{"gene":"DDX39B","run_date":"2026-04-28T17:46:02","timeline":{"discoveries":[{"year":2001,"finding":"UAP56 directly interacts with the mRNA export adaptor Aly/REF, and this interaction recruits Aly to the spliced mRNP, coupling pre-mRNA splicing to mRNA export. Excess UAP56 acts as a dominant-negative inhibitor of mRNA export and blocks Aly recruitment to the spliced mRNP.","method":"Co-immunoprecipitation, dominant-negative overexpression in HeLa nuclear extracts, Aly mutation that blocks UAP56 interaction prevents Aly recruitment to spliced mRNP","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with functional validation by dominant-negative and separation-of-function mutation; foundational paper with 330 citations","pmids":["11675789"],"is_preprint":false},{"year":2001,"finding":"Drosophila HEL (UAP56 ortholog) is essential for bulk mRNA nuclear export; depletion causes nuclear accumulation of poly(A)+ RNA and inhibits protein synthesis from both spliced and intronless mRNAs.","method":"RNAi depletion in Drosophila Schneider cells, fluorescence in situ hybridization for poly(A)+ RNA, [35S]methionine incorporation assay","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype, replicated across transcript types; 198 citations","pmids":["11696332"],"is_preprint":false},{"year":2001,"finding":"UAP56 (RAF-2p48/BAT1) is a cellular splicing factor that interacts directly with influenza virus nucleoprotein (NP); it binds RNA-free NP but not RNA-bound NP, and facilitates NP-RNA complex formation required for viral RNA synthesis.","method":"Yeast two-hybrid, in vitro binding assays with purified proteins, influenza RNA synthesis reconstitution assay","journal":"Journal of Virology","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro binding + reconstituted RNA synthesis assay with domain mapping; 144 citations","pmids":["11160689"],"is_preprint":false},{"year":2004,"finding":"Crystal structure of human UAP56 reveals two RecA-like helicase domains connected by a flexible linker; ADP binding induces significant conformational changes in the ATP-binding pocket. Purified UAP56 is an active RNA-dependent ATPase. Structure suggests a protein-RNA displacement model for UAP56/Sub2 function.","method":"X-ray crystallography of UAP56 alone, UAP56-ADP complex, and DECD→DEAD mutant; in vitro ATPase assay","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus in vitro enzymatic validation; 105 citations","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 reveal RecA-like folds similar to eIF4A; the N-terminal domain shows a dimer interface potentially important for UAP56 function. The NTP-binding pocket contains a citrate ion mimicking phosphates, retaining the P-loop in open conformation.","method":"X-ray crystallography","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with functional interpretation; 59 citations","pmids":["15296731"],"is_preprint":false},{"year":2006,"finding":"Human cytomegalovirus pUL69 interacts directly with UAP56 and URH49 via a 12-amino-acid N-terminal domain, and this interaction plus nucleocytoplasmic shuttling are both required for pUL69-mediated nuclear export of unspliced viral mRNA.","method":"Co-immunoprecipitation, domain mapping, heterokaryon shuttling assay, mRNA export reporter assay","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, domain-mapping mutagenesis, functional export assay; 102 citations","pmids":["16478985"],"is_preprint":false},{"year":2007,"finding":"UAP56 promotes ATP-dependent loading of Aly/REF onto intronless mRNAs in vitro. ATP-bound UAP56 binds both RNA and Aly/REF simultaneously, and ATP hydrolysis drives UAP56 dissociation after Aly loading. An ATP-binding-deficient UAP56 mutant specifically inhibits mRNA export in Xenopus oocytes.","method":"In vitro RNA-binding assay, ATP analogue experiments, Xenopus oocyte mRNA export assay with dominant-negative mutant","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro reconstitution with biochemical dissection of ATP cycle plus Xenopus functional assay; 97 citations","pmids":["17984224"],"is_preprint":false},{"year":2007,"finding":"UAP56 is an RNA-stimulated ATPase that specifically hydrolyzes ATP 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.","method":"In vitro ATPase assay, in vitro helicase unwinding assay, site-directed mutagenesis of conserved motifs","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — biochemical characterization with mutagenesis; 83 citations","pmids":["17562711"],"is_preprint":false},{"year":2008,"finding":"ATP binding by UAP56 is required for mRNA export but not for RNA splicing. UAP56 localizes to nuclear splicing speckle domains and is in dynamic equilibrium in complexes containing SRm160, as measured by FRAP; ATP binding regulates this equilibrium.","method":"Confocal microscopy, FRAP (live cells and in vitro digitonin-extracted cells), ATP-binding-deficient point mutant, mRNA export assay","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 2 — FRAP with functional mutant, live-cell localization tied to functional consequence; 55 citations","pmids":["18411249"],"is_preprint":false},{"year":2010,"finding":"UAP56 mediates ATP-dependent interactions between the THO complex and both CIP29 and Aly to assemble the human TREX complex. Using recombinant proteins, UAP56, Aly, and CIP29 form an ATP-dependent trimeric complex in which UAP56 bridges CIP29 and Aly interactions.","method":"Proteomics (immunopurification/MS), recombinant protein reconstitution in E. coli, ATP-dependency biochemical assays","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with purified recombinant proteins plus proteomic identification; 148 citations","pmids":["20844015"],"is_preprint":false},{"year":2010,"finding":"UAP56 forms the human TREX complex (distinct from URH49-containing AREX complex), and its depletion causes mitotic delay and sister chromatid cohesion defects; genome-wide analysis shows UAP56 and URH49 regulate distinct sets of target mRNAs including different mitotic regulators.","method":"siRNA depletion, immunofluorescence, mitotic phenotype analysis, genome-wide mRNA profiling","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype (mitotic defects) and genome-wide target identification; 87 citations","pmids":["20573985"],"is_preprint":false},{"year":2011,"finding":"UAP56 depletion in influenza A virus-infected cells leads to rapid accumulation of double-stranded RNA (dsRNA) in the perinuclear region and robust activation of PKR, suggesting UAP56 is recruited by influenza virus to prevent dsRNA formation and thereby suppress innate immune activation.","method":"siRNA depletion, immunofluorescence for dsRNA, PKR activation assay, actinomycin D and cycloheximide controls","journal":"Journal of Virology","confidence":"High","confidence_rationale":"Tier 2 — clean KD with defined molecular phenotype; 61 citations","pmids":["21680511"],"is_preprint":false},{"year":2011,"finding":"Interferon-induced antiviral GTPase MxA directly binds UAP56 and URH49 in vitro and forms complexes with them in the perinuclear region in cells; mouse Mx1 also binds UAP56/URH49 in distinct nuclear dots.","method":"Immunoprecipitation, in vitro binding assay with purified recombinant proteins, immunofluorescence co-localization","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro binding with purified proteins confirmed by co-IP in cells; 35 citations","pmids":["21859714"],"is_preprint":false},{"year":2011,"finding":"UAP56 undergoes CRM1-independent nucleocytoplasmic shuttling; the intranuclear localization domain maps to aa81-381 and the shuttling domain maps to the C-terminus (aa195-428), which also mediates REF interaction. Shuttling is independent of Rae1 in human cells.","method":"Heterokaryon assay, deletion mapping with truncation mutants, immunofluorescence","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 — heterokaryon shuttling assay with domain mapping; single lab","pmids":["21799930"],"is_preprint":false},{"year":2011,"finding":"Polo-like kinase 1 (Plk1) physically interacts with UAP56, phosphorylates it in vitro and in vivo, and this phosphorylation triggers ubiquitination and proteasomal degradation of UAP56, inversely correlating protein levels of UAP56 and Plk1 during the cell cycle.","method":"Co-immunoprecipitation, in vitro kinase assay, in vivo phosphorylation, ubiquitination assay, proteasome inhibitor treatment","journal":"Molecular Biology Reports","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro kinase assay + in vivo functional consequence; single lab","pmids":["21637952"],"is_preprint":false},{"year":2012,"finding":"In Drosophila, nuclear UAP56 colocalizes with the heterochromatin protein