion/truncation mutant mapping, co-immunoprecipitation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with heterokaryon assay, single lab\",\n      \"pmids\": [\"21799930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In Drosophila, UAP56 colocalizes with the piRNA cluster-associated HP1 variant Rhino in the nucleus; cluster transcripts immunoprecipitate with both UAP56 and Vasa. A charge-substitution mutation of a conserved surface residue in UAP56 disrupts colocalization with Rhino, germline piRNA production, transposon silencing, and perinuclear localization of Vasa, establishing UAP56 as a component of the nuclear phase of a piRNA processing compartment spanning the nuclear envelope.\",\n      \"method\": \"Immunofluorescence colocalization, RNA immunoprecipitation, piRNA sequencing, transposon silencing assay, UAP56 charge-substitution mutant analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (imaging, RIP, sequencing, genetic mutant), single lab but rigorous mechanistic dissection\",\n      \"pmids\": [\"23141543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DDX39B (UAP56) directly binds FUT3 pre-mRNA and promotes its splicing and nuclear export in colorectal cancer cells; upregulation of FUT3 activates TGFβ signaling via fucosylation of TGFβR-I, driving EMT.\",\n      \"method\": \"RIP-seq, minigene splicing assay, nuclear/cytoplasmic RNA fractionation, RNA-seq, gain/loss-of-function assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq plus orthogonal minigene splicing and fractionation assays, single lab\",\n      \"pmids\": [\"33436563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"shRNA screen identified DDX39B as a regulator of AR-V7 splice variant mRNA expression in prostate cancer; simultaneous knockdown of DDX39B and its paralog DDX39A drastically and selectively downregulated AR-V7 mRNA in multiple AR-V7-positive cell lines.\",\n      \"method\": \"shRNA library screen, siRNA knockdown, RT-PCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — focused knockdown screen with RT-PCR readout, no biochemical mechanistic follow-up, single lab\",\n      \"pmids\": [\"28025139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"UAP56 forms a complex with trimeric NP of influenza virus (not monomeric NP); two trimeric NP molecules are connected by UAP56 in the complex. UAP56 stimulates trimeric NP formation from monomeric NP and facilitates viral RNP formation by transferring trimeric NP to viral RNA, also preventing excess NP binding to RNA.\",\n      \"method\": \"Gel filtration, atomic force microscopy, co-immunoprecipitation, in vitro NP oligomerization assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with AFM structural analysis plus functional assays, single lab\",\n      \"pmids\": [\"29070793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DDX39B overexpression promotes global translation by upregulating pre-ribosomal RNA levels, regulating both the stability and synthesis of pre-rRNA.\",\n      \"method\": \"Overexpression, ribosomal RNA stability assays, translation assays\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression-based functional analysis, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"30176153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UAP56/DDX39B is a cotranscriptional RNA-DNA helicase that unwinds R loops genome-wide; its depletion causes R-loop accumulation, R-loop-mediated genome instability, and replication fork stalling. Overexpression of UAP56 suppresses R loops and genome instability induced by depletion of five different unrelated factors. UAP56 localizes to active chromatin.\",\n      \"method\": \"siRNA depletion, R-loop detection (S9.6 antibody), DNA damage assays, replication fork assay (DNA fiber), RNA-DNA helicase activity assay in vitro, ChIP-seq\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro helicase activity demonstrated plus genome-wide R-loop mapping, overexpression suppression of five independent perturbations, multiple orthogonal methods\",\n      \"pmids\": [\"32439635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DDX39B inhibits NF-κB activity by inhibiting p65 phosphorylation; mechanistically, DDX39B interacts with the pattern recognition receptor LGP2 in a pathway requiring cellular response to cytoplasmic dsRNA. DDX39B protein abundance is regulated by site-specific sumoylation (mediated by SUMO E3 ligase PIASx-β) that promotes its poly-ubiquitination and degradation.