{"gene":"ILF2","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1994,"finding":"NF45 (ILF2) and NF90 are the 45-kDa and 90-kDa subunits of the NF-AT transcription factor complex that binds the IL-2 enhancer antigen receptor response element (ARRE); affinity-purified histidine-tagged NF45 and NF90 reconstitute NF-AT DNA-binding activity that is enhanced by T-cell stimulation and blocked by cyclosporin A or FK506. Both proteins localize to the nucleus of Jurkat T-cells.","method":"Affinity purification (nickel chelate), EMSA, immunofluorescence microscopy, transient expression of tagged proteins in Jurkat T-cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstituted DNA-binding activity with purified proteins, multiple orthogonal methods (EMSA, immunofluorescence, affinity purification), original discovery paper","pmids":["7519613"],"is_preprint":false},{"year":1998,"finding":"NF45 and NF90 interact with the DNA-dependent protein kinase (DNA-PK) complex (DNA-PKcs and Ku subunits) and stabilize a DNA-PKcs–Ku–DNA complex; NF45 and NF90 are substrates for DNA-PK phosphorylation in vitro; recombinant NF90 promotes DNA-PKcs–Ku–DNA complex formation; antibodies to NF90 or NF45 co-immunoprecipitate DNA-PKcs.","method":"EMSA, in vitro kinase assay, co-immunoprecipitation, amino-terminal sequence analysis, immunoblotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay with recombinant proteins, reciprocal co-IP, multiple orthogonal methods in one study","pmids":["9442054"],"is_preprint":false},{"year":1998,"finding":"NF45 and NF90, together with Ku70, Ku80, and DNA-PKcs, form a purine-box/NFAT DNA-binding complex in human bronchial epithelial cells; antibodies to Ku potently inhibit the purine-box DNA-binding complex.","method":"Immunohistochemistry, EMSA with blocking antibodies, co-immunoprecipitation","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, multiple supporting methods but largely confirmatory of PMID 9442054","pmids":["9843854"],"is_preprint":false},{"year":2005,"finding":"NF45 (ILF2) functions as a transcriptional activator of IL-2 gene expression; stable overexpression of NF45 sense cDNA in Jurkat T-cells increased IL-2 luciferase reporter activity ~120-fold and IL-2 protein ~2-fold; antisense suppression had the opposite effect. The human NF45 gene was mapped to chromosome 1q21.3.","method":"Stable transfection, luciferase reporter assay, ELISA, fluorescence in situ hybridization","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional gain/loss-of-function in relevant cell line with reporter and protein readouts, single lab","pmids":["15817156"],"is_preprint":false},{"year":2006,"finding":"The DRBP76 (NF90)–NF45 heterodimer selectively forms in neuronal but not glioma cells, binds the HRV2 IRES, associates with the translation apparatus, and arrests translation at the HRV2 IRES by preventing PV-RIPO RNA assembly into polysomes.","method":"Size exclusion chromatography, ribosomal profile analysis (polysome fractionation), IRES-binding assay, cell-type specific heterokaryon analysis","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical reconstitution (size exclusion), polysome profiling, functional translation inhibition assay, multiple orthogonal methods","pmids":["16809299"],"is_preprint":false},{"year":2008,"finding":"NF45 is a regulatory subunit of NF90-NF45 and NF110-NF45 heterodimeric core complexes; depletion of NF45 by RNAi causes dramatic reduction in NF90 and NF110 protein levels (and vice versa for NF90 depletion), demonstrating post-transcriptional co-stabilization by protein–protein interaction. Depletion of NF90-NF45 (but not NF110-NF45) inhibits DNA synthesis and causes formation of giant multinucleated cells, revealing a critical role in normal cell division.","method":"RNA interference (siRNA), immunoblotting, flow cytometry, cell growth assays, time-lapse microscopy","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean RNAi knockdown of multiple subunits with defined cellular phenotypes, reciprocal depletion experiments, replicated across conditions","pmids":["18458058"],"is_preprint":false},{"year":2009,"finding":"The NF90–NF45 complex functions as a negative regulator of miRNA biogenesis: overexpression inhibits pri-miRNA processing to pre-miRNA, causing accumulation of pri-miRNAs; NF90-NF45 binds endogenous pri-miRNAs (higher affinity for pri-let-7a) but does not interact with the Microprocessor complex, suggesting steric blocking of Microprocessor access.","method":"Overexpression, quantitative RT-PCR, RNA immunoprecipitation, RNA polymerase II inhibition assay (alpha-amanitin), RNAi knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (OE, KD, RIP, pri-miRNA accumulation assay), negative control (no Microprocessor interaction), single lab but mechanistically rigorous","pmids":["19398578"],"is_preprint":false},{"year":2009,"finding":"NF45 is an IRES trans-acting factor (ITAF) required for cap-independent translation of cIAP1 mRNA during the unfolded protein response; NF45 binds the cIAP1 IRES (identified by RNA affinity chromatography) and enhances IRES-dependent translation of endogenous cIAP1.","method":"RNA affinity chromatography, enzymatic cleavage mapping (secondary structure), RNAi knockdown, IRES-driven translation assay","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — RNA affinity chromatography plus functional translation assay with KD, multiple methods, single lab","pmids":["19893574"],"is_preprint":false},{"year":2010,"finding":"NF45 co-localizes with IBDV viral proteins VP1, VP2, and VP3 at viral replication sites in the cytoplasm of infected cells; co-immunoprecipitation confirmed protein–protein association; siRNA-mediated NF45 knockdown increased virus yield ~5-fold, indicating NF45 restricts IBDV replication as part of a cellular defense mechanism.","method":"Immunofluorescence, co-immunoprecipitation, siRNA knockdown, viral yield assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal co-IP and functional knockdown with quantitative viral yield, single lab","pmids":["20702628"],"is_preprint":false},{"year":2010,"finding":"NF45 and NF90 bind the HS4 element in the IL-13 distal promoter and are required for HS4-dependent IL-13 transcription in T cells; binding was demonstrated by DNA affinity chromatography with mass spectrometry, ChIP, and gel shift; HS4 activity was virtually abrogated in NF45+/- primary Th2 cells.","method":"DNA affinity chromatography coupled with tandem MS, ChIP, EMSA, transient transfection of HS4-IL13 reporters in primary NF45+/- Th2 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (MS-confirmed binding, ChIP, EMSA, primary-cell KO reporter), direct genetic evidence from haploinsufficient mice","pmids":["20051514"],"is_preprint":false},{"year":2011,"finding":"The NF90/NF45 complex participates in DNA double-strand break repair via non-homologous end joining (NHEJ): immunodepletion of NF90/NF45 from nuclear extracts reduced in vitro DNA end-joining activity; NF90/NF45-depleted cells accumulated γ-H2AX foci and showed increased sensitivity to ionizing radiation; in vivo end-joining was also reduced. Multinucleated phenotype upon depletion was traced to incomplete cytokinesis followed by cell fusion.","method":"In vitro NHEJ assay with immunodepletion, gamma-H2AX foci quantification, ionizing radiation sensitivity assay, time-lapse microscopy, RNAi knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstituted NHEJ assay with immunodepletion plus multiple in vivo validation methods, mechanistically rigorous","pmids":["21969602"],"is_preprint":false},{"year":2011,"finding":"NF45 interacts with HCV core protein (HCVc174) in an RNA-dependent manner; NF45 and HCVc174 co-localize in nucleus and cytoplasm, with co-localization shifting to cytoplasm when virus replicates.","method":"Affinity purification, LC-MS/MS proteomics, pull-down, confocal imaging","journal":"Journal of proteome research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pulldown/MS identification with imaging, no functional follow-up for NF45 specifically","pmids":["21823664"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of the NF90/NF45 dimerization complex at 1.9-Å resolution reveals that both proteins contain a 'DZF' domain with structural similarity to template-free nucleotidyltransferases, but both have lost critical catalytic residues and are not functional enzymes; NF45 also dimerizes with SPNR and Zfr through the same NF90 binding interface, demonstrated by co-immunoprecipitation with site-specific NF90 interface mutants.","method":"X-ray crystallography (1.9-Å), co-immunoprecipitation with site-specific mutants","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis-validated interaction interface, orthogonal biochemical confirmation","pmids":["22833610"],"is_preprint":false},{"year":2012,"finding":"2'-fluoro (2'-F) modified antisense oligonucleotides form heteroduplexes that are specifically recognized by the ILF2/ILF3 (NF45/NF90) complex; recruitment of ILF2/3 to pre-mRNA near an exon causes exon skipping in cell culture and in mice, demonstrating that ILF2/3 can modulate alternative splicing.","method":"2'-F ASO treatment, cell culture and in vivo mouse experiments, exon skipping analysis, protein recruitment assay","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional splicing modulation in cells and in vivo mice, mechanistic link to ILF2/3 recruitment, replicated in multiple systems","pmids":["22504300"],"is_preprint":false},{"year":2012,"finding":"NF45 ITAF activity is required for IRES-mediated translation of XIAP and cIAP1 mRNAs; cells deficient in NF45 show reduced IRES-dependent translation of these targets, leading to dysregulated survivin and cyclin E expression, explaining cytokinesis impairment and senescence-like phenotype; AU-rich content (>60%) of 5' UTRs predicts NF45 dependence.","method":"RNAi knockdown, IRES reporter assays, bioinformatic analysis of 5' UTR composition, cell cycle and ploidy analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional IRES translation assays with KD plus downstream phenotype readout, single lab with multiple targets","pmids":["23129811"],"is_preprint":false},{"year":2012,"finding":"Depletion of NF90/NF45 in HPV-transformed cervical carcinoma cells restores p53 and p21 protein expression; p53 is regulated post-transcriptionally (mRNA level unchanged), while p21 induction is p53-dependent at the transcriptional level; NF90 depletion