HP1 variant Rhino at piRNA cluster loci; cluster transcripts immunoprecipitate with both UAP56 and Vasa; a charge-substitution mutation in UAP56 disrupts Rhino colocalization, germline piRNA production, transposon silencing, and perinuclear Vasa localization, placing UAP56 at the nuclear side of a piRNA-processing compartment spanning the nuclear envelope.","method":"Immunofluorescence, RNA immunoprecipitation, charge-substitution mutagenesis, piRNA sequencing","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — functional mutagenesis + RNA-IP + localization with defined pathway phenotype; 184 citations","pmids":["23141543"],"is_preprint":false},{"year":2012,"finding":"UAP56 interacts with Bcr kinase; knockdown of UAP56 blocks Bcr-induced DNA synthesis and reverses Bcr-mediated upregulation of cyclin E and downregulation of p27 in vascular smooth muscle cells.","method":"Co-immunoprecipitation, siRNA knockdown, DNA synthesis assay, cyclin E/p27 western blot","journal":"Biochemical and Biophysical Research Communications","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP with partial functional follow-up; single lab","pmids":["22446327"],"is_preprint":false},{"year":2016,"finding":"DDX39B (and its paralog DDX39A) regulate the generation of androgen receptor splice variant AR-V7; simultaneous knockdown of both DDX39B and DDX39A drastically and selectively downregulated AR-V7 mRNA expression in multiple prostate cancer cell lines.","method":"shRNA screen of spliceosome-related genes, siRNA knockdown of DDX39B and DDX39A in multiple cell lines, RT-PCR quantification of AR-V7","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 — functional screen plus validation in multiple cell lines; single lab","pmids":["28025139"],"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. UAP56 overexpression suppresses R loops and genome instability induced by depletion of five unrelated factors. RNA-DNA helicase activity was demonstrated in vitro.","method":"In vitro RNA-DNA helicase assay, DRIP-seq (genome-wide R-loop mapping), DNA damage markers, replication fork assays, overexpression rescue experiments","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 1 — in vitro helicase activity demonstrated with genome-wide functional validation and rescue across multiple perturbations; 111 citations","pmids":["32439635"],"is_preprint":false},{"year":2020,"finding":"DDX39B facilitates DNA repair by homologous recombination through binding to and stabilizing BRCA1 mRNA; DDX39B-deficient cells show impaired ssDNA formation and RAD51 accumulation at DSB sites, and hypersensitivity to platinum and PARPi.","method":"RNA immunoprecipitation, mRNA stability assay, DNA damage repair assays (ssDNA formation, RAD51 foci), CRISPR/siRNA depletion, mouse knockout phenotype","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — RIP plus functional DNA repair assays; single lab","pmids":["32989256"],"is_preprint":false},{"year":2020,"finding":"DDX39B inhibits NF-κB activity by inhibiting p65 phosphorylation through interaction with the pattern recognition receptor LGP2, a pathway requiring cellular response to cytoplasmic dsRNA. DDX39B protein abundance is regulated by PIASx-β-mediated sumoylation that promotes poly-ubiquitination and degradation.","method":"Streptavidin-agarose pull-down with κB DNA probes, RNAi, CRISPR/Cas9 KO, p65 phosphorylation assay, Co-IP with LGP2, sumoylation/ubiquitination assays","journal":"BMC Biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (pull-down, CRISPR, PTM assays); single lab","pmids":["32209106"],"is_preprint":false},{"year":2020,"finding":"UAP56 features two NP-binding sites: the RecA-domain core and an N-terminal extension (NTE) that recognizes the nucleic acid-binding region of influenza NP. UAP56-NTE binding to NP is mutually exclusive with RNA binding to NP, explaining how UAP56 chaperones RNA-free NP for vRNP assembly.","method":"In vitro binding assay with recombinant proteins, domain mapping, competition assay between UAP56-NTE and RNA for NP binding","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 1/2 — in vitro reconstitution with domain mapping; single lab","pmids":["32085897"],"is_preprint":false},{"year":2021,"finding":"DDX39B binds directly to FUT3 pre-mRNA, promotes its splicing, and enhances FUT3 mRNA export; elevated FUT3 leads to fucosylation of TGFβR-I, activating TGFβ signaling and driving EMT in colorectal cancer.","method":"RIP-seq, RNA-seq, minigene splicing assay, nuclear/cytoplasmic RNA fractionation, gain/loss-of-function assays","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 — RIP-seq plus minigene splicing validation plus fractionation; single lab","pmids":["33436563"],"is_preprint":false},{"year":2022,"finding":"DDX39B directly binds to the first exon of CDK6 and CCND1 pre-mRNAs (confirmed by RIP-seq) and promotes their splicing; CDK6/CCND1 upregulation drives G1/S cell cycle transition and CRC cell proliferation.","method":"RIP-seq, in vitro splicing RT-PCR, flow cytometry, rescue experiments, orthotopic xenograft model","journal":"Cell Death Discovery","confidence":"Medium","confidence_rationale":"Tier 2 — RIP-seq plus splicing assay plus rescue experiments; single lab","pmids":["35046400"],"is_preprint":false},{"year":2023,"finding":"DDX39B controls splicing of FOXP3 pre-mRNA introns that have C-rich/U-poor polypyrimidine tracts; DDX39B knockdown reduces FOXP3 expression, resulting in loss of immune-regulatory and gain of immune-effector gene expression signatures in T cells. DDX39B also controls splicing of many other MS susceptibility genes.","method":"siRNA knockdown, RT-PCR splicing assays, transcriptomic profiling of human T cells","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — clean KD with defined splicing phenotype replicated across multiple immune transcripts; multi-method","pmids":["37261960"],"is_preprint":false},{"year":2023,"finding":"Crystal structure of a yeast Tho1 (SARNP)/DDX39B/RNA complex reveals that SARNP engages DDX39B through tandem DDX39B-interacting motifs, forming a high-order complex where human SARNP can bind up to five DDX39B molecules simultaneously. SARNP knockdown preferentially affects export of GC-rich RNAs.","method":"X-ray crystallography, biochemical reconstitution, RNA-seq from SARNP knockdown cells","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation; single but rigorous study","pmids":["37578863"],"is_preprint":false},{"year":2023,"finding":"DDX39B directly interacts with SREBP1 protein, stabilizes SREBP1 by preventing FBXW7-mediated ubiquitination and degradation, and promotes SREBP1 nuclear translocation and transcriptional activation of lipogenic genes in hepatocellular carcinoma.","method":"Co-immunoprecipitation, immunofluorescence for nuclear translocation, luciferase transcriptional activity assay, ubiquitination assay, xenograft mouse model","journal":"Cellular Oncology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus ubiquitination and localization assays; single lab","pmids":["37052853"],"is_preprint":false},{"year":2024,"finding":"DDX39B specifically regulates splicing of pre-mRNAs with C-rich/U-poor polypyrimidine tracts (e.g., IL7R exon 6, FOXP3 introns) that DDX39A cannot complement; the variant polypyrimidine tract is necessary and sufficient for DDX39B-specific dependency.","method":"siRNA knockdown of DDX39A and DDX39B individually and combined, minigene splicing assay with polypyrimidine tract mutations, RT-PCR","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 — clean comparative KD with mechanistic minigene mutagenesis; multi-method","pmids":["38801080"],"is_preprint":false},{"year":2024,"finding":"FOXP3 introns with C-rich/U-poor polypyrimidine tracts cause deficient DDX39B recruitment and inefficient pre-spliceosome assembly; the altered U2AF2 conformation on C-rich tracts has lower affinity for DDX39B, explaining how DDX39B levels gate commitment complex to pre-spliceosome conversion on these introns.","method":"In vitro splicing commitment complex assembly assay, U2AF2 binding assays, spliceosome assembly analysis","journal":"RNA","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro spliceosome assembly assays with mechanistic dissection","pmids":["38575347"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM and crystal structures of TREX-2/DDX39B and TREX-2.1/DDX39B complexes reveal that a conserved trigger loop in GANP (TREX-2) and LENG8 (TREX-2.1) regulates DDX39B release from mRNPs; LENG8 knockdown selectively affects nucleocytoplasmic ratio of GC-rich mRNAs.","method":"Cryo-EM structure determination, X-ray crystallography, mutagenesis of trigger loop, RNA-seq from LENG8 knockdown