\",\n      \"method\": \"Streptavidin-agarose pull-down with κB DNA probes, RNAi, CRISPR/Cas9, NF-κB reporter assay, Co-IP for LGP2 interaction, sumoylation and ubiquitination assays\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including pull-down, RNAi, CRISPR, and PTM assays, single lab\",\n      \"pmids\": [\"32209106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DDX39B binds to and stabilizes BRCA1 mRNA; DDX39B depletion reduces BRCA1 levels, impairs ssDNA formation and RAD51 accumulation at DSBs, and sensitizes ovarian cancer cells to platinum/PARPi. DDX39B-deficient mice show embryonic lethality reminiscent of BRCA1 knockout.\",\n      \"method\": \"RIP (RNA immunoprecipitation), siRNA knockdown, CRISPR knockout, DNA repair assays (RPA/RAD51 foci), mRNA stability assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus functional DNA repair assays and mouse phenotype, single lab\",\n      \"pmids\": [\"32989256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UAP56 interacts with influenza A virus NP at two sites: the canonical UAP56 core (two RecA domains) and a previously unidentified N-terminal extension (NTE); the NTE recognizes the nucleic acid binding region of NP and binding of UAP56-NTE and RNA to NP is mutually exclusive.\",\n      \"method\": \"In vitro binding assays with recombinant proteins, domain mapping, competition binding assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with recombinant proteins and domain mapping, single lab\",\n      \"pmids\": [\"32085897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DDX39B directly binds the first exon of CDK6 and CCND1 pre-mRNAs (confirmed by RIP-seq) and promotes their splicing; CDK6/CCND1 are downstream effectors mediating DDX39B-driven G1/S cell cycle progression in colorectal cancer cells.\",\n      \"method\": \"RIP-seq, minigene splicing assay (RT-PCR/gel electrophoresis), flow cytometry, rescue experiments\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq plus orthogonal splicing assay and rescue experiment, single lab\",\n      \"pmids\": [\"35046400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RETSAT interacts with DDX39B at replication forks; RETSAT detains DDX39B on forks to resolve R-loops via DDX39B's helicase activity, preventing fork damage and CHK1-initiated apoptosis.\",\n      \"method\": \"iPOND combined with mass spectrometry, co-immunoprecipitation, DNA fiber assay\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — iPOND/MS interaction discovery plus Co-IP, limited direct mechanistic reconstitution, single lab\",\n      \"pmids\": [\"36109793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Crystal structure of a Tho1/SARNP–DDX39B/RNA complex was determined, revealing that SARNP/Tho1 engages DDX39B through tandem DDX39B-interacting motifs forming a high-order multivalent complex. Human SARNP can engage up to five DDX39B molecules. The SARNP/DDX39B/RNA high-order complex is evolutionarily conserved and affects export of GC-rich mRNAs.\",\n      \"method\": \"X-ray crystallography, co-immunoprecipitation, RNA-seq from SARNP knockdown cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation by RNA-seq from knockdown and biochemical binding assays, single lab\",\n      \"pmids\": [\"37578863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DDX39B controls FOXP3 pre-mRNA splicing; DDX39B knockdown leads to loss of immune-regulatory and gain of immune-effector expression signatures. FOXP3 introns have C-rich/U-poor polypyrimidine tracts that confer exquisite sensitivity to DDX39B levels.\",\n      \"method\": \"siRNA knockdown, splicing assays, transcriptomics (RNA-seq), T regulatory cell functional assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with splicing and transcriptomic readouts, defined molecular mechanism (C-rich/U-poor py tracts), single lab\",\n      \"pmids\": [\"37261960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DDX39B directly interacts with SREBP1 protein; DDX39B deficiency promotes FBXW7-mediated ubiquitination and degradation of SREBP1, reducing SREBP1 nuclear translocation and activation, resulting in decreased lipid accumulation in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence for nuclear translocation, luciferase transcriptional activity assay, ubiquitination assay\",\n      \"journal\": \"Cellular oncology (Dordrecht, Netherlands)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP plus indirect pathway assays, single lab, no biochemical reconstitution of the interaction\",\n      \"pmids\": [\"37052853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of TREX-2.1/DDX39B and TREX-2/DDX39B complexes were determined. A novel nuclear complex TREX-2.1 (LENG8, PCID2, DSS1) was identified that facilitates release of DDX39B from mRNP; TREX-2.1 and TREX-2 share a conserved 'trigger loop' in LENG8 and GANP subunits respectively that is critical for DDX39B regulation. LENG8 knockdown alters nucleocytoplasmic ratio of GC-rich mRNAs.