attenuates HPV E6 RNA expression by inhibiting transcription from the HPV early promoter, thereby de-repressing the E6/E6AP-mediated p53 degradation pathway.","method":"RNAi knockdown, immunoblotting, qRT-PCR, p53 RNAi epistasis, PARP cleavage assay, camptothecin sensitivity assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis experiment (p53 RNAi rescues), mRNA vs. protein level analysis separating transcriptional from post-transcriptional regulation, single lab","pmids":["23208500"],"is_preprint":false},{"year":2015,"finding":"The NF45/NF90 heterodimer associates with precursors to 60S ribosomal subunits (pre-60S particles) in nucleoli; association requires the dsRNA-binding domains of NF90; depletion of NF45 and NF90 causes a 60S biogenesis defect, alters nucleolar morphology to a characteristic spherical shape, and triggers a p53/p21 response dependent on RPL11.","method":"Tandem affinity purification, density gradient sedimentation, RNAi knockdown, nucleolar morphology analysis, RPL11 epistasis (double knockdown), rRNA processing assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — affinity purification, gradient fractionation, domain requirement, epistasis with RPL11, multiple orthogonal readouts, single lab","pmids":["26240280"],"is_preprint":false},{"year":2015,"finding":"NF45-NF90 and NF45-NF110 complexes function as transcriptional coactivators of the c-fos gene: purified complexes stimulate c-fos transcription in a defined in vitro system via both the upstream enhancer and core promoter; coactivation does not require dsRNA binding domains; the complexes cooperate with PC4 and Mediator; ChIP shows dynamic occupancy at the c-fos enhancer/promoter before and after serum induction.","method":"In vitro transcription reconstitution with purified components, ChIP, RNAi knockdown in mouse cells, domain-deletion mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstituted transcription assay with purified proteins, ChIP, domain dissection, multiple orthogonal methods","pmids":["26381409"],"is_preprint":false},{"year":2015,"finding":"Overexpression of NF90-NF45 in transgenic mice suppresses myogenic miRNA biogenesis (including miR-133a) by binding pri-miR-133a-1 and inhibiting its processing, resulting in elevated dynamin 2 expression, skeletal muscle atrophy, and centronuclear muscle fibers in vivo.","method":"NF90-NF45 double-transgenic mouse model, miRNA microarray, qRT-PCR, in vitro pri-miRNA binding assay, histological analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic model with defined molecular mechanism (pri-miRNA binding), in vitro binding confirmation, multiple orthogonal readouts","pmids":["25918244"],"is_preprint":false},{"year":2016,"finding":"NF90-NF45 negatively regulates miR-7 biogenesis in hepatocellular carcinoma by binding pri-miR-7-1 in vitro, blocking its processing; NF90/NF45 depletion elevates mature miR-7, decreases EGFR levels, reduces AKT phosphorylation, and inhibits HCC cell proliferation.","method":"miRNA microarray, qRT-PCR, RNAi knockdown, in vitro pri-miRNA binding assay, overexpression, immunoblotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro pri-miRNA binding assay, gain- and loss-of-function, downstream signaling readout, single lab with multiple orthogonal methods","pmids":["27519414"],"is_preprint":false},{"year":2016,"finding":"NF90 (DRBP76) has selective RNA chaperone activity (RNA annealing and strand displacement) that is substantially enhanced by heterodimer formation with NF45; NF45 acts as a conformational scaffold improving NF90 'matchmaking' of complementary ssRNAs; the NF90-NF45 complex stimulates the first step of HCV RNA replication in vitro and stabilizes a regulatory element in VEGF mRNA by protein-guided RNA structural changes.","method":"In vitro RNA chaperone assays (annealing, strand displacement), biophysical binding analysis, HCV replication assay in vitro, VEGF mRNA structural analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution of RNA chaperone activity, mechanistic dissection of annealing mechanism, functional virus replication assay, multiple orthogonal experiments","pmids":["29040738"],"is_preprint":false},{"year":2016,"finding":"Complex formation of NF90 with NF45 substantially improves NF90 RNA-binding capacity, modifies binding mode, enhances affinity for both ss- and dsRNA, and provides thermodynamic stabilization; NF45 is proposed to act as a conformational scaffold altering the cooperative interplay of NF90's RNA-binding motifs.","method":"Biophysical analysis (purified recombinant proteins), biochemical RNA-binding assays comparing monomer vs. heterodimer","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biophysical and biochemical analysis with purified recombinant proteins, single lab","pmids":["28062840"],"is_preprint":false},{"year":2017,"finding":"Elevated ILF2 expression (driven by 1q21 amplification) promotes tolerance of genomic instability and resistance to DNA-damaging agents in multiple myeloma by modulating YB-1 nuclear localization and its interaction with splicing factor U2AF65, which promotes mRNA processing and stabilization of transcripts involved in homologous recombination.","method":"siRNA knockdown, overexpression, co-immunoprecipitation (ILF2-YB-1 and YB-1-U2AF65), mRNA stability assay, drug sensitivity assay, in vivo xenograft","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic co-IP showing ILF2-YB-1-U2AF65 pathway, functional rescue experiments, multiple orthogonal methods, high-impact peer-reviewed venue","pmids":["28669490"],"is_preprint":false},{"year":2017,"finding":"NF45 and NF90/NF110 regulate embryonic stem cell pluripotency and differentiation; loss of NF45 or NF90+NF110 impairs ESC proliferation and causes dysregulated differentiation; NF45 and NF90/NF110 physically interact and influence each other's expression; NF90/NF110 RIP-seq identified direct target mRNAs involved in proliferation and RNA processing.","method":"RNAi screen, CRISPR KO, RNA immunoprecipitation followed by sequencing (RIP-seq), transcriptome analysis, proliferation assays","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide RIP-seq, CRISPR KO, multiple cell line validations, mechanistic epistasis","pmids":["28487382"],"is_preprint":false},{"year":2019,"finding":"NF45 and NF90/NF110 pre-occupy the promoters of immediate early genes (EGR1, FOS, JUN) constitutively; cellular stimulation with PMA increases NF90/NF110 chromatin association while decreasing NF45 association at these promoters; knockdown of either NF90/NF110 or NF45 attenuates inducible expression of EGR1, FOS, and JUN.","method":"ChIP, inducible shRNA knockdown, qRT-PCR, immunoblotting","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with functional knockdown, single lab, two orthogonal methods","pmids":["31022259"],"is_preprint":false},{"year":2019,"finding":"ILF2 functions as a transcription factor that directly binds the upstream regulatory region of PTEN and suppresses its expression; ChIP and luciferase reporter assays demonstrated direct binding; this enables anchorage-independent survival of NSCLC cells.","method":"ChIP, luciferase reporter assay, cell adhesion and apoptosis assays in suspension culture","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay confirm direct binding to PTEN promoter, functional cell survival readout, single lab","pmids":["31423236"],"is_preprint":false},{"year":2019,"finding":"ILF2 directly binds CREB protein via the pKID domain of CREB; ILF2 stabilizes CREB at the protein level (not mRNA level) and promotes CREB phosphorylation at Ser133; this interaction promotes malignant phenotypes of liver cancer cells.","method":"Co-immunoprecipitation, immunoblotting, domain mapping, protein stability assays","journal":"Analytical cellular pathology (Amsterdam)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP with domain identification, limited mechanistic follow-up, single lab","pmids":["30881868"],"is_preprint":false},{"year":2019,"finding":"ILF2 interacts with E2F1 in small cell lung cancer cells; ILF2 maintains mitochondrial quality and promotes oxidative phosphorylation; suppression of E2F1 reverses ILF2-induced tumor growth and mitochondrial function enhancement.","method":"Co-immunoprecipitation, RNA-seq, dual luciferase reporter assay, mitochondrial membrane potential assay, oxygen consumption rate measurement, xenograft models","journal":"Cancer biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirmed interaction, E2F1 epistasis experiment, multiple metabolic readouts, single lab","pmids":["31908894"],"is_preprint":false},{"year":2019,"finding":"ILF2 inhibits Japanese encephalitis virus (JEV) replication: ILF2 interacts with JEV NS3 protein (identified by co-IP and LC-MS/MS); ILF2 knockdown increases JEV propagation, and ILF2 overexpression reduces JEV genome synthesis; ILF2 is decreased in JEV-infected cells.","method":"Co-immunoprecipitation, LC-MS/MS, shRNA knockdown, overexpression, JEV replicon assay","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with MS identification, gain- and loss-of-function with viral replication readouts, single lab","pmids":["31212927"],"is_preprint":false},{"year":2019,"finding":"EV71 nonstructural protein 2B interacts with ILF2 and promotes ILF2 translocation from nucleus to cytoplasm, thereby antagonizing ILF2's antiviral effects; ILF2 overexpression reduces EV71 TCID50 and plaque formation.","method":"Co-immunoprecipitation, subcellular fractionation/immunofluorescence, viral titer assay (TCID50 and PFU), microarray, siRNA knockdown","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP, localization shift, functional antiviral assays, single lab","pmids":["31878072"],"is_preprint":false},{"year":2021,"finding":"Upon T-cell activation, NFAT translocates to the nucleolus and interacts with the NF45/NF90 complex to promote rDNA transcription; NF45/NF90 directly binds ARRE2-like sequences in the rDNA promoter; elevated pre-rRNA is required for T-cell activation and can be suppressed by CX5461 (rDNA transcription inhibitor) to prevent allograft rejection.","method":"Co-immunoprecipitation (NFAT-NF45/NF90), ChIP (NF45/NF90 at rDNA promoter), pre-rRNA quantification, mouse transplantation models, pharmacological inhibition","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP confirms direct rDNA binding, co-IP confirms NFAT interaction, in vivo mouse models validate functional relevance, multiple orthogonal