cells","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with mutagenesis and transcriptomic functional validation","pmids":["40595470"],"is_preprint":false},{"year":2024,"finding":"Unique structural features of UAP56 (versus URH49) are responsible for formation of their respective distinct apo-complexes (apo-TREX vs. apo-AREX); chimeric mutant analysis identifies terminal regions critical for complex formation specificity.","method":"Structural comparison, chimeric mutant analysis, co-immunoprecipitation, mRNA export assays","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 — structural and biochemical comparison with chimeric mutants; single lab","pmids":["38225262"],"is_preprint":false},{"year":2024,"finding":"DDX39B promotes splicing and cytoplasmic export of GPX4 pre-mRNA; inhibition of DDX39B ATPase activity by CCT018159 represses GPX4 pre-mRNA splicing and export, sensitizing HCC cells to sorafenib-induced ferroptosis.","method":"RIP, mRNA splicing assays, nuclear/cytoplasmic fractionation, ATPase inhibitor (CCT018159) treatment, lipid peroxidation and ferroptosis assays","journal":"Biochemical Pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — RIP plus splicing and fractionation with pharmacological inhibition; single lab","pmids":["38701867"],"is_preprint":false},{"year":2025,"finding":"DDX39B undergoes K63-linked ubiquitination mediated by TRIM28 E3 ligase at residues Lys241, Lys384, and Lys398 (via interaction through DDX39B Pro322), leading to DDX39B protein stabilization; stabilized DDX39B then directly binds E-cadherin (ECAD) and promotes its lysosomal degradation by recruiting Src and Hakai, activating β-catenin signaling—independently of RNA helicase activity.","method":"Co-immunoprecipitation, ubiquitination assay, immunofluorescence, lysosome inhibitor experiments, structure-based virtual screening","journal":"Signal Transduction and Targeted Therapy","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with ubiquitination mapping and functional rescue; 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 editing efficiency genome-wide.","method":"Genome-scale CRISPR screen, single-cell CRISPR RNA-seq (scCREDIT-seq), transcriptome-wide A-to-I editing profiling","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 — genome-scale screen with transcriptomic validation; novel mechanism identified","pmids":["40652511"],"is_preprint":false},{"year":2025,"finding":"The PAXT-associated LENG8-PCID2-SEM1 (LENG8-PS) trimeric complex is structurally and functionally equivalent to the GANP-PCID2-SEM1 trimer of TREX-2, and competes with NPC-associated TREX-2 for UAP56-bound pA+ RNPs; PAXT releases RNAs from UAP56 for nuclear exosome decay while TREX-2 releases them for export, thereby governing nuclear RNA fate.","method":"Structural analysis, mutagenesis, transcriptomic analysis (RNA fate mapping), biochemical reconstitution","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1/2 — structural + mutagenesis + transcriptomic data; preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2017,"finding":"UAP56 stimulates trimeric NP formation from monomeric NP and forms a complex with trimeric NP (two trimeric NPs bridged by UAP56); trimeric NP has higher RNA-binding activity, and UAP56 facilitates viral RNP assembly by promoting NP trimerization and controlled NP transfer to viral RNA.","method":"Gel filtration chromatography, atomic force microscopy, NP oligomerization assay, RNA-binding assay","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 1/2 — in vitro biochemical reconstitution with multiple biophysical methods; single lab","pmids":["29070793"],"is_preprint":false},{"year":2018,"finding":"DDX39B affects levels of pre-ribosomal RNA by regulating its stability and synthesis, thereby promoting global translation and cell proliferation independently of its mRNA export function.","method":"Pre-rRNA stability and synthesis assays, polysome profiling, overexpression and knockdown experiments","journal":"RNA Biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple mechanistic assays (rRNA stability + synthesis + translation); single lab","pmids":["30176153"],"is_preprint":false},{"year":2002,"finding":"HEL (Chironomus UAP56) binds to Balbiani ring pre-mRNP cotranscriptionally and in an intron-independent manner, accompanies the mRNP to the nuclear pore, and is released during translocation to the cytoplasm before Aly/REF release.","method":"Immunoelectron microscopy on polytene chromosomes and nuclear pore complexes","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 2 — direct in situ visualization of cotranscriptional loading and tracking to NPC; 54 citations","pmids":["12015125"],"is_preprint":false},{"year":2025,"finding":"De novo and inherited missense variants in DDX39B impair TREX complex assembly (variants p.Gly92Asp and c.433-1G>T) or cause aberrant splicing (variants p.Gly37Cys, p.Arg123Gln, c.433-1G>T), establishing DDX39B loss-of-function as a cause of a neurodevelopmental syndrome. Zebrafish morpholino knockdown of DDX39B causes reduced head size and body length rescued by DDX39B mRNA.","method":"In vitro Co-IP with HA-tagged variants, blood transcriptomics (aberrant splicing), Drosophila transgenic overexpression lethality assay, zebrafish morpholino knockdown with mRNA rescue","journal":"Brain","confidence":"High","confidence_rationale":"Tier 1/2 — multiple orthogonal in vitro and in vivo assays with patient variants; novel genetic disease mechanism","pmids":["39918047"],"is_preprint":false}],"current_model":"DDX39B (UAP56) is an ATP-dependent DEAD-box RNA helicase that cotranscriptionally loads onto pre-mRNPs, uses ATP binding and hydrolysis to chaperone the export adaptor Aly/REF onto spliced and intronless mRNAs, bridges THO complex–Aly–CIP29 assembly within the TREX complex, facilitates spliceosome A-complex formation (especially on introns with C-rich polypyrimidine tracts via U2AF65 collaboration), unwinds harmful co-transcriptional R-loops genome-wide, shuttles to the cytoplasm in a CRM1-independent manner, and is regulated by Plk1-mediated phosphorylation-induced proteasomal degradation and PIASx-β-mediated sumoylation; its release from mRNPs at the nuclear pore is governed by TREX-2 (and competing PAXT-associated LENG8-PS module), with structural specificity in complex partners distinguishing UAP56 from its paralog URH49."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing DDX39B as the adaptor-loading machine for mRNA export resolved how splicing and export are coupled: UAP56 directly recruits Aly/REF to spliced mRNPs, and dominant-negative UAP56 blocks both Aly recruitment and mRNA export.","evidence":"Co-immunoprecipitation, dominant-negative overexpression in HeLa nuclear extracts, separation-of-function Aly mutant; RNAi in Drosophila S2 cells with poly(A)+ FISH","pmids":["11675789","11696332"],"confidence":"High","gaps":["Mechanism of UAP56 recruitment to mRNP not yet defined","Whether ATP hydrolysis is needed for Aly loading was unknown"]},{"year":2004,"claim":"Crystal structures of UAP56 revealed two RecA-like helicase domains and showed ADP-induced conformational changes, providing the first structural framework for understanding its chaperone mechanism.","evidence":"X-ray crystallography of apo and ADP-bound UAP56 at 1.9 Å resolution; in vitro ATPase assay","pmids":["15585580","15296731"],"confidence":"High","gaps":["No structure with RNA or protein partner bound","Whether dimerization observed crystallographically is functionally relevant remained unclear"]},{"year":2007,"claim":"Dissection of the ATP cycle showed that ATP-bound UAP56 simultaneously engages RNA and Aly/REF, with ATP hydrolysis triggering UAP56 dissociation after Aly deposition—establishing UAP56 as an ATP-driven chaperone rather than a processive helicase for export adaptor loading.","evidence":"In vitro RNA-binding and Aly-loading assays with ATP analogues; Xenopus oocyte mRNA export with ATP-binding mutant; in vitro helicase unwinding assays with motif mutants","pmids":["17984224","17562711"],"confidence":"High","gaps":["How UAP56 selects specific mRNPs was unknown","Structural basis of simultaneous RNA and Aly binding not resolved"]},{"year":2010,"claim":"Reconstitution of the human TREX complex showed UAP56 bridges THO–Aly–CIP29 in an ATP-dependent manner, and depletion revealed UAP56-specific (versus URH49-specific) mRNA targets and mitotic phenotypes, establishing paralog-specific export pathways.","evidence":"Recombinant protein reconstitution, immunopurification/MS proteomics; siRNA depletion with genome-wide mRNA profiling and mitotic phenotype analysis","pmids":["20844015","20573985"],"confidence":"High","gaps":["Structural basis of paralog specificity not defined","How UAP56 vs URH49 select distinct mRNA subsets was unknown"]},{"year":2012,"claim":"In Drosophila, UAP56 was shown to function at piRNA cluster loci with the heterochromatin protein Rhino, linking its RNA handling activity to transposon silencing and germline genome defense beyond canonical mRNA export.","evidence":"Immunofluorescence co-localization, RNA immunoprecipitation of piRNA cluster transcripts, charge-substitution mutagenesis disrupting Rhino interaction and piRNA production","pmids":["23141543"],"confidence":"High","gaps":["Whether this piRNA function is conserved in mammals","Direct enzymatic activity on piRNA precursors not demonstrated"]},{"year":2020,"claim":"DDX39B was established as a cotranscriptional RNA-DNA helicase that resolves R-loops genome-wide; its overexpression rescues R-loop accumulation caused by depletion of five unrelated factors, positioning DDX39B as a general guardian of genome stability.","evidence":"In vitro RNA-DNA helicase assay, DRIP-seq, DNA damage markers, replication fork assays, overexpression rescue","pmids":["32439635"],"confidence":"High","gaps":["How DDX39B is recruited to R-loop sites versus mRNP export sites not resolved","Relative contribution of R-loop resolution versus mRNA export to genome stability phenotype unclear"]},{"year":2020,"claim":"DDX39B was linked to innate immune regulation: it inhibits NF-κB via interaction with LGP2, and its protein abundance is controlled by PIASx-β sumoylation promoting poly-ubiquitination and degradation, revealing post-translational regulatory layers.","evidence":"CRISPR KO, Co-IP with LGP2, p65 phosphorylation assays, sumoylation/ubiquitination assays in multiple cell types","pmids":["32209106"],"confidence":"Medium","gaps":["NF-κB inhibition mechanism downstream of LGP2 interaction not fully elucidated","Whether sumoylation-mediated degradation is the dominant regulatory mode in vivo unclear"]},{"year":2023,"claim":"The discovery that DDX39B specifically controls splicing of introns with C-rich/U-poor polypyrimidine tracts—including FOXP3 and other MS susceptibility genes—revealed a non-redundant splicing function distinct from its paralog DDX39A and linked DDX39B to immune homeostasis.","evidence":"siRNA knockdown with RT-PCR splicing assays and transcriptomic profiling in human T cells; crystal structure of SARNP/DDX39B/RNA complex","pmids":["37261960","37578863"],"confidence":"High","gaps":["Whether DDX39B directly contacts the C-rich polypyrimidine tract or acts through U2AF2 remodeling was unresolved","Full scope of immune-relevant DDX39B-dependent splicing events not catalogued"]},{"year":2024,"claim":"Mechanistic dissection showed that C-rich polypyrimidine tracts adopt an altered U2AF2 conformation with reduced DDX39B affinity, explaining how DDX39B protein levels gate commitment-to-A-complex conversion on specific introns—a rate-limiting step in selective splicing.","evidence":"In vitro spliceosome assembly assays, U2AF2 binding assays; minigene mutagenesis of polypyrimidine tracts","pmids":["38575347","38801080"],"confidence":"High","gaps":["Structural basis of the altered U2AF2–DDX39B interface on C-rich tracts not determined","Whether additional cofactors modulate this selectivity in vivo"]},{"year":2024,"claim":"Cryo-EM structures of TREX-2/DDX39B complexes revealed a conserved trigger loop in GANP that controls DDX39B release from mRNPs at the nuclear pore, and identified LENG8 (TREX-2.1) as an alternative release factor preferentially affecting GC-rich mRNA export; chimeric analyses defined terminal regions of UAP56 dictating TREX versus AREX complex specificity.","evidence":"Cryo-EM and X-ray crystallography, trigger-loop mutagenesis, RNA-seq from LENG8 KD; chimeric UAP56/URH49 mutants with Co-IP","pmids":["40595470","38225262"],"confidence":"High","gaps":["How TREX-2 versus PAXT pathway competition is regulated in different cell types","Whether the trigger loop mechanism is conserved in non-mammalian TREX-2"]},{"year":2025,"claim":"Human genetics established DDX39B loss-of-function as causal for a neurodevelopmental syndrome: patient missense variants impair TREX complex assembly or cause aberrant splicing, and zebrafish knockdown recapitulates developmental defects rescued by DDX39B mRNA.","evidence":"In vitro Co-IP with patient variants, blood transcriptomics, zebrafish morpholino knockdown with mRNA rescue, Drosophila transgenic assays","pmids":["39918047"],"confidence":"High","gaps":["Genotype-phenotype correlations across the variant spectrum not fully defined","Which DDX39B-dependent splicing events are most critical for neurodevelopment unknown"]},{"year":2025,"claim":"DDX39B was identified as a global repressor of A-to-I RNA editing: its helicase activity prevents dsRNA accumulation that would otherwise serve as ADAR substrates, expanding its role in RNA structure surveillance beyond R-loop resolution.","evidence":"Genome-scale CRISPR screen, single-cell CRISPR RNA-seq, transcriptome-wide A-to-I editing profiling","pmids":["40652511"],"confidence":"Medium","gaps":["Whether DDX39B acts directly on ADAR substrates or indirectly via global dsRNA levels","Relationship between editing suppression and innate immune dsRNA sensing not explored"]},{"year":null,"claim":"Key open questions include the structural basis for how DDX39B discriminates between R-loops, dsRNA, and mRNP substrates; how the TREX-2 versus PAXT competition is regulated to determine RNA fate; and which DDX39B-dependent splicing events are most critical for neurodevelopment and immune regulation.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of DDX39B bound simultaneously to R-loop substrate and regulatory partners","Mechanism governing DDX39B allocation between splicing, export, and R-loop resolution functions unknown","Tissue-specific consequences of DDX39B haploinsufficiency not systematically characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3,6,7,8,9]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[6,7,18,22,25]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[18,33]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[18]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,6,21,35]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[8,15,37]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,13,37]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,6,9,24,27,28]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,5,6,22,29,37]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[18,19]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[10,14,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[20,24]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[24,27,28]}],"complexes":["TREX","TREX-2"],"partners":["ALYREF","SARNP","THOC1","U2AF2","GANP","LENG8","MXA","LGP2"],"other_free_text":[]},"mechanistic_narrative":"DDX39B (UAP56) is an essential ATP-dependent DEAD-box RNA helicase that functions as a central hub connecting pre-mRNA splicing, mRNA nuclear export, R-loop resolution, and genome stability maintenance. It cotranscriptionally loads onto nascent pre-mRNPs, uses ATP binding and hydrolysis to chaperone the export adaptor Aly/REF onto mRNAs, and bridges THO complex–Aly–CIP29 interactions to assemble the TREX complex required for bulk mRNA export [PMID:11675789, PMID:20844015, PMID:12015125]. DDX39B specifically promotes pre-spliceosome (A-complex) formation on introns bearing C-rich/U-poor polypyrimidine tracts—including those in FOXP3 and IL7R—by collaborating with U2AF2, and its depletion globally impairs splicing of these transcripts; additionally, its RNA-DNA helicase activity resolves co-transcriptional R-loops genome-wide, preventing R-loop-mediated replication stress and DNA damage [PMID:38575347, PMID:37261960, PMID:32439635]. Loss-of-function missense and splice-site variants in DDX39B cause a neurodevelopmental syndrome characterized by impaired TREX complex assembly and aberrant splicing [PMID:39918047]."},"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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Excess UAP56 acts as a dominant-negative inhibitor of mRNA export and blocks Aly recruitment to the spliced mRNP.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative overexpression in HeLa nuclear extracts, Aly mutation that blocks UAP56 interaction prevents Aly recruitment to spliced mRNP\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with functional validation by dominant-negative and separation-of-function mutation; foundational paper with 330 citations\",\n      \"pmids\": [\"11675789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Drosophila HEL (UAP56 ortholog) is essential for bulk mRNA nuclear export; depletion causes nuclear accumulation of poly(A)+ RNA and inhibits protein synthesis from both spliced and intronless mRNAs.\",\n      \"method\": \"RNAi depletion in Drosophila Schneider cells, fluorescence in situ hybridization for poly(A)+ RNA, [35S]methionine incorporation assay\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype, replicated across transcript types; 198 citations\",\n      \"pmids\": [\"11696332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"UAP56 (RAF-2p48/BAT1) is a cellular splicing factor that interacts directly with influenza virus nucleoprotein (NP); it binds RNA-free NP but not RNA-bound NP, and facilitates NP-RNA complex formation required for viral RNA synthesis.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assays with purified proteins, influenza RNA synthesis reconstitution assay\",\n      \"journal\": \"Journal of Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro binding + reconstituted RNA synthesis assay with domain mapping; 144 citations\",\n      \"pmids\": [\"11160689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Crystal structure of human UAP56 reveals two RecA-like helicase domains connected by a flexible linker; ADP binding induces significant conformational changes in the ATP-binding pocket. Purified UAP56 is an active RNA-dependent ATPase. Structure suggests a protein-RNA displacement model for UAP56/Sub2 function.\",\n      \"method\": \"X-ray crystallography of UAP56 alone, UAP56-ADP complex, and DECD→DEAD mutant; in vitro ATPase assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus in vitro enzymatic validation; 105 citations\",\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 reveal RecA-like folds similar to eIF4A; the N-terminal domain shows a dimer interface potentially important for UAP56 function. The NTP-binding pocket contains a citrate ion mimicking phosphates, retaining the P-loop in open conformation.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with functional interpretation; 59 citations\",\n      \"pmids\": [\"15296731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human cytomegalovirus pUL69 interacts directly with UAP56 and URH49 via a 12-amino-acid N-terminal domain, and this interaction plus nucleocytoplasmic shuttling are both required for pUL69-mediated nuclear export of unspliced viral mRNA.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, heterokaryon shuttling assay, mRNA export reporter assay\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, domain-mapping mutagenesis, functional export assay; 102 citations\",\n      \"pmids\": [\"16478985\"],\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-bound UAP56 binds both RNA and Aly/REF simultaneously, and ATP hydrolysis drives UAP56 dissociation after Aly loading. An ATP-binding-deficient UAP56 mutant specifically inhibits mRNA export in Xenopus oocytes.\",\n      \"method\": \"In vitro RNA-binding assay, ATP analogue experiments, Xenopus oocyte mRNA export assay with dominant-negative mutant\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro reconstitution with biochemical dissection of ATP cycle plus Xenopus functional assay; 97 citations\",\n      \"pmids\": [\"17984224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UAP56 is an RNA-stimulated ATPase that specifically hydrolyzes ATP 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.\",\n      \"method\": \"In vitro ATPase assay, in vitro helicase unwinding assay, site-directed mutagenesis of conserved motifs\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical characterization with mutagenesis; 83 citations\",\n      \"pmids\": [\"17562711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ATP binding by UAP56 is required for mRNA export but not for RNA splicing. UAP56 localizes to nuclear splicing speckle domains and is in dynamic equilibrium in complexes containing SRm160, as measured by FRAP; ATP binding regulates this equilibrium.\",\n      \"method\": \"Confocal microscopy, FRAP (live cells and in vitro digitonin-extracted cells), ATP-binding-deficient point mutant, mRNA export assay\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — FRAP with functional mutant, live-cell localization tied to functional consequence; 55 citations\",\n      \"pmids\": [\"18411249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UAP56 mediates ATP-dependent interactions between the THO complex and both CIP29 and Aly to assemble the human TREX complex. Using recombinant proteins, UAP56, Aly, and CIP29 form an ATP-dependent trimeric complex in which UAP56 bridges CIP29 and Aly interactions.\",\n      \"method\": \"Proteomics (immunopurification/MS), recombinant protein reconstitution in E. coli, ATP-dependency biochemical assays\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with purified recombinant proteins plus proteomic identification; 148 citations\",\n      \"pmids\": [\"20844015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UAP56 forms the human TREX complex (distinct from URH49-containing AREX complex), and its depletion causes mitotic delay and sister chromatid cohesion defects; genome-wide analysis shows UAP56 and URH49 regulate distinct sets of target mRNAs including different mitotic regulators.\",\n      \"method\": \"siRNA depletion, immunofluorescence, mitotic phenotype analysis, genome-wide mRNA profiling\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype (mitotic defects) and genome-wide target identification; 87 citations\",\n      \"pmids\": [\"20573985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"UAP56 depletion in influenza A virus-infected cells leads to rapid accumulation of double-stranded RNA (dsRNA) in the perinuclear region and robust activation of PKR, suggesting UAP56 is recruited by influenza virus to prevent dsRNA formation and thereby suppress innate immune activation.\",\n      \"method\": \"siRNA depletion, immunofluorescence for dsRNA, PKR activation assay, actinomycin D and cycloheximide controls\",\n      \"journal\": \"Journal of Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined molecular phenotype; 61 citations\",\n      \"pmids\": [\"21680511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Interferon-induced antiviral GTPase MxA directly binds UAP56 and URH49 in vitro and forms complexes with them in the perinuclear region in cells; mouse Mx1 also binds UAP56/URH49 in distinct nuclear dots.\",\n      \"method\": \"Immunoprecipitation, in vitro binding assay with purified recombinant proteins, immunofluorescence co-localization\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro binding with purified proteins confirmed by co-IP in cells; 35 citations\",\n      \"pmids\": [\"21859714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"UAP56 undergoes CRM1-independent nucleocytoplasmic shuttling; the intranuclear localization domain maps to aa81-381 and the shuttling domain maps to the C-terminus (aa195-428), which also mediates REF interaction. Shuttling is independent of Rae1 in human cells.\",\n      \"method\": \"Heterokaryon assay, deletion mapping with truncation mutants, immunofluorescence\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — heterokaryon shuttling assay with domain mapping; single lab\",\n      \"pmids\": [\"21799930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Polo-like kinase 1 (Plk1) physically interacts with UAP56, phosphorylates it in vitro and in vivo, and this phosphorylation triggers ubiquitination and proteasomal degradation of UAP56, inversely correlating protein levels of UAP56 and Plk1 during the cell cycle.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, in vivo phosphorylation, ubiquitination assay, proteasome inhibitor treatment\",\n      \"journal\": \"Molecular Biology Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro kinase assay + in vivo functional consequence; single lab\",\n      \"pmids\": [\"21637952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In Drosophila, nuclear UAP56 colocalizes with the heterochromatin protein HP1 variant Rhino at piRNA cluster loci; cluster transcripts immunoprecipitate with both UAP56 and Vasa; a charge-substitution mutation in UAP56 disrupts Rhino colocalization, germline piRNA production, transposon silencing, and perinuclear Vasa localization, placing UAP56 at the nuclear side of a piRNA-processing compartment spanning the nuclear envelope.\",\n      \"method\": \"Immunofluorescence, RNA immunoprecipitation, charge-substitution mutagenesis, piRNA sequencing\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional mutagenesis + RNA-IP + localization with defined pathway phenotype; 184 citations\",\n      \"pmids\": [\"23141543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"UAP56 interacts with Bcr kinase; knockdown of UAP56 blocks Bcr-induced DNA synthesis and reverses Bcr-mediated upregulation of cyclin E and downregulation of p27 in vascular smooth muscle cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, DNA synthesis assay, cyclin E/p27 western blot\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with partial functional follow-up; single lab\",\n      \"pmids\": [\"22446327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DDX39B (and its paralog DDX39A) regulate the generation of androgen receptor splice variant AR-V7; simultaneous knockdown of both DDX39B and DDX39A drastically and selectively downregulated AR-V7 mRNA expression in multiple prostate cancer cell lines.\",\n      \"method\": \"shRNA screen of spliceosome-related genes, siRNA knockdown of DDX39B and DDX39A in multiple cell lines, RT-PCR quantification of AR-V7\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional screen plus validation in multiple cell lines; single lab\",\n      \"pmids\": [\"28025139\"],\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. UAP56 overexpression suppresses R loops and genome instability induced by depletion of five unrelated factors. RNA-DNA helicase activity was demonstrated in vitro.\",\n      \"method\": \"In vitro RNA-DNA helicase assay, DRIP-seq (genome-wide R-loop mapping), DNA damage markers, replication fork assays, overexpression rescue experiments\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro helicase activity demonstrated with genome-wide functional validation and rescue across multiple perturbations; 111 citations\",\n      \"pmids\": [\"32439635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DDX39B facilitates DNA repair by homologous recombination through binding to and stabilizing BRCA1 mRNA; DDX39B-deficient cells show impaired ssDNA formation and RAD51 accumulation at DSB sites, and hypersensitivity to platinum and PARPi.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assay, DNA damage repair assays (ssDNA formation, RAD51 foci), CRISPR/siRNA depletion, mouse knockout phenotype\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP plus functional DNA repair assays; single lab\",\n      \"pmids\": [\"32989256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DDX39B inhibits NF-κB activity by inhibiting p65 phosphorylation through interaction with the pattern recognition receptor LGP2, a pathway requiring cellular response to cytoplasmic dsRNA. DDX39B protein abundance is regulated by PIASx-β-mediated sumoylation that promotes poly-ubiquitination and degradation.\",\n      \"method\": \"Streptavidin-agarose pull-down with κB DNA probes, RNAi, CRISPR/Cas9 KO, p65 phosphorylation assay, Co-IP with LGP2, sumoylation/ubiquitination assays\",\n      \"journal\": \"BMC Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (pull-down, CRISPR, PTM assays); single lab\",\n      \"pmids\": [\"32209106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UAP56 features two NP-binding sites: the RecA-domain core and an N-terminal extension (NTE) that recognizes the nucleic acid-binding region of influenza NP. UAP56-NTE binding to NP is mutually exclusive with RNA binding to NP, explaining how UAP56 chaperones RNA-free NP for vRNP assembly.\",\n      \"method\": \"In vitro binding assay with recombinant proteins, domain mapping, competition assay between UAP56-NTE and RNA for NP binding\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro reconstitution with domain mapping; single lab\",\n      \"pmids\": [\"32085897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DDX39B binds directly to FUT3 pre-mRNA, promotes its splicing, and enhances FUT3 mRNA export; elevated FUT3 leads to fucosylation of TGFβR-I, activating TGFβ signaling and driving EMT in colorectal cancer.\",\n      \"method\": \"RIP-seq, RNA-seq, minigene splicing assay, nuclear/cytoplasmic RNA fractionation, gain/loss-of-function assays\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP-seq plus minigene splicing validation plus fractionation; single lab\",\n      \"pmids\": [\"33436563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DDX39B directly binds to the first exon of CDK6 and CCND1 pre-mRNAs (confirmed by RIP-seq) and promotes their splicing; CDK6/CCND1 upregulation drives G1/S cell cycle transition and CRC cell proliferation.\",\n      \"method\": \"RIP-seq, in vitro splicing RT-PCR, flow cytometry, rescue experiments, orthotopic xenograft model\",\n      \"journal\": \"Cell Death Discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP-seq plus splicing assay plus rescue experiments; single lab\",\n      \"pmids\": [\"35046400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DDX39B controls splicing of FOXP3 pre-mRNA introns that have C-rich/U-poor polypyrimidine tracts; DDX39B knockdown reduces FOXP3 expression, resulting in loss of immune-regulatory and gain of immune-effector gene expression signatures in T cells. DDX39B also controls splicing of many other MS susceptibility genes.\",\n      \"method\": \"siRNA knockdown, RT-PCR splicing assays, transcriptomic profiling of human T cells\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined splicing phenotype replicated across multiple immune transcripts; multi-method\",\n      \"pmids\": [\"37261960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Crystal structure of a yeast Tho1 (SARNP)/DDX39B/RNA complex reveals that SARNP engages DDX39B through tandem DDX39B-interacting motifs, forming a high-order complex where human SARNP can bind up to five DDX39B molecules simultaneously. SARNP knockdown preferentially affects export of GC-rich RNAs.\",\n      \"method\": \"X-ray crystallography, biochemical reconstitution, RNA-seq from SARNP knockdown cells\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation; single but rigorous study\",\n      \"pmids\": [\"37578863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DDX39B directly interacts with SREBP1 protein, stabilizes SREBP1 by preventing FBXW7-mediated ubiquitination and degradation, and promotes SREBP1 nuclear translocation and transcriptional activation of lipogenic genes in hepatocellular carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence for nuclear translocation, luciferase transcriptional activity assay, ubiquitination assay, xenograft mouse model\",\n      \"journal\": \"Cellular Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus ubiquitination and localization assays; single lab\",\n      \"pmids\": [\"37052853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DDX39B specifically regulates splicing of pre-mRNAs with C-rich/U-poor polypyrimidine tracts (e.g., IL7R exon 6, FOXP3 introns) that DDX39A cannot complement; the variant polypyrimidine tract is necessary and sufficient for DDX39B-specific dependency.\",\n      \"method\": \"siRNA knockdown of DDX39A and DDX39B individually and combined, minigene splicing assay with polypyrimidine tract mutations, RT-PCR\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean comparative KD with mechanistic minigene mutagenesis; multi-method\",\n      \"pmids\": [\"38801080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXP3 introns with C-rich/U-poor polypyrimidine tracts cause deficient DDX39B recruitment and inefficient pre-spliceosome assembly; the altered U2AF2 conformation on C-rich tracts has lower affinity for DDX39B, explaining how DDX39B levels gate commitment complex to pre-spliceosome conversion on these introns.\",\n      \"method\": \"In vitro splicing commitment complex assembly assay, U2AF2 binding assays, spliceosome assembly analysis\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro spliceosome assembly assays with mechanistic dissection\",\n      \"pmids\": [\"38575347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM and crystal structures of TREX-2/DDX39B and TREX-2.1/DDX39B complexes reveal that a conserved trigger loop in GANP (TREX-2) and LENG8 (TREX-2.1) regulates DDX39B release from mRNPs; LENG8 knockdown selectively affects nucleocytoplasmic ratio of GC-rich mRNAs.\",\n      \"method\": \"Cryo-EM structure determination, X-ray crystallography, mutagenesis of trigger loop, RNA-seq from LENG8 knockdown cells\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with mutagenesis and transcriptomic functional validation\",\n      \"pmids\": [\"40595470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Unique structural features of UAP56 (versus URH49) are responsible for formation of their respective distinct apo-complexes (apo-TREX vs. apo-AREX); chimeric mutant analysis identifies terminal regions critical for complex formation specificity.\",\n      \"method\": \"Structural comparison, chimeric mutant analysis, co-immunoprecipitation, mRNA export assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structural and biochemical comparison with chimeric mutants; single lab\",\n      \"pmids\": [\"38225262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DDX39B promotes splicing and cytoplasmic export of GPX4 pre-mRNA; inhibition of DDX39B ATPase activity by CCT018159 represses GPX4 pre-mRNA splicing and export, sensitizing HCC cells to sorafenib-induced ferroptosis.\",\n      \"method\": \"RIP, mRNA splicing assays, nuclear/cytoplasmic fractionation, ATPase inhibitor (CCT018159) treatment, lipid peroxidation and ferroptosis assays\",\n      \"journal\": \"Biochemical Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP plus splicing and fractionation with pharmacological inhibition; single lab\",\n      \"pmids\": [\"38701867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DDX39B undergoes K63-linked ubiquitination mediated by TRIM28 E3 ligase at residues Lys241, Lys384, and Lys398 (via interaction through DDX39B Pro322), leading to DDX39B protein stabilization; stabilized DDX39B then directly binds E-cadherin (ECAD) and promotes its lysosomal degradation by recruiting Src and Hakai, activating β-catenin signaling—independently of RNA helicase activity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, immunofluorescence, lysosome inhibitor experiments, structure-based virtual screening\",\n      \"journal\": \"Signal Transduction and Targeted Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with ubiquitination mapping and functional rescue; 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 editing efficiency genome-wide.\",\n      \"method\": \"Genome-scale CRISPR screen, single-cell CRISPR RNA-seq (scCREDIT-seq), transcriptome-wide A-to-I editing profiling\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-scale screen with transcriptomic validation; novel mechanism identified\",\n      \"pmids\": [\"40652511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The PAXT-associated LENG8-PCID2-SEM1 (LENG8-PS) trimeric complex is structurally and functionally equivalent to the GANP-PCID2-SEM1 trimer of TREX-2, and competes with NPC-associated TREX-2 for UAP56-bound pA+ RNPs; PAXT releases RNAs from UAP56 for nuclear exosome decay while TREX-2 releases them for export, thereby governing nuclear RNA fate.\",\n      \"method\": \"Structural analysis, mutagenesis, transcriptomic analysis (RNA fate mapping), biochemical reconstitution\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — structural + mutagenesis + transcriptomic data; preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"UAP56 stimulates trimeric NP formation from monomeric NP and forms a complex with trimeric NP (two trimeric NPs bridged by UAP56); trimeric NP has higher RNA-binding activity, and UAP56 facilitates viral RNP assembly by promoting NP trimerization and controlled NP transfer to viral RNA.\",\n      \"method\": \"Gel filtration chromatography, atomic force microscopy, NP oligomerization assay, RNA-binding assay\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro biochemical reconstitution with multiple biophysical methods; single lab\",\n      \"pmids\": [\"29070793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DDX39B affects levels of pre-ribosomal RNA by regulating its stability and synthesis, thereby promoting global translation and cell proliferation independently of its mRNA export function.\",\n      \"method\": \"Pre-rRNA stability and synthesis assays, polysome profiling, overexpression and knockdown experiments\",\n      \"journal\": \"RNA Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mechanistic assays (rRNA stability + synthesis + translation); single lab\",\n      \"pmids\": [\"30176153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HEL (Chironomus UAP56) binds to Balbiani ring pre-mRNP cotranscriptionally and in an intron-independent manner, accompanies the mRNP to the nuclear pore, and is released during translocation to the cytoplasm before Aly/REF release.\",\n      \"method\": \"Immunoelectron microscopy on polytene chromosomes and nuclear pore complexes\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct in situ visualization of cotranscriptional loading and tracking to NPC; 54 citations\",\n      \"pmids\": [\"12015125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"De novo and inherited missense variants in DDX39B impair TREX complex assembly (variants p.Gly92Asp and c.433-1G>T) or cause aberrant splicing (variants p.Gly37Cys, p.Arg123Gln, c.433-1G>T), establishing DDX39B loss-of-function as a cause of a neurodevelopmental syndrome. Zebrafish morpholino knockdown of DDX39B causes reduced head size and body length rescued by DDX39B mRNA.\",\n      \"method\": \"In vitro Co-IP with HA-tagged variants, blood transcriptomics (aberrant splicing), Drosophila transgenic overexpression lethality assay, zebrafish morpholino knockdown with mRNA rescue\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple orthogonal in vitro and in vivo assays with patient variants; novel genetic disease mechanism\",\n      \"pmids\": [\"39918047\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DDX39B (UAP56) is an ATP-dependent DEAD-box RNA helicase that cotranscriptionally loads onto pre-mRNPs, uses ATP binding and hydrolysis to chaperone the export adaptor Aly/REF onto spliced and intronless mRNAs, bridges THO complex–Aly–CIP29 assembly within the TREX complex, facilitates spliceosome A-complex formation (especially on introns with C-rich polypyrimidine tracts via U2AF65 collaboration), unwinds harmful co-transcriptional R-loops genome-wide, shuttles to the cytoplasm in a CRM1-independent manner, and is regulated by Plk1-mediated phosphorylation-induced proteasomal degradation and PIASx-β-mediated sumoylation; its release from mRNPs at the nuclear pore is governed by TREX-2 (and competing PAXT-associated LENG8-PS module), with structural specificity in complex partners distinguishing UAP56 from its paralog URH49.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DDX39B (UAP56) is an essential ATP-dependent DEAD-box RNA helicase that functions as a central hub connecting pre-mRNA splicing, mRNA nuclear export, R-loop resolution, and genome stability maintenance. It cotranscriptionally loads onto nascent pre-mRNPs, uses ATP binding and hydrolysis to chaperone the export adaptor Aly/REF onto mRNAs, and bridges THO complex–Aly–CIP29 interactions to assemble the TREX complex required for bulk mRNA export [PMID:11675789, PMID:20844015, PMID:12015125]. DDX39B specifically promotes pre-spliceosome (A-complex) formation on introns bearing C-rich/U-poor polypyrimidine tracts—including those in FOXP3 and IL7R—by collaborating with U2AF2, and its depletion globally impairs splicing of these transcripts; additionally, its RNA-DNA helicase activity resolves co-transcriptional R-loops genome-wide, preventing R-loop-mediated replication stress and DNA damage [PMID:38575347, PMID:37261960, PMID:32439635]. Loss-of-function missense and splice-site variants in DDX39B cause a neurodevelopmental syndrome characterized by impaired TREX complex assembly and aberrant splicing [PMID:39918047].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing DDX39B as the adaptor-loading machine for mRNA export resolved how splicing and export are coupled: UAP56 directly recruits Aly/REF to spliced mRNPs, and dominant-negative UAP56 blocks both Aly recruitment and mRNA export.\",\n      \"evidence\": \"Co-immunoprecipitation, dominant-negative overexpression in HeLa nuclear extracts, separation-of-function Aly mutant; RNAi in Drosophila S2 cells with poly(A)+ FISH\",\n      \"pmids\": [\"11675789\", \"11696332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of UAP56 recruitment to mRNP not yet defined\", \"Whether ATP hydrolysis is needed for Aly loading was unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Crystal structures of UAP56 revealed two RecA-like helicase domains and showed ADP-induced conformational changes, providing the first structural framework for understanding its chaperone mechanism.\",\n      \"evidence\": \"X-ray crystallography of apo and ADP-bound UAP56 at 1.9 Å resolution; in vitro ATPase assay\",\n      \"pmids\": [\"15585580\", \"15296731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure with RNA or protein partner bound\", \"Whether dimerization observed crystallographically is functionally relevant remained unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Dissection of the ATP cycle showed that ATP-bound UAP56 simultaneously engages RNA and Aly/REF, with ATP hydrolysis triggering UAP56 dissociation after Aly deposition—establishing UAP56 as an ATP-driven chaperone rather than a processive helicase for export adaptor loading.\",\n      \"evidence\": \"In vitro RNA-binding and Aly-loading assays with ATP analogues; Xenopus oocyte mRNA export with ATP-binding mutant; in vitro helicase unwinding assays with motif mutants\",\n      \"pmids\": [\"17984224\", \"17562711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How UAP56 selects specific mRNPs was unknown\", \"Structural basis of simultaneous RNA and Aly binding not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Reconstitution of the human TREX complex showed UAP56 bridges THO–Aly–CIP29 in an ATP-dependent manner, and depletion revealed UAP56-specific (versus URH49-specific) mRNA targets and mitotic phenotypes, establishing paralog-specific export pathways.\",\n      \"evidence\": \"Recombinant protein reconstitution, immunopurification/MS proteomics; siRNA depletion with genome-wide mRNA profiling and mitotic phenotype analysis\",\n      \"pmids\": [\"20844015\", \"20573985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of paralog specificity not defined\", \"How UAP56 vs URH49 select distinct mRNA subsets was unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"In Drosophila, UAP56 was shown to function at piRNA cluster loci with the heterochromatin protein Rhino, linking its RNA handling activity to transposon silencing and germline genome defense beyond canonical mRNA export.\",\n      \"evidence\": \"Immunofluorescence co-localization, RNA immunoprecipitation of piRNA cluster transcripts, charge-substitution mutagenesis disrupting Rhino interaction and piRNA production\",\n      \"pmids\": [\"23141543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this piRNA function is conserved in mammals\", \"Direct enzymatic activity on piRNA precursors not demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"DDX39B was established as a cotranscriptional RNA-DNA helicase that resolves R-loops genome-wide; its overexpression rescues R-loop accumulation caused by depletion of five unrelated factors, positioning DDX39B as a general guardian of genome stability.\",\n      \"evidence\": \"In vitro RNA-DNA helicase assay, DRIP-seq, DNA damage markers, replication fork assays, overexpression rescue\",\n      \"pmids\": [\"32439635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DDX39B is recruited to R-loop sites versus mRNP export sites not resolved\", \"Relative contribution of R-loop resolution versus mRNA export to genome stability phenotype unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"DDX39B was linked to innate immune regulation: it inhibits NF-κB via interaction with LGP2, and its protein abundance is controlled by PIASx-β sumoylation promoting poly-ubiquitination and degradation, revealing post-translational regulatory layers.\",\n      \"evidence\": \"CRISPR KO, Co-IP with LGP2, p65 phosphorylation assays, sumoylation/ubiquitination assays in multiple cell types\",\n      \"pmids\": [\"32209106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NF-κB inhibition mechanism downstream of LGP2 interaction not fully elucidated\", \"Whether sumoylation-mediated degradation is the dominant regulatory mode in vivo unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The discovery that DDX39B specifically controls splicing of introns with C-rich/U-poor polypyrimidine tracts—including FOXP3 and other MS susceptibility genes—revealed a non-redundant splicing function distinct from its paralog DDX39A and linked DDX39B to immune homeostasis.\",\n      \"evidence\": \"siRNA knockdown with RT-PCR splicing assays and transcriptomic profiling in human T cells; crystal structure of SARNP/DDX39B/RNA complex\",\n      \"pmids\": [\"37261960\", \"37578863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DDX39B directly contacts the C-rich polypyrimidine tract or acts through U2AF2 remodeling was unresolved\", \"Full scope of immune-relevant DDX39B-dependent splicing events not catalogued\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mechanistic dissection showed that C-rich polypyrimidine tracts adopt an altered U2AF2 conformation with reduced DDX39B affinity, explaining how DDX39B protein levels gate commitment-to-A-complex conversion on specific introns—a rate-limiting step in selective splicing.\",\n      \"evidence\": \"In vitro spliceosome assembly assays, U2AF2 binding assays; minigene mutagenesis of polypyrimidine tracts\",\n      \"pmids\": [\"38575347\", \"38801080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the altered U2AF2–DDX39B interface on C-rich tracts not determined\", \"Whether additional cofactors modulate this selectivity in vivo\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-EM structures of TREX-2/DDX39B complexes revealed a conserved trigger loop in GANP that controls DDX39B release from mRNPs at the nuclear pore, and identified LENG8 (TREX-2.1) as an alternative release factor preferentially affecting GC-rich mRNA export; chimeric analyses defined terminal regions of UAP56 dictating TREX versus AREX complex specificity.\",\n      \"evidence\": \"Cryo-EM and X-ray crystallography, trigger-loop mutagenesis, RNA-seq from LENG8 KD; chimeric UAP56/URH49 mutants with Co-IP\",\n      \"pmids\": [\"40595470\", \"38225262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TREX-2 versus PAXT pathway competition is regulated in different cell types\", \"Whether the trigger loop mechanism is conserved in non-mammalian TREX-2\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Human genetics established DDX39B loss-of-function as causal for a neurodevelopmental syndrome: patient missense variants impair TREX complex assembly or cause aberrant splicing, and zebrafish knockdown recapitulates developmental defects rescued by DDX39B mRNA.\",\n      \"evidence\": \"In vitro Co-IP with patient variants, blood transcriptomics, zebrafish morpholino knockdown with mRNA rescue, Drosophila transgenic assays\",\n      \"pmids\": [\"39918047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype correlations across the variant spectrum not fully defined\", \"Which DDX39B-dependent splicing events are most critical for neurodevelopment unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"DDX39B was identified as a global repressor of A-to-I RNA editing: its helicase activity prevents dsRNA accumulation that would otherwise serve as ADAR substrates, expanding its role in RNA structure surveillance beyond R-loop resolution.\",\n      \"evidence\": \"Genome-scale CRISPR screen, single-cell CRISPR RNA-seq, transcriptome-wide A-to-I editing profiling\",\n      \"pmids\": [\"40652511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DDX39B acts directly on ADAR substrates or indirectly via global dsRNA levels\", \"Relationship between editing suppression and innate immune dsRNA sensing not explored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis for how DDX39B discriminates between R-loops, dsRNA, and mRNP substrates; how the TREX-2 versus PAXT competition is regulated to determine RNA fate; and which DDX39B-dependent splicing events are most critical for neurodevelopment and immune regulation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of DDX39B bound simultaneously to R-loop substrate and regulatory partners\", \"Mechanism governing DDX39B allocation between splicing, export, and R-loop resolution functions unknown\", \"Tissue-specific consequences of DDX39B haploinsufficiency not systematically characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3, 6, 7, 8, 9]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6, 7, 18, 22, 25]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [18, 33]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 6, 21, 35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [8, 15, 37]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 13, 37]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 6, 9, 24, 27, 28]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 5, 6, 22, 29, 37]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [18, 19]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10, 14, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [20, 24]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [24, 27, 28]}\n    ],\n    \"complexes\": [\n      \"TREX\",\n      \"TREX-2\"\n    ],\n    \"partners\": [\n      \"ALYREF\",\n      \"SARNP\",\n      \"THOC1\",\n      \"U2AF2\",\n      \"GANP\",\n      \"LENG8\",\n      \"MXA\",\n      \"LGP2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}