\",\n      \"method\": \"Cryo-EM structure determination, co-immunoprecipitation, siRNA knockdown, RNA-seq\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structures of two complexes with functional validation by knockdown and RNA-seq, single lab\",\n      \"pmids\": [\"40595470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DDX39B promotes FOXP3 intron splicing at the pre-spliceosome assembly step; FOXP3 introns have C-rich/U-poor polypyrimidine tracts that reduce U2AF2 affinity and alter U2AF2 conformation, causing deficient recruitment of DDX39B to commitment complexes and inefficient CC-to-pre-spliceosome conversion.\",\n      \"method\": \"In vitro splicing/commitment complex assembly assays, RNA-protein binding assays, mutagenesis of polypyrimidine tracts\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro spliceosome assembly assays with mechanistic dissection, single lab\",\n      \"pmids\": [\"38575347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DDX39A and DDX39B have significant redundancy in splicing targets but also unique targets; DDX39A cannot complement DDX39B-dependent splicing of IL7R exon 6. Cassette exons uniquely dependent on DDX39B have U-poor/C-rich polypyrimidine tracts in the upstream intron, which is required for DDX39B dependency.\",\n      \"method\": \"siRNA knockdown, RNA-seq, minigene splicing assay, polypyrimidine tract mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic knockdown with RNA-seq and functional mutagenesis of cis-elements, single lab\",\n      \"pmids\": [\"38801080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The structural basis of functional divergence between UAP56 and URH49 was established by comparing crystal structures and chimeric mutant analysis; unique structural features at the terminal regions of each helicase contribute to formation of distinct apo-TREX and apo-AREX complexes. Additional apo-AREX components physically and functionally associated with URH49 were identified.\",\n      \"method\": \"X-ray crystallography (UAP56 and URH49 structures), chimeric mutant analysis, co-immunoprecipitation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures plus chimeric mutant functional analysis and Co-IP, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"38225262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DDX39B directly binds GPX4 pre-mRNA and promotes its splicing and cytoplasmic export; inhibition of DDX39B ATPase activity by CCT018159 represses GPX4 pre-mRNA splicing and export, sensitizing HCC cells to sorafenib-induced ferroptosis.\",\n      \"method\": \"RIP, nuclear/cytoplasmic fractionation, chemical inhibitor (CCT018159) of ATPase activity, splicing assay\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus fractionation and pharmacological inhibition with functional readout, single lab\",\n      \"pmids\": [\"38701867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The terminal regions of UAP56 are indispensable for TREX complex formation; a specific C-terminal amino acid of UAP56 is critical for complex formation, and its alanine substitution impairs complex formation and subsequently mRNA processing and export activity.\",\n      \"method\": \"Co-immunoprecipitation with deletion mutants, alanine substitution mutagenesis, mRNA export assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP-based domain mapping with single amino acid mutant, single lab, limited mechanistic depth\",\n      \"pmids\": [\"38377942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"De novo missense variants in DDX39B (e.g., p.Gly92Asp) and a splicing variant (c.433-1G>T) impair interaction with other TREX complex members in vitro; patient blood transcriptomics shows elevated aberrant splicing events; Drosophila and zebrafish models confirm loss-of-function effects on development.\",\n      \"method\": \"In vitro overexpression Co-IP for TREX interaction, blood transcriptomics, Drosophila transgenic overexpression lethality assay, zebrafish morpholino knockdown with mRNA rescue\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple model systems with orthogonal readouts, in vitro interaction studies, but variant effects are complex and partially variant-specific\",\n      \"pmids\": [\"39918047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DDX39B undergoes TRIM28-mediated K63-linked ubiquitination at Lys241, Lys384, and Lys398 via interaction through Pro322; this ubiquitination stabilizes DDX39B protein. Stabilized DDX39B directly binds ECAD and promotes its lysosomal degradation by recruiting Src and Hakai, independent of DDX39B's RNA helicase activity, activating β-catenin signaling.