methods","pmids":["33555115"],"is_preprint":false},{"year":2021,"finding":"ILF2 binds THO complex protein THOC4 as a regulatory cofactor, interacts selectively with pluripotency factor mRNAs (SOX2, NANOG, SALL4), promotes their nuclear export through assembly into export-competent mRNP complexes, and inhibits hMTR4-mediated exosomal degradation to stabilize these transcripts; nicotine induces ILF2 via JAK2/STAT3 signaling.","method":"Co-immunoprecipitation (ILF2-THOC4), RIP, RNA stability assays, mRNA nuclear export assay, ILF2 depletion in vitro and in vivo xenograft","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, RIP, functional mRNA export and stability readouts, single lab","pmids":["33975879"],"is_preprint":false},{"year":2022,"finding":"ILF2 enhances the DNA cytosine deaminase activity of APOBEC3B by ~30% when overexpressed, and ILF2 knockdown suppresses A3B deaminase activity by ~30%; ILF2 interacts with A3B in high-molecular-mass complexes identified by mass spectrometry; most interactions are RNA-dependent except for SAFB.","method":"Mass spectrometry (A3B interactome), density gradient sedimentation, deaminase activity assay, siRNA knockdown, overexpression","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical deaminase activity assay with gain- and loss-of-function, MS identification of interaction, single lab","pmids":["35145187"],"is_preprint":false},{"year":2022,"finding":"NF90-NF45 acts as a negative regulator of m6A modification of pri-miRNAs: NF90-NF45 attenuates METTL3/14-mediated m6A modification of pri-mir-7-1 in vitro (but not pri-mir-200a, which has lower NF90 binding affinity), thereby suppressing miR-7 biogenesis; NF90-NF45 does not interact with METTL3/14 (negative finding).","method":"In vitro m6A modification assay, overexpression, miRNA biogenesis assay, immunoprecipitation (NF90-METTL3/14 interaction—negative result)","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro m6A modification assay with recombinant components, functional miRNA readout, single lab","pmids":["41351330"],"is_preprint":false},{"year":2022,"finding":"NF90-NF45 is essential for beta-cell compensation under high-fat diet metabolic stress; beta-cell-specific NF90-NF45-deficient mice develop hyperglycemia and decreased islet mass; NF90-NF45 suppresses p53 signaling pathway in beta cells, and a dominant-negative p53 rescues the growth retardation in NF90-NF45-depleted beta cells.","method":"Beta-cell-specific conditional knockout mice, microarray, p53-responsive luciferase reporter, dominant-negative p53 rescue, cell growth assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional knockout model with epistasis (dominant-negative p53 rescue), mechanistically defined p53 pathway, multiple readouts","pmids":["35614067"],"is_preprint":false},{"year":2023,"finding":"NUSAP1 interacts with ILF2 (verified by co-immunoprecipitation and confocal colocalization) through its microtubule and charged helical domains; depletion of ILF2 alone increases camptothecin-induced R-loop accumulation and DNA damage; NUSAP1 depletion abolishes this effect, placing ILF2 as a regulator of R-loop homeostasis in response to DNA damage.","method":"Affinity purification-mass spectrometry, co-immunoprecipitation, confocal microscopy, ILF2 depletion, R-loop immunostaining (S9.6 antibody), domain truncation mapping","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping, functional R-loop assay with genetic epistasis, single lab","pmids":["37047232"],"is_preprint":false},{"year":2024,"finding":"DYNLL1 interacts with ILF2 and facilitates ILF2 expression; ILF2 in turn interacts with CDK4 mRNA and delays its degradation, activating G1/S cell cycle progression and downstream CDK4 targets to promote HCC development.","method":"Co-immunoprecipitation, mass spectrometry, RNA sequencing, mRNA stability assay (RIP for CDK4 mRNA), xenograft and orthotopic mouse models","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, RIP confirming ILF2-CDK4 mRNA interaction, mRNA stability assay, functional in vivo models, single lab","pmids":["38824222"],"is_preprint":false},{"year":2025,"finding":"USP5 is a deubiquitinase that stabilizes ILF2 by removing ubiquitin modifications; co-IP and MS identified the USP5-ILF2 interaction; catalytically inactive USP5 failed to reduce ILF2 ubiquitination, demonstrating the requirement for USP5 catalytic activity; USP5 inhibitor WP1130 downregulates ILF2 and inhibits CRC cell growth, reversed by ILF2 overexpression.","method":"Co-immunoprecipitation, LC-MS/MS, ubiquitination assay, catalytic mutant USP5, pharmacological inhibition (WP1130), xenograft mouse model","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with MS, catalytic mutant demonstrates enzyme requirement, functional rescue by ILF2 overexpression, single lab","pmids":["41523258"],"is_preprint":false},{"year":2025,"finding":"Integrative structural analysis of NF45-NF90 using SAXS, quantitative cross-linking mass spectrometry, machine learning, and negative-stain EM reveals architectural rearrangements upon dsRNA binding; NF45-NF90 complexes can oligomerize to coat long dsRNA stretches (>50 bp); in human cells, NF45-NF90 primarily interacts with Alu inverted repeats (AluIRs) in introns, regulating adenosine-to-inosine editing, cassette exon and back splicing, and splicing fidelity.","method":"Small angle X-ray scattering (SAXS), quantitative cross-linking mass spectrometry, machine learning structural modeling, negative stain electron microscopy, phylogenetic analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple biophysical structural methods (SAXS, CLMS, EM) with functional annotations, single lab but rigorous multi-method approach","pmids":["40156862"],"is_preprint":false},{"year":2026,"finding":"ICAM1 mRNA and its cis-antisense transcript ICAM1-AS form a dsRNA that entraps the ILF2/ILF3 complex, inhibiting its DNA binding in a length-dependent manner; this suppresses EIF4E transcription and global protein synthesis; the mechanism is independent of ICAM1 protein coding function.","method":"CRISPR-Cas9 protein knockout vs. shRNA knockdown comparison, overexpression of mutated ICAM1 mRNA and CDS, dsRNA pulldown of ILF2/ILF3, EIF4E transcription assay, global protein synthesis measurement","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dsRNA-ILF2/3 entrapment demonstrated with pulldown and functional readouts, single lab but orthogonal genetic approaches","pmids":["41512856"],"is_preprint":false},{"year":2025,"finding":"ILF2 orchestrates transcriptional and RNA splicing programs in kidney medullary epithelial cells; ILF2 knockdown disrupts gene expression and splicing programs linked to cell proliferation, cytoskeletal organization, and stress adaptation; ILF2-deficient cells show reduced proliferation, impaired nuclear integrity, and increased sensitivity to hyperosmotic stress; ILF2 expression increases during tubular repair after ischemia-reperfusion injury in mice.","method":"Single-nucleus RNA-seq, single-cell CRISPR interference screening (Perturb-seq), bulk RNA-seq, splicing analysis, hyperosmotic stress assay, mouse IRI model","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Perturb-seq with genome-wide functional readout, in vivo mouse model, multiple orthogonal methods; preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"ILF2 orchestrates recruitment of RNA:DNA helicases to resolve R-loops; pharmacological disruption of the ILF2 complex with compound NYH0002 inhibits RNA:DNA helicase activity, elicits genome-wide DNA breaks, and induces lethality selectively in homologous recombination-deficient cancers; tumors with elevated cyclin E and E2F1 are sensitive to NYH0002.","method":"Direct binding assay (NYH0002 to ILF2 complex), helicase activity assay, genome-wide DNA damage assay, HR-deficient cancer cell lines, in vivo tumor models","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and helicase activity assay with compound, functional in vivo models; preprint not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"ILF2 (NF45) functions primarily as an obligate heterodimeric partner of NF90/ILF3: together they form a structurally defined complex (DZF domain crystal structure at 1.9 Å) that binds double-stranded RNA and DNA to regulate gene expression at multiple levels—as a transcriptional coactivator (IL-2, IL-13, c-fos, IEGs, rDNA), as a negative regulator of miRNA biogenesis by binding pri-miRNAs and blocking Microprocessor access, as an RNA chaperone that remodels RNA structure, as an IRES trans-acting factor promoting cap-independent translation of cIAP1 and XIAP, as a modulator of nuclear mRNA export (via THOC4) and mRNA stability (CDK4, HIF-1α), as a participant in DNA double-strand break repair via NHEJ through interaction with DNA-PK, as a regulator of R-loop homeostasis by recruiting RNA:DNA helicases, and as a 60S ribosomal subunit biogenesis factor; NF45 protein stability is reciprocally co-regulated with NF90 post-transcriptionally, and ILF2 itself is subject to ubiquitin-mediated degradation reversed by the deubiquitinase USP5."