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, immunofluorescence, functional metastasis assays\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutational mapping of ubiquitination sites plus functional assays, single lab\",\n      \"pmids\": [\"40664668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DDX39B functions as a global repressor of A-to-I RNA editing by preventing double-stranded RNA accumulation through its helicase activity; DDX39B depletion significantly enhances A-to-I RNA editing efficiency genome-wide.\",\n      \"method\": \"CRISPR-based genetic screen (CREDITS/scCREDIT-seq), RNA editing transcriptomics, mechanistic follow-up with DDX39B knockdown\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-scale CRISPR screen with mechanistic follow-up, single lab\",\n      \"pmids\": [\"40652511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The PAXT complex harbors a TREX-2-like LENG8-PCID2-SEM1 (LENG8-PS) module structurally and functionally equivalent to the GANP-PCID2-SEM1 trimer of TREX-2; this module releases pA+ RNAs from UAP56 for nuclear exosome-mediated decay. The nuclear fate of pA+ RNPs is governed by competition between nucleoplasmic PAXT and NPC-associated TREX-2, both interpreting RNA-bound UAP56 as a signal for either RNA decay or export, respectively.\",\n      \"method\": \"Structural analysis (cryo-EM/mutagenesis), RNA-seq, interaction/pulldown assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural and mutagenesis data plus transcriptomics, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.16.676470\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Loss of UAP56 in Drosophila c4da sensory neurons causes dendrite and presynapse pruning defects during metamorphosis; this is linked to impaired ecdysone-induced expression of the actin-severing enzyme Mical and to actin accumulation at pruning presynapses, demonstrating a role for UAP56-dependent mRNA export in actin regulation during neuronal remodeling.\",\n      \"method\": \"Drosophila genetics (loss-of-function), immunofluorescence, live imaging, mRNA expression analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with specific molecular and cellular readouts (Mical expression, actin accumulation, pruning defect), single lab\",\n      \"pmids\": [\"41958408\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DDX39B/UAP56 is a conserved ATP-dependent DEAD-box RNA helicase whose crystal/cryo-EM structures reveal two RecA-like domains that undergo ADP-induced conformational changes; it functions as an RNA-stimulated ATPase and ATP-dependent RNA-DNA helicase that: (1) recruits the mRNA export adaptor Aly/REF onto both spliced and intronless mRNAs in an ATP-dependent manner, bridging splicing and export by assembling the TREX complex (UAP56–Aly–CIP29/SARNP–THO) and coupling to the NPC-associated TREX-2 for mRNP release; (2) promotes pre-spliceosome assembly, particularly on introns with C-rich/U-poor polypyrimidine tracts such as those in FOXP3 and IL7R; (3) cotranscriptionally unwinds harmful R-loops genome-wide to prevent transcription-replication conflicts; (4) represses A-to-I RNA editing by preventing dsRNA accumulation; (5) participates in piRNA biogenesis by coupling nuclear cluster transcripts to perinuclear nuage; (6) acts as a molecular chaperone for influenza NP to facilitate viral RNP assembly; and (7) is post-translationally regulated by Plk1-mediated phosphorylation (triggering proteasomal degradation) and PIASx-β-mediated sumoylation-dependent ubiquitination, with its protein abundance and complex formation critically dependent on specific C-terminal residues.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DDX39B/UAP56 is a conserved DEAD-box ATP-dependent RNA helicase that couples nuclear mRNA biogenesis to export and safeguards genome integrity by resolving aberrant nucleic acid structures [#0, #5, #25]. Crystal and cryo-EM structures reveal two RecA-like helicase domains that undergo ADP-induced conformational changes, supporting an RNA-stimulated ATPase that hydrolyzes only ATP and an ATP-dependent helicase that unwinds RNA duplexes with diverse end structures [#5, #6, #11]. Through ATP-dependent loading of the export adaptor Aly/REF onto both spliced and intronless mRNAs, DDX39B bridges splicing and export by nucleating the human TREX complex, in which it directly links Aly and CIP29/SARNP; loss of DDX39B causes nuclear retention of poly(A)+ RNA and is essential across metazoa [#0, #1, #10, #14]. SARNP engages DDX39B through tandem motifs to build a high-order multivalent mRNP, and release of DDX39B from the export-competent mRNP is governed at the nuclear pore by TREX-2 and the related TREX-2.1 (LENG8-PCID2-DSS1) complex, which together direct GC-rich transcripts toward export [#31, #34]. Beyond export, DDX39B promotes pre-spliceosome assembly on introns bearing C-rich/U-poor polypyrimidine tracts—such as those in FOXP3 and IL7R—conferring substrate-specific dependence not shared with its paralog DDX39A [#32, #35, #36]. As a cotranscriptional RNA-DNA helicase it unwinds R-loops genome-wide to prevent transcription-replication conflicts and replication fork stalling, and it represses A-to-I RNA editing by limiting double-stranded RNA accumulation [#25, #42]. DDX39B is post-translationally controlled by Plk1-dependent phosphorylation and PIASx-β-mediated sumoylation that trigger its ubiquitination and degradation, while its abundance and TREX assembly depend on specific terminal residues [#18, #26, #39]. In addition to its cellular roles, DDX39B acts as a chaperone for influenza nucleoprotein, promoting trimeric NP formation and viral RNP assembly [#23, #28]. De novo DDX39B variants that impair TREX interaction cause aberrant splicing and developmental defects in patients and animal models, linking the gene to a neurodevelopmental disorder [#40].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established how splicing is mechanistically coupled to mRNA export by showing DDX39B recruits the export adaptor Aly/REF onto spliced mRNPs.\",\n      \"evidence\": \"Reciprocal Co-IP, dominant-negative overexpression, and interaction-blocking mutagenesis in Xenopus and mammalian systems\",\n      \"pmids\": [\"11675789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ATP-dependence of Aly recruitment not yet resolved at this stage\", \"Intronless mRNA handling not addressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined DDX39B as an essential bulk mRNA export factor, linking its loss to global nuclear poly(A)+ RNA retention.\",\n      \"evidence\": \"RNAi depletion in Drosophila with nuclear fractionation, protein synthesis measurement, and human spliced-mRNP association\",\n      \"pmids\": [\"11696332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of release at the pore not addressed\", \"Helicase activity not yet biochemically demonstrated\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified DDX39B as an influenza NP-interacting host factor that promotes NP-RNA complex formation, revealing a viral-hijacking function.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, and biochemical viral RNA synthesis assays\",\n      \"pmids\": [\"11160689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of NP recognition unresolved at this stage\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Provided the structural framework: two RecA-like helicase domains with an ADP-responsive nucleotide pocket and validated RNA-dependent ATPase activity.\",\n      \"evidence\": \"X-ray crystallography of apo, ADP-bound, and mutant forms plus in vitro ATPase assays, replicated by an independent structure\",\n      \"pmids\": [\"15585580\", \"15296731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational cycle on RNA substrate not captured\", \"Coupling of structure to TREX assembly not yet shown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved the enzymology: DDX39B is an ATP-specific RNA-stimulated ATPase and ATP-dependent helicase whose activity drives Aly loading onto RNA.\",\n      \"evidence\": \"In vitro ATPase, RNA helicase unwinding, and Aly-loading assays with helicase-motif mutagenesis and Xenopus export assay\",\n      \"pmids\": [\"17562711\", \"17984224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ATP hydrolysis versus binding suffices for export not fully separated here\", \"In vivo substrate selectivity unaddressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that TREX assembly is ATP-dependent and DDX39B bridges Aly and CIP29/SARNP, defining the architecture of the export-competent mRNP nucleator.\",\n      \"evidence\": \"Proteomics of immunopurified TREX and in vitro reconstitution with recombinant proteins\",\n      \"pmids\": [\"20844015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the complex not yet defined\", \"How TREX engages the NPC unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Distinguished DDX39B from its paralog by showing it nucleates the canonical TREX complex with distinct genome-wide targets and mitotic functions.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA depletion, genome-wide microarray, flow cytometry, and live-cell imaging\",\n      \"pmids\": [\"20573985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinants of paralog divergence not yet defined\", \"Mechanism linking export to cohesion unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a genome-protective role: DDX39B is a cotranscriptional RNA-DNA helicase that unwinds R-loops to prevent transcription-replication conflicts.\",\n      \"evidence\": \"siRNA depletion, S9.6 R-loop detection, DNA fiber assays, in vitro RNA-DNA helicase assay, and ChIP-seq\",\n      \"pmids\": [\"32439635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recruitment to specific R-loop-prone loci not fully mapped\", \"Relationship between export and R-loop functions unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established substrate-specific splicing control: DDX39B promotes pre-spliceosome assembly on introns with C-rich/U-poor polypyrimidine tracts such as FOXP3.\",\n      \"evidence\": \"siRNA knockdown, in vitro commitment-complex assembly assays, polypyrimidine-tract mutagenesis, and Treg transcriptomics\",\n      \"pmids\": [\"37261960\", \"38575347\", \"38801080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How U2AF2 conformation gates DDX39B recruitment mechanistically incomplete\", \"Generality across the transcriptome partially defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the multivalent SARNP-DDX39B mRNP architecture and its role in GC-rich mRNA export.\",\n      \"evidence\": \"X-ray crystallography of a Tho1/SARNP-DDX39B/RNA complex, Co-IP, and RNA-seq from knockdown\",\n      \"pmids\": [\"37578863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of variable DDX39B occupancy not resolved\", \"Disassembly mechanism not defined here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified the nuclear machinery that releases DDX39B from mRNP, showing TREX-2 and a new TREX-2.1 complex control export of GC-rich transcripts via a conserved trigger loop.\",\n      \"evidence\": \"Cryo-EM of TREX-2/DDX39B and TREX-2.1/DDX39B complexes, Co-IP, knockdown, and RNA-seq\",\n      \"pmids\": [\"40595470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo competition between release pathways not fully quantified\", \"Trigger-loop catalytic mechanism partially defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected DDX39B to human disease by showing de novo variants impair TREX interaction and cause developmental defects.\",\n      \"evidence\": \"In vitro Co-IP of variants, patient blood transcriptomics, and Drosophila/zebrafish models\",\n      \"pmids\": [\"39918047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Variant effects are partly variant-specific and complex\", \"Tissue-specific disease mechanism not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded RNA fate control: DDX39B-bound RNA is interpreted by competing PAXT (decay) and TREX-2 (export) machineries, and DDX39B represses A-to-I editing by limiting dsRNA.\",\n      \"evidence\": \"Structural/mutagenesis and RNA-seq analyses (one preprint); CRISPR editing screen with knockdown follow-up\",\n      \"pmids\": [\"40652511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants steering RNA toward decay versus export not fully defined\", \"PAXT-competition model from preprint awaits peer review\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DDX39B's distinct functions—export, splicing, R-loop resolution, editing repression, and helicase-independent roles—are spatially and temporally partitioned within a single cell remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model coordinating multiple activities\", \"Determinants of substrate and pathway choice undefined\", \"In vivo regulation by PTMs across functions not unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [5, 10, 11]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [10, 11, 25]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [11, 25]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 10, 14]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [5, 11, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [13, 19]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [25]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 13, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 14, 31, 34]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [32, 35, 36]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [25, 27]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 10]}\n    ],\n    \"complexes\": [\"TREX\", \"TREX-2\", \"TREX-2.1\"],\n    \"partners\": [\"ALYREF\", \"SARNP\", \"DDX39A\", \"PLK1\", \"LENG8\", \"PCID2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":9,"faith_pct":88.88888888888889}}