},"narrative":{"mechanistic_narrative":"ILF2 (NF45) is a nucleic-acid-binding regulatory protein that operates principally as the obligate dimerization partner of NF90/NF110 (ILF3), forming heterodimers that act on DNA and RNA across transcription, RNA metabolism, and genome maintenance [PMID:7519613, PMID:18458058, PMID:22833610]. Structurally, NF45 and its partner each contain a catalytically dead DZF (nucleotidyltransferase-like) domain that mediates dimerization, and NF45 uses the same interface to bind alternative partners such as SPNR and Zfr [PMID:22833610]; NF45 acts as a conformational scaffold that substantially enhances NF90's affinity and altered binding mode for both single- and double-stranded RNA and confers RNA chaperone (annealing/strand-displacement) activity on the complex [PMID:29040738, PMID:28062840]. At the chromatin level the complex serves as a sequence-specific transcriptional regulator, reconstituting NF-AT DNA-binding at the IL-2 enhancer, driving IL-13, c-fos, and immediate-early gene (EGR1, FOS, JUN) transcription, and being recruited by NFAT to the rDNA promoter to support T-cell activation [PMID:7519613, PMID:20051514, PMID:26381409, PMID:31022259, PMID:33555115]. In RNA metabolism the complex is a negative regulator of miRNA biogenesis, binding pri-miRNAs (let-7a, miR-133a, miR-7) to block Microprocessor access and attenuate METTL3/14-mediated m6A modification of pri-miRNAs, with physiological consequences in muscle and hepatocellular carcinoma [PMID:19398578, PMID:25918244, PMID:27519414, PMID:41351330]; it additionally functions as an IRES trans-acting factor for cIAP1 and XIAP translation, governs Alu-inverted-repeat-dependent A-to-I editing and splicing, and modulates mRNA export and stability of selected transcripts via THOC4 [PMID:19893574, PMID:23129811, PMID:40156862, PMID:33975879]. ILF2 also maintains genome integrity, participating in NHEJ-mediated double-strand-break repair through the DNA-PK complex and resolving R-loops by recruiting RNA:DNA helicases, and the NF90-NF45 complex is required for proper cell division, 60S ribosomal subunit biogenesis, and suppression of a p53/p21 response [PMID:9442054, PMID:21969602, PMID:37047232, PMID:26240280, PMID:18458058]. ILF2 is frequently exploited in cancer, where 1q21-amplified ILF2 promotes tolerance of genomic instability in multiple myeloma via YB-1/U2AF65 and is stabilized post-translationally by the deubiquitinase USP5 [PMID:28669490, PMID:41523258].","teleology":[{"year":1994,"claim":"Established ILF2's founding identity by showing NF45 is a subunit of the NF-AT DNA-binding complex at the IL-2 enhancer, defining a transcriptional role from the outset.","evidence":"Affinity-purified His-tagged NF45/NF90 reconstituting NF-AT EMSA activity in Jurkat T-cells with immunofluorescence localization","pmids":["7519613"],"confidence":"High","gaps":["Did not resolve which subunit confers sequence specificity","No structural basis for DNA binding"]},{"year":1998,"claim":"Linked NF45/NF90 to genome maintenance by showing physical and functional association with the DNA-PK (DNA-PKcs–Ku) complex, foreshadowing a DSB-repair role.","evidence":"Reciprocal co-IP, in vitro DNA-PK kinase assay using recombinant proteins, EMSA in two cell systems","pmids":["9442054","9843854"],"confidence":"High","gaps":["Functional consequence of phosphorylation unknown at the time","Direct role in repair not yet demonstrated"]},{"year":2005,"claim":"Provided gain/loss-of-function evidence that NF45 directly activates IL-2 gene expression, moving beyond binding to causal transcriptional output.","evidence":"Stable sense/antisense NF45 expression in Jurkat with IL-2 luciferase reporter and ELISA","pmids":["15817156"],"confidence":"Medium","gaps":["Large reporter effect versus modest protein change unexplained","Single cell line"]},{"year":2008,"claim":"Defined NF45 as a regulatory subunit reciprocally co-stabilizing NF90/NF110 at the protein level and essential for normal cell division.","evidence":"Reciprocal siRNA depletion with immunoblotting, flow cytometry, and time-lapse microscopy showing multinucleated cells","pmids":["18458058"],"confidence":"High","gaps":["Mechanism of post-transcriptional co-stabilization not defined","Cause of division defect not yet traced"]},{"year":2009,"claim":"Identified the complex as a negative regulator of miRNA biogenesis acting by steric occlusion of the Microprocessor, and as an IRES trans-acting factor for cIAP1.","evidence":"Overexpression/knockdown with RIP and pri-miRNA accumulation assays; RNA affinity chromatography plus IRES translation assay","pmids":["19398578","19893574"],"confidence":"High","gaps":["Exact structural basis of Microprocessor blocking not resolved","Generality across pri-miRNAs incomplete"]},{"year":2011,"claim":"Demonstrated a direct functional role in NHEJ-mediated double-strand-break repair, converting the earlier DNA-PK association into a mechanistic repair function.","evidence":"In vitro NHEJ assay with immunodepletion, γ-H2AX foci, IR sensitivity, and in vivo end-joining","pmids":["21969602"],"confidence":"High","gaps":["Precise step in NHEJ catalysis acted upon unclear","Relationship to RNA-binding functions not addressed"]},{"year":2012,"claim":"Provided the structural foundation—an atomic model of the DZF dimerization interface—revealing catalytically dead nucleotidyltransferase folds and explaining partner promiscuity.","evidence":"1.9-Å crystal structure of NF90/NF45 plus interface-mutant co-IP with SPNR and Zfr; parallel splicing-modulation and XIAP/cIAP1 ITAF studies","pmids":["22833610","22504300","23129811"],"confidence":"High","gaps":["Structure of RNA-bound complex not solved","How dimer architecture dictates each downstream activity unresolved"]},{"year":2015,"claim":"Expanded the functional repertoire to ribosome biogenesis and to transcriptional coactivation of c-fos, while linking miRNA suppression to in vivo muscle phenotypes.","evidence":"Pre-60S affinity purification with RPL11 epistasis; in vitro reconstituted c-fos transcription with ChIP; NF90-NF45 transgenic mouse with pri-miR-133a binding","pmids":["26240280","26381409","25918244"],"confidence":"High","gaps":["How one complex coordinates ribosome biogenesis with transcription unknown","Domain requirements differ across functions"]},{"year":2016,"claim":"Mechanistically defined how NF45 potentiates NF90, establishing the heterodimer as an RNA chaperone and enhanced RNA-binding module.","evidence":"In vitro RNA annealing/strand-displacement assays, biophysical binding comparison of monomer vs heterodimer, HCV replication and VEGF mRNA assays","pmids":["29040738","28062840","27519414"],"confidence":"High","gaps":["Structural basis of scaffold-induced affinity change not visualized","Cellular targets of chaperone activity incompletely mapped"]},{"year":2017,"claim":"Connected ILF2 to cancer-associated genomic instability tolerance and to stem-cell/pluripotency gene regulation, broadening its physiological reach.","evidence":"ILF2-YB-1-U2AF65 co-IP and mRNA stability/drug-sensitivity assays in myeloma; CRISPR KO and RIP-seq in ESCs","pmids":["28669490","28487382"],"confidence":"High","gaps":["Whether YB-1 axis is general or myeloma-specific unclear","Direct ILF2 RNA targets in ESCs only partially defined"]},{"year":2019,"claim":"Catalogued additional partner- and target-specific roles spanning transcriptional repression of PTEN, CREB/E2F1 interactions, and antiviral restriction.","evidence":"ChIP/luciferase at PTEN promoter; co-IP domain mapping for CREB and E2F1; co-IP and viral replication assays for JEV and EV71","pmids":["31423236","30881868","31908894","31212927","31878072"],"confidence":"Medium","gaps":["Several interactions rest on single co-IPs without reciprocal validation","Direct versus complex-mediated DNA binding not always separated"]},{"year":2021,"claim":"Tied the complex's transcriptional activity to T-cell activation through NFAT-driven nucleolar rDNA transcription and to oncogenic mRNA export via THOC4.","evidence":"NFAT-NF45/NF90 co-IP and rDNA-promoter ChIP with mouse transplant models; ILF2-THOC4 co-IP, RIP, export and stability assays","pmids":["33555115","33975879"],"confidence":"Medium","gaps":["How ARRE2-like rDNA recognition occurs structurally unknown","Selectivity of pluripotency-mRNA export incompletely explained"]},{"year":2022,"claim":"Extended ILF2's RNA-related functions to APOBEC3B deaminase modulation, pri-miRNA m6A regulation, and beta-cell metabolic compensation via p53 suppression.","evidence":"A3B interactome MS and deaminase assays; in vitro m6A modification assay; beta-cell conditional KO with dominant-negative p53 rescue","pmids":["35145187","41351330","35614067"],"confidence":"Medium","gaps":["Direct vs RNA-bridged A3B interaction partly unresolved","Mechanism of p53 suppression in beta cells not molecularly defined"]},{"year":2023,"claim":"Established ILF2 as a regulator of R-loop homeostasis acting with NUSAP1 to limit DNA-damage-induced R-loop accumulation.","evidence":"AP-MS, co-IP with domain mapping, confocal colocalization, S9.6 R-loop immunostaining with NUSAP1 epistasis","pmids":["37047232"],"confidence":"Medium","gaps":["Whether ILF2 acts via helicase recruitment here not yet shown","Single-lab functional epistasis"]},{"year":2025,"claim":"Refined the structural model of dsRNA recognition (oligomeric coating of long dsRNA, Alu-inverted-repeat targeting) and defined post-translational control of ILF2 stability by USP5, alongside cancer-relevant CDK4 mRNA stabilization.","evidence":"SAXS/CLMS/EM integrative modeling with Alu-IR functional annotation; USP5 co-IP, catalytic-mutant ubiquitination assay, WP1130 rescue; DYNLL1-ILF2-CDK4 mRNA RIP and stability assays","pmids":["40156862","41523258","38824222"],"confidence":"Medium","gaps":["High-resolution dsRNA-bound structure still lacking","USP5 and DYNLL1 axes each rest on single-lab data"]},{"year":2026,"claim":"Showed that endogenous dsRNAs (ICAM1/ICAM1-AS) can entrap and inactivate the ILF2/ILF3 complex to repress EIF4E and global translation, revealing a sensing/sequestration mode of regulation.","evidence":"dsRNA pulldown of ILF2/ILF3, CRISPR KO vs shRNA comparison, EIF4E transcription and global protein synthesis assays","pmids":["41512856"],"confidence":"Medium","gaps":["Generality of dsRNA entrapment beyond ICAM1 unknown","Single-lab mechanism"]},{"year":null,"claim":"How a single scaffold partner integrates and switches between transcription, miRNA/splicing/editing control, ribosome biogenesis, DSB repair, and R-loop resolution—and what determines target selection in each context—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking distinct molecular activities","No high-resolution structure of nucleic-acid-bound functional states","Determinants of context-specific target choice unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[6,7,20,21,38]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,9,17,25,30]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,17,24,30]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[20]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[7,14]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[39]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,24,30]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[16,30]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,11,29]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,9,17,24,30]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[6,18,19,31,38]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,10,35]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,36]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[16,30]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,9,30]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,14,39]}],"complexes":["NF90-NF45 (ILF3-ILF2) heterodimer","NF110-NF45 heterodimer","DNA-PK complex (DNA-PKcs-Ku70-Ku80)","NF-AT/purine-box DNA-binding complex"],"partners":["ILF3","DNA-PKCS","KU70","KU80","THOC4","YB-1","USP5","NUSAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12905","full_name":"Interleukin enhancer-binding factor 2","aliases":["Nuclear factor of activated T-cells 45 kDa"],"length_aa":390,"mass_kda":43.1,"function":"Chromatin-interacting protein that forms a stable heterodimer with interleukin enhancer-binding factor 3/ILF3 and plays a role in several biological processes including transcription, innate immunity or cell growth (PubMed:18458058, PubMed:31212927). Essential for the efficient reshuttling of ILF3 (isoform 1 and isoform 2) into the nucleus. Together with ILF3, forms an RNA-binding complex that is required for mitotic progression and cytokinesis by regulating the expression of a cluster of mitotic genes. Mechanistically, competes with STAU1/STAU2-mediated mRNA decay (PubMed:32433969). Also plays a role in the inhibition of various viruses including Japanese encephalitis virus or enterovirus 71 (Microbial infection) Plays a positive role in HIV-1 virus production by binding to and thereby stabilizing HIV-1 RNA, together with ILF3","subcellular_location":"Nucleus, nucleolus; Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q12905/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ILF2","classification":"Common 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ILF2","url":"https://www.omim.org/entry/603181"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ILF2"},"hgnc":{"alias_symbol":["NF45"],"prev_symbol":[]},"alphafold":{"accession":"Q12905","domains":[{"cath_id":"1.10.1410.40","chopping":"28-41_48-64_217-359","consensus_level":"medium","plddt":97.4277,"start":28,"end":359},{"cath_id":"3.30.460.10","chopping":"66-215","consensus_level":"medium","plddt":97.2315,"start":66,"end":215}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12905","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12905-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12905-F1-predicted_aligned_error_v6.png","plddt_mean":89.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ILF2","jax_strain_url":"https://www.jax.org/strain/search?query=ILF2"},"sequence":{"accession":"Q12905","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12905.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12905/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12905"}},"corpus_meta":[{"pmid":"7519613","id":"PMC_7519613","title":"Cloning 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FK506. Both proteins localize to the nucleus of Jurkat T-cells.\",\n      \"method\": \"Affinity purification (nickel chelate), EMSA, immunofluorescence microscopy, transient expression of tagged proteins in Jurkat T-cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstituted DNA-binding activity with purified proteins, multiple orthogonal methods (EMSA, immunofluorescence, affinity purification), original discovery paper\",\n      \"pmids\": [\"7519613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"NF45 and NF90 interact with the DNA-dependent protein kinase (DNA-PK) complex (DNA-PKcs and Ku subunits) and stabilize a DNA-PKcs–Ku–DNA complex; NF45 and NF90 are substrates for DNA-PK phosphorylation in vitro; recombinant NF90 promotes DNA-PKcs–Ku–DNA complex formation; antibodies to NF90 or NF45 co-immunoprecipitate DNA-PKcs.\",\n      \"method\": \"EMSA, in vitro kinase assay, co-immunoprecipitation, amino-terminal sequence analysis, immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay with recombinant proteins, reciprocal co-IP, multiple orthogonal methods in one study\",\n      \"pmids\": [\"9442054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"NF45 and NF90, together with Ku70, Ku80, and DNA-PKcs, form a purine-box/NFAT DNA-binding complex in human bronchial epithelial cells; antibodies to Ku potently inhibit the purine-box DNA-binding complex.\",\n      \"method\": \"Immunohistochemistry, EMSA with blocking antibodies, co-immunoprecipitation\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, multiple supporting methods but largely confirmatory of PMID 9442054\",\n      \"pmids\": [\"9843854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"NF45 (ILF2) functions as a transcriptional activator of IL-2 gene expression; stable overexpression of NF45 sense cDNA in Jurkat T-cells increased IL-2 luciferase reporter activity ~120-fold and IL-2 protein ~2-fold; antisense suppression had the opposite effect. The human NF45 gene was mapped to chromosome 1q21.3.\",\n      \"method\": \"Stable transfection, luciferase reporter assay, ELISA, fluorescence in situ hybridization\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional gain/loss-of-function in relevant cell line with reporter and protein readouts, single lab\",\n      \"pmids\": [\"15817156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The DRBP76 (NF90)–NF45 heterodimer selectively forms in neuronal but not glioma cells, binds the HRV2 IRES, associates with the translation apparatus, and arrests translation at the HRV2 IRES by preventing PV-RIPO RNA assembly into polysomes.\",\n      \"method\": \"Size exclusion chromatography, ribosomal profile analysis (polysome fractionation), IRES-binding assay, cell-type specific heterokaryon analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical reconstitution (size exclusion), polysome profiling, functional translation inhibition assay, multiple orthogonal methods\",\n      \"pmids\": [\"16809299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NF45 is a regulatory subunit of NF90-NF45 and NF110-NF45 heterodimeric core complexes; depletion of NF45 by RNAi causes dramatic reduction in NF90 and NF110 protein levels (and vice versa for NF90 depletion), demonstrating post-transcriptional co-stabilization by protein–protein interaction. Depletion of NF90-NF45 (but not NF110-NF45) inhibits DNA synthesis and causes formation of giant multinucleated cells, revealing a critical role in normal cell division.\",\n      \"method\": \"RNA interference (siRNA), immunoblotting, flow cytometry, cell growth assays, time-lapse microscopy\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean RNAi knockdown of multiple subunits with defined cellular phenotypes, reciprocal depletion experiments, replicated across conditions\",\n      \"pmids\": [\"18458058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The NF90–NF45 complex functions as a negative regulator of miRNA biogenesis: overexpression inhibits pri-miRNA processing to pre-miRNA, causing accumulation of pri-miRNAs; NF90-NF45 binds endogenous pri-miRNAs (higher affinity for pri-let-7a) but does not interact with the Microprocessor complex, suggesting steric blocking of Microprocessor access.\",\n      \"method\": \"Overexpression, quantitative RT-PCR, RNA immunoprecipitation, RNA polymerase II inhibition assay (alpha-amanitin), RNAi knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (OE, KD, RIP, pri-miRNA accumulation assay), negative control (no Microprocessor interaction), single lab but mechanistically rigorous\",\n      \"pmids\": [\"19398578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NF45 is an IRES trans-acting factor (ITAF) required for cap-independent translation of cIAP1 mRNA during the unfolded protein response; NF45 binds the cIAP1 IRES (identified by RNA affinity chromatography) and enhances IRES-dependent translation of endogenous cIAP1.\",\n      \"method\": \"RNA affinity chromatography, enzymatic cleavage mapping (secondary structure), RNAi knockdown, IRES-driven translation assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — RNA affinity chromatography plus functional translation assay with KD, multiple methods, single lab\",\n      \"pmids\": [\"19893574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NF45 co-localizes with IBDV viral proteins VP1, VP2, and VP3 at viral replication sites in the cytoplasm of infected cells; co-immunoprecipitation confirmed protein–protein association; siRNA-mediated NF45 knockdown increased virus yield ~5-fold, indicating NF45 restricts IBDV replication as part of a cellular defense mechanism.\",\n      \"method\": \"Immunofluorescence, co-immunoprecipitation, siRNA knockdown, viral yield assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal co-IP and functional knockdown with quantitative viral yield, single lab\",\n      \"pmids\": [\"20702628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NF45 and NF90 bind the HS4 element in the IL-13 distal promoter and are required for HS4-dependent IL-13 transcription in T cells; binding was demonstrated by DNA affinity chromatography with mass spectrometry, ChIP, and gel shift; HS4 activity was virtually abrogated in NF45+/- primary Th2 cells.\",\n      \"method\": \"DNA affinity chromatography coupled with tandem MS, ChIP, EMSA, transient transfection of HS4-IL13 reporters in primary NF45+/- Th2 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (MS-confirmed binding, ChIP, EMSA, primary-cell KO reporter), direct genetic evidence from haploinsufficient mice\",\n      \"pmids\": [\"20051514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The NF90/NF45 complex participates in DNA double-strand break repair via non-homologous end joining (NHEJ): immunodepletion of NF90/NF45 from nuclear extracts reduced in vitro DNA end-joining activity; NF90/NF45-depleted cells accumulated γ-H2AX foci and showed increased sensitivity to ionizing radiation; in vivo end-joining was also reduced. Multinucleated phenotype upon depletion was traced to incomplete cytokinesis followed by cell fusion.\",\n      \"method\": \"In vitro NHEJ assay with immunodepletion, gamma-H2AX foci quantification, ionizing radiation sensitivity assay, time-lapse microscopy, RNAi knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstituted NHEJ assay with immunodepletion plus multiple in vivo validation methods, mechanistically rigorous\",\n      \"pmids\": [\"21969602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NF45 interacts with HCV core protein (HCVc174) in an RNA-dependent manner; NF45 and HCVc174 co-localize in nucleus and cytoplasm, with co-localization shifting to cytoplasm when virus replicates.\",\n      \"method\": \"Affinity purification, LC-MS/MS proteomics, pull-down, confocal imaging\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pulldown/MS identification with imaging, no functional follow-up for NF45 specifically\",\n      \"pmids\": [\"21823664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of the NF90/NF45 dimerization complex at 1.9-Å resolution reveals that both proteins contain a 'DZF' domain with structural similarity to template-free nucleotidyltransferases, but both have lost critical catalytic residues and are not functional enzymes; NF45 also dimerizes with SPNR and Zfr through the same NF90 binding interface, demonstrated by co-immunoprecipitation with site-specific NF90 interface mutants.\",\n      \"method\": \"X-ray crystallography (1.9-Å), co-immunoprecipitation with site-specific mutants\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis-validated interaction interface, orthogonal biochemical confirmation\",\n      \"pmids\": [\"22833610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"2'-fluoro (2'-F) modified antisense oligonucleotides form heteroduplexes that are specifically recognized by the ILF2/ILF3 (NF45/NF90) complex; recruitment of ILF2/3 to pre-mRNA near an exon causes exon skipping in cell culture and in mice, demonstrating that ILF2/3 can modulate alternative splicing.\",\n      \"method\": \"2'-F ASO treatment, cell culture and in vivo mouse experiments, exon skipping analysis, protein recruitment assay\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional splicing modulation in cells and in vivo mice, mechanistic link to ILF2/3 recruitment, replicated in multiple systems\",\n      \"pmids\": [\"22504300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NF45 ITAF activity is required for IRES-mediated translation of XIAP and cIAP1 mRNAs; cells deficient in NF45 show reduced IRES-dependent translation of these targets, leading to dysregulated survivin and cyclin E expression, explaining cytokinesis impairment and senescence-like phenotype; AU-rich content (>60%) of 5' UTRs predicts NF45 dependence.\",\n      \"method\": \"RNAi knockdown, IRES reporter assays, bioinformatic analysis of 5' UTR composition, cell cycle and ploidy analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional IRES translation assays with KD plus downstream phenotype readout, single lab with multiple targets\",\n      \"pmids\": [\"23129811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Depletion of NF90/NF45 in HPV-transformed cervical carcinoma cells restores p53 and p21 protein expression; p53 is regulated post-transcriptionally (mRNA level unchanged), while p21 induction is p53-dependent at the transcriptional level; NF90 depletion attenuates HPV E6 RNA expression by inhibiting transcription from the HPV early promoter, thereby de-repressing the E6/E6AP-mediated p53 degradation pathway.\",\n      \"method\": \"RNAi knockdown, immunoblotting, qRT-PCR, p53 RNAi epistasis, PARP cleavage assay, camptothecin sensitivity assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis experiment (p53 RNAi rescues), mRNA vs. protein level analysis separating transcriptional from post-transcriptional regulation, single lab\",\n      \"pmids\": [\"23208500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The NF45/NF90 heterodimer associates with precursors to 60S ribosomal subunits (pre-60S particles) in nucleoli; association requires the dsRNA-binding domains of NF90; depletion of NF45 and NF90 causes a 60S biogenesis defect, alters nucleolar morphology to a characteristic spherical shape, and triggers a p53/p21 response dependent on RPL11.\",\n      \"method\": \"Tandem affinity purification, density gradient sedimentation, RNAi knockdown, nucleolar morphology analysis, RPL11 epistasis (double knockdown), rRNA processing assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — affinity purification, gradient fractionation, domain requirement, epistasis with RPL11, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"26240280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NF45-NF90 and NF45-NF110 complexes function as transcriptional coactivators of the c-fos gene: purified complexes stimulate c-fos transcription in a defined in vitro system via both the upstream enhancer and core promoter; coactivation does not require dsRNA binding domains; the complexes cooperate with PC4 and Mediator; ChIP shows dynamic occupancy at the c-fos enhancer/promoter before and after serum induction.\",\n      \"method\": \"In vitro transcription reconstitution with purified components, ChIP, RNAi knockdown in mouse cells, domain-deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstituted transcription assay with purified proteins, ChIP, domain dissection, multiple orthogonal methods\",\n      \"pmids\": [\"26381409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Overexpression of NF90-NF45 in transgenic mice suppresses myogenic miRNA biogenesis (including miR-133a) by binding pri-miR-133a-1 and inhibiting its processing, resulting in elevated dynamin 2 expression, skeletal muscle atrophy, and centronuclear muscle fibers in vivo.\",\n      \"method\": \"NF90-NF45 double-transgenic mouse model, miRNA microarray, qRT-PCR, in vitro pri-miRNA binding assay, histological analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic model with defined molecular mechanism (pri-miRNA binding), in vitro binding confirmation, multiple orthogonal readouts\",\n      \"pmids\": [\"25918244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NF90-NF45 negatively regulates miR-7 biogenesis in hepatocellular carcinoma by binding pri-miR-7-1 in vitro, blocking its processing; NF90/NF45 depletion elevates mature miR-7, decreases EGFR levels, reduces AKT phosphorylation, and inhibits HCC cell proliferation.\",\n      \"method\": \"miRNA microarray, qRT-PCR, RNAi knockdown, in vitro pri-miRNA binding assay, overexpression, immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro pri-miRNA binding assay, gain- and loss-of-function, downstream signaling readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27519414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NF90 (DRBP76) has selective RNA chaperone activity (RNA annealing and strand displacement) that is substantially enhanced by heterodimer formation with NF45; NF45 acts as a conformational scaffold improving NF90 'matchmaking' of complementary ssRNAs; the NF90-NF45 complex stimulates the first step of HCV RNA replication in vitro and stabilizes a regulatory element in VEGF mRNA by protein-guided RNA structural changes.\",\n      \"method\": \"In vitro RNA chaperone assays (annealing, strand displacement), biophysical binding analysis, HCV replication assay in vitro, VEGF mRNA structural analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution of RNA chaperone activity, mechanistic dissection of annealing mechanism, functional virus replication assay, multiple orthogonal experiments\",\n      \"pmids\": [\"29040738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Complex formation of NF90 with NF45 substantially improves NF90 RNA-binding capacity, modifies binding mode, enhances affinity for both ss- and dsRNA, and provides thermodynamic stabilization; NF45 is proposed to act as a conformational scaffold altering the cooperative interplay of NF90's RNA-binding motifs.\",\n      \"method\": \"Biophysical analysis (purified recombinant proteins), biochemical RNA-binding assays comparing monomer vs. heterodimer\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biophysical and biochemical analysis with purified recombinant proteins, single lab\",\n      \"pmids\": [\"28062840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Elevated ILF2 expression (driven by 1q21 amplification) promotes tolerance of genomic instability and resistance to DNA-damaging agents in multiple myeloma by modulating YB-1 nuclear localization and its interaction with splicing factor U2AF65, which promotes mRNA processing and stabilization of transcripts involved in homologous recombination.\",\n      \"method\": \"siRNA knockdown, overexpression, co-immunoprecipitation (ILF2-YB-1 and YB-1-U2AF65), mRNA stability assay, drug sensitivity assay, in vivo xenograft\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic co-IP showing ILF2-YB-1-U2AF65 pathway, functional rescue experiments, multiple orthogonal methods, high-impact peer-reviewed venue\",\n      \"pmids\": [\"28669490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NF45 and NF90/NF110 regulate embryonic stem cell pluripotency and differentiation; loss of NF45 or NF90+NF110 impairs ESC proliferation and causes dysregulated differentiation; NF45 and NF90/NF110 physically interact and influence each other's expression; NF90/NF110 RIP-seq identified direct target mRNAs involved in proliferation and RNA processing.\",\n      \"method\": \"RNAi screen, CRISPR KO, RNA immunoprecipitation followed by sequencing (RIP-seq), transcriptome analysis, proliferation assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide RIP-seq, CRISPR KO, multiple cell line validations, mechanistic epistasis\",\n      \"pmids\": [\"28487382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NF45 and NF90/NF110 pre-occupy the promoters of immediate early genes (EGR1, FOS, JUN) constitutively; cellular stimulation with PMA increases NF90/NF110 chromatin association while decreasing NF45 association at these promoters; knockdown of either NF90/NF110 or NF45 attenuates inducible expression of EGR1, FOS, and JUN.\",\n      \"method\": \"ChIP, inducible shRNA knockdown, qRT-PCR, immunoblotting\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with functional knockdown, single lab, two orthogonal methods\",\n      \"pmids\": [\"31022259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ILF2 functions as a transcription factor that directly binds the upstream regulatory region of PTEN and suppresses its expression; ChIP and luciferase reporter assays demonstrated direct binding; this enables anchorage-independent survival of NSCLC cells.\",\n      \"method\": \"ChIP, luciferase reporter assay, cell adhesion and apoptosis assays in suspension culture\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay confirm direct binding to PTEN promoter, functional cell survival readout, single lab\",\n      \"pmids\": [\"31423236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ILF2 directly binds CREB protein via the pKID domain of CREB; ILF2 stabilizes CREB at the protein level (not mRNA level) and promotes CREB phosphorylation at Ser133; this interaction promotes malignant phenotypes of liver cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, immunoblotting, domain mapping, protein stability assays\",\n      \"journal\": \"Analytical cellular pathology (Amsterdam)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP with domain identification, limited mechanistic follow-up, single lab\",\n      \"pmids\": [\"30881868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ILF2 interacts with E2F1 in small cell lung cancer cells; ILF2 maintains mitochondrial quality and promotes oxidative phosphorylation; suppression of E2F1 reverses ILF2-induced tumor growth and mitochondrial function enhancement.\",\n      \"method\": \"Co-immunoprecipitation, RNA-seq, dual luciferase reporter assay, mitochondrial membrane potential assay, oxygen consumption rate measurement, xenograft models\",\n      \"journal\": \"Cancer biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP confirmed interaction, E2F1 epistasis experiment, multiple metabolic readouts, single lab\",\n      \"pmids\": [\"31908894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ILF2 inhibits Japanese encephalitis virus (JEV) replication: ILF2 interacts with JEV NS3 protein (identified by co-IP and LC-MS/MS); ILF2 knockdown increases JEV propagation, and ILF2 overexpression reduces JEV genome synthesis; ILF2 is decreased in JEV-infected cells.\",\n      \"method\": \"Co-immunoprecipitation, LC-MS/MS, shRNA knockdown, overexpression, JEV replicon assay\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with MS identification, gain- and loss-of-function with viral replication readouts, single lab\",\n      \"pmids\": [\"31212927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EV71 nonstructural protein 2B interacts with ILF2 and promotes ILF2 translocation from nucleus to cytoplasm, thereby antagonizing ILF2's antiviral effects; ILF2 overexpression reduces EV71 TCID50 and plaque formation.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/immunofluorescence, viral titer assay (TCID50 and PFU), microarray, siRNA knockdown\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP, localization shift, functional antiviral assays, single lab\",\n      \"pmids\": [\"31878072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Upon T-cell activation, NFAT translocates to the nucleolus and interacts with the NF45/NF90 complex to promote rDNA transcription; NF45/NF90 directly binds ARRE2-like sequences in the rDNA promoter; elevated pre-rRNA is required for T-cell activation and can be suppressed by CX5461 (rDNA transcription inhibitor) to prevent allograft rejection.\",\n      \"method\": \"Co-immunoprecipitation (NFAT-NF45/NF90), ChIP (NF45/NF90 at rDNA promoter), pre-rRNA quantification, mouse transplantation models, pharmacological inhibition\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP confirms direct rDNA binding, co-IP confirms NFAT interaction, in vivo mouse models validate functional relevance, multiple orthogonal methods\",\n      \"pmids\": [\"33555115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ILF2 binds THO complex protein THOC4 as a regulatory cofactor, interacts selectively with pluripotency factor mRNAs (SOX2, NANOG, SALL4), promotes their nuclear export through assembly into export-competent mRNP complexes, and inhibits hMTR4-mediated exosomal degradation to stabilize these transcripts; nicotine induces ILF2 via JAK2/STAT3 signaling.\",\n      \"method\": \"Co-immunoprecipitation (ILF2-THOC4), RIP, RNA stability assays, mRNA nuclear export assay, ILF2 depletion in vitro and in vivo xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, RIP, functional mRNA export and stability readouts, single lab\",\n      \"pmids\": [\"33975879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ILF2 enhances the DNA cytosine deaminase activity of APOBEC3B by ~30% when overexpressed, and ILF2 knockdown suppresses A3B deaminase activity by ~30%; ILF2 interacts with A3B in high-molecular-mass complexes identified by mass spectrometry; most interactions are RNA-dependent except for SAFB.\",\n      \"method\": \"Mass spectrometry (A3B interactome), density gradient sedimentation, deaminase activity assay, siRNA knockdown, overexpression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical deaminase activity assay with gain- and loss-of-function, MS identification of interaction, single lab\",\n      \"pmids\": [\"35145187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NF90-NF45 acts as a negative regulator of m6A modification of pri-miRNAs: NF90-NF45 attenuates METTL3/14-mediated m6A modification of pri-mir-7-1 in vitro (but not pri-mir-200a, which has lower NF90 binding affinity), thereby suppressing miR-7 biogenesis; NF90-NF45 does not interact with METTL3/14 (negative finding).\",\n      \"method\": \"In vitro m6A modification assay, overexpression, miRNA biogenesis assay, immunoprecipitation (NF90-METTL3/14 interaction—negative result)\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro m6A modification assay with recombinant components, functional miRNA readout, single lab\",\n      \"pmids\": [\"41351330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NF90-NF45 is essential for beta-cell compensation under high-fat diet metabolic stress; beta-cell-specific NF90-NF45-deficient mice develop hyperglycemia and decreased islet mass; NF90-NF45 suppresses p53 signaling pathway in beta cells, and a dominant-negative p53 rescues the growth retardation in NF90-NF45-depleted beta cells.\",\n      \"method\": \"Beta-cell-specific conditional knockout mice, microarray, p53-responsive luciferase reporter, dominant-negative p53 rescue, cell growth assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional knockout model with epistasis (dominant-negative p53 rescue), mechanistically defined p53 pathway, multiple readouts\",\n      \"pmids\": [\"35614067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NUSAP1 interacts with ILF2 (verified by co-immunoprecipitation and confocal colocalization) through its microtubule and charged helical domains; depletion of ILF2 alone increases camptothecin-induced R-loop accumulation and DNA damage; NUSAP1 depletion abolishes this effect, placing ILF2 as a regulator of R-loop homeostasis in response to DNA damage.\",\n      \"method\": \"Affinity purification-mass spectrometry, co-immunoprecipitation, confocal microscopy, ILF2 depletion, R-loop immunostaining (S9.6 antibody), domain truncation mapping\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping, functional R-loop assay with genetic epistasis, single lab\",\n      \"pmids\": [\"37047232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DYNLL1 interacts with ILF2 and facilitates ILF2 expression; ILF2 in turn interacts with CDK4 mRNA and delays its degradation, activating G1/S cell cycle progression and downstream CDK4 targets to promote HCC development.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, RNA sequencing, mRNA stability assay (RIP for CDK4 mRNA), xenograft and orthotopic mouse models\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, RIP confirming ILF2-CDK4 mRNA interaction, mRNA stability assay, functional in vivo models, single lab\",\n      \"pmids\": [\"38824222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP5 is a deubiquitinase that stabilizes ILF2 by removing ubiquitin modifications; co-IP and MS identified the USP5-ILF2 interaction; catalytically inactive USP5 failed to reduce ILF2 ubiquitination, demonstrating the requirement for USP5 catalytic activity; USP5 inhibitor WP1130 downregulates ILF2 and inhibits CRC cell growth, reversed by ILF2 overexpression.\",\n      \"method\": \"Co-immunoprecipitation, LC-MS/MS, ubiquitination assay, catalytic mutant USP5, pharmacological inhibition (WP1130), xenograft mouse model\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with MS, catalytic mutant demonstrates enzyme requirement, functional rescue by ILF2 overexpression, single lab\",\n      \"pmids\": [\"41523258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Integrative structural analysis of NF45-NF90 using SAXS, quantitative cross-linking mass spectrometry, machine learning, and negative-stain EM reveals architectural rearrangements upon dsRNA binding; NF45-NF90 complexes can oligomerize to coat long dsRNA stretches (>50 bp); in human cells, NF45-NF90 primarily interacts with Alu inverted repeats (AluIRs) in introns, regulating adenosine-to-inosine editing, cassette exon and back splicing, and splicing fidelity.\",\n      \"method\": \"Small angle X-ray scattering (SAXS), quantitative cross-linking mass spectrometry, machine learning structural modeling, negative stain electron microscopy, phylogenetic analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biophysical structural methods (SAXS, CLMS, EM) with functional annotations, single lab but rigorous multi-method approach\",\n      \"pmids\": [\"40156862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ICAM1 mRNA and its cis-antisense transcript ICAM1-AS form a dsRNA that entraps the ILF2/ILF3 complex, inhibiting its DNA binding in a length-dependent manner; this suppresses EIF4E transcription and global protein synthesis; the mechanism is independent of ICAM1 protein coding function.\",\n      \"method\": \"CRISPR-Cas9 protein knockout vs. shRNA knockdown comparison, overexpression of mutated ICAM1 mRNA and CDS, dsRNA pulldown of ILF2/ILF3, EIF4E transcription assay, global protein synthesis measurement\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dsRNA-ILF2/3 entrapment demonstrated with pulldown and functional readouts, single lab but orthogonal genetic approaches\",\n      \"pmids\": [\"41512856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ILF2 orchestrates transcriptional and RNA splicing programs in kidney medullary epithelial cells; ILF2 knockdown disrupts gene expression and splicing programs linked to cell proliferation, cytoskeletal organization, and stress adaptation; ILF2-deficient cells show reduced proliferation, impaired nuclear integrity, and increased sensitivity to hyperosmotic stress; ILF2 expression increases during tubular repair after ischemia-reperfusion injury in mice.\",\n      \"method\": \"Single-nucleus RNA-seq, single-cell CRISPR interference screening (Perturb-seq), bulk RNA-seq, splicing analysis, hyperosmotic stress assay, mouse IRI model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Perturb-seq with genome-wide functional readout, in vivo mouse model, multiple orthogonal methods; preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ILF2 orchestrates recruitment of RNA:DNA helicases to resolve R-loops; pharmacological disruption of the ILF2 complex with compound NYH0002 inhibits RNA:DNA helicase activity, elicits genome-wide DNA breaks, and induces lethality selectively in homologous recombination-deficient cancers; tumors with elevated cyclin E and E2F1 are sensitive to NYH0002.\",\n      \"method\": \"Direct binding assay (NYH0002 to ILF2 complex), helicase activity assay, genome-wide DNA damage assay, HR-deficient cancer cell lines, in vivo tumor models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and helicase activity assay with compound, functional in vivo models; preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ILF2 (NF45) functions primarily as an obligate heterodimeric partner of NF90/ILF3: together they form a structurally defined complex (DZF domain crystal structure at 1.9 Å) that binds double-stranded RNA and DNA to regulate gene expression at multiple levels—as a transcriptional coactivator (IL-2, IL-13, c-fos, IEGs, rDNA), as a negative regulator of miRNA biogenesis by binding pri-miRNAs and blocking Microprocessor access, as an RNA chaperone that remodels RNA structure, as an IRES trans-acting factor promoting cap-independent translation of cIAP1 and XIAP, as a modulator of nuclear mRNA export (via THOC4) and mRNA stability (CDK4, HIF-1α), as a participant in DNA double-strand break repair via NHEJ through interaction with DNA-PK, as a regulator of R-loop homeostasis by recruiting RNA:DNA helicases, and as a 60S ribosomal subunit biogenesis factor; NF45 protein stability is reciprocally co-regulated with NF90 post-transcriptionally, and ILF2 itself is subject to ubiquitin-mediated degradation reversed by the deubiquitinase USP5.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ILF2 (NF45) is a nucleic-acid-binding regulatory protein that operates principally as the obligate dimerization partner of NF90/NF110 (ILF3), forming heterodimers that act on DNA and RNA across transcription, RNA metabolism, and genome maintenance [#0, #5, #12]. Structurally, NF45 and its partner each contain a catalytically dead DZF (nucleotidyltransferase-like) domain that mediates dimerization, and NF45 uses the same interface to bind alternative partners such as SPNR and Zfr [#12]; NF45 acts as a conformational scaffold that substantially enhances NF90's affinity and altered binding mode for both single- and double-stranded RNA and confers RNA chaperone (annealing/strand-displacement) activity on the complex [#20, #21]. At the chromatin level the complex serves as a sequence-specific transcriptional regulator, reconstituting NF-AT DNA-binding at the IL-2 enhancer, driving IL-13, c-fos, and immediate-early gene (EGR1, FOS, JUN) transcription, and being recruited by NFAT to the rDNA promoter to support T-cell activation [#0, #9, #17, #24, #30]. In RNA metabolism the complex is a negative regulator of miRNA biogenesis, binding pri-miRNAs (let-7a, miR-133a, miR-7) to block Microprocessor access and attenuate METTL3/14-mediated m6A modification of pri-miRNAs, with physiological consequences in muscle and hepatocellular carcinoma [#6, #18, #19, #33]; it additionally functions as an IRES trans-acting factor for cIAP1 and XIAP translation, governs Alu-inverted-repeat-dependent A-to-I editing and splicing, and modulates mRNA export and stability of selected transcripts via THOC4 [#7, #14, #38, #31]. ILF2 also maintains genome integrity, participating in NHEJ-mediated double-strand-break repair through the DNA-PK complex and resolving R-loops by recruiting RNA:DNA helicases, and the NF90-NF45 complex is required for proper cell division, 60S ribosomal subunit biogenesis, and suppression of a p53/p21 response [#1, #10, #35, #16, #5]. ILF2 is frequently exploited in cancer, where 1q21-amplified ILF2 promotes tolerance of genomic instability in multiple myeloma via YB-1/U2AF65 and is stabilized post-translationally by the deubiquitinase USP5 [#22, #37].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established ILF2's founding identity by showing NF45 is a subunit of the NF-AT DNA-binding complex at the IL-2 enhancer, defining a transcriptional role from the outset.\",\n      \"evidence\": \"Affinity-purified His-tagged NF45/NF90 reconstituting NF-AT EMSA activity in Jurkat T-cells with immunofluorescence localization\",\n      \"pmids\": [\"7519613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which subunit confers sequence specificity\", \"No structural basis for DNA binding\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Linked NF45/NF90 to genome maintenance by showing physical and functional association with the DNA-PK (DNA-PKcs–Ku) complex, foreshadowing a DSB-repair role.\",\n      \"evidence\": \"Reciprocal co-IP, in vitro DNA-PK kinase assay using recombinant proteins, EMSA in two cell systems\",\n      \"pmids\": [\"9442054\", \"9843854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of phosphorylation unknown at the time\", \"Direct role in repair not yet demonstrated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Provided gain/loss-of-function evidence that NF45 directly activates IL-2 gene expression, moving beyond binding to causal transcriptional output.\",\n      \"evidence\": \"Stable sense/antisense NF45 expression in Jurkat with IL-2 luciferase reporter and ELISA\",\n      \"pmids\": [\"15817156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Large reporter effect versus modest protein change unexplained\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined NF45 as a regulatory subunit reciprocally co-stabilizing NF90/NF110 at the protein level and essential for normal cell division.\",\n      \"evidence\": \"Reciprocal siRNA depletion with immunoblotting, flow cytometry, and time-lapse microscopy showing multinucleated cells\",\n      \"pmids\": [\"18458058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of post-transcriptional co-stabilization not defined\", \"Cause of division defect not yet traced\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the complex as a negative regulator of miRNA biogenesis acting by steric occlusion of the Microprocessor, and as an IRES trans-acting factor for cIAP1.\",\n      \"evidence\": \"Overexpression/knockdown with RIP and pri-miRNA accumulation assays; RNA affinity chromatography plus IRES translation assay\",\n      \"pmids\": [\"19398578\", \"19893574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact structural basis of Microprocessor blocking not resolved\", \"Generality across pri-miRNAs incomplete\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated a direct functional role in NHEJ-mediated double-strand-break repair, converting the earlier DNA-PK association into a mechanistic repair function.\",\n      \"evidence\": \"In vitro NHEJ assay with immunodepletion, γ-H2AX foci, IR sensitivity, and in vivo end-joining\",\n      \"pmids\": [\"21969602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise step in NHEJ catalysis acted upon unclear\", \"Relationship to RNA-binding functions not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided the structural foundation—an atomic model of the DZF dimerization interface—revealing catalytically dead nucleotidyltransferase folds and explaining partner promiscuity.\",\n      \"evidence\": \"1.9-Å crystal structure of NF90/NF45 plus interface-mutant co-IP with SPNR and Zfr; parallel splicing-modulation and XIAP/cIAP1 ITAF studies\",\n      \"pmids\": [\"22833610\", \"22504300\", \"23129811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of RNA-bound complex not solved\", \"How dimer architecture dictates each downstream activity unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Expanded the functional repertoire to ribosome biogenesis and to transcriptional coactivation of c-fos, while linking miRNA suppression to in vivo muscle phenotypes.\",\n      \"evidence\": \"Pre-60S affinity purification with RPL11 epistasis; in vitro reconstituted c-fos transcription with ChIP; NF90-NF45 transgenic mouse with pri-miR-133a binding\",\n      \"pmids\": [\"26240280\", \"26381409\", \"25918244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How one complex coordinates ribosome biogenesis with transcription unknown\", \"Domain requirements differ across functions\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mechanistically defined how NF45 potentiates NF90, establishing the heterodimer as an RNA chaperone and enhanced RNA-binding module.\",\n      \"evidence\": \"In vitro RNA annealing/strand-displacement assays, biophysical binding comparison of monomer vs heterodimer, HCV replication and VEGF mRNA assays\",\n      \"pmids\": [\"29040738\", \"28062840\", \"27519414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of scaffold-induced affinity change not visualized\", \"Cellular targets of chaperone activity incompletely mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected ILF2 to cancer-associated genomic instability tolerance and to stem-cell/pluripotency gene regulation, broadening its physiological reach.\",\n      \"evidence\": \"ILF2-YB-1-U2AF65 co-IP and mRNA stability/drug-sensitivity assays in myeloma; CRISPR KO and RIP-seq in ESCs\",\n      \"pmids\": [\"28669490\", \"28487382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether YB-1 axis is general or myeloma-specific unclear\", \"Direct ILF2 RNA targets in ESCs only partially defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Catalogued additional partner- and target-specific roles spanning transcriptional repression of PTEN, CREB/E2F1 interactions, and antiviral restriction.\",\n      \"evidence\": \"ChIP/luciferase at PTEN promoter; co-IP domain mapping for CREB and E2F1; co-IP and viral replication assays for JEV and EV71\",\n      \"pmids\": [\"31423236\", \"30881868\", \"31908894\", \"31212927\", \"31878072\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several interactions rest on single co-IPs without reciprocal validation\", \"Direct versus complex-mediated DNA binding not always separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tied the complex's transcriptional activity to T-cell activation through NFAT-driven nucleolar rDNA transcription and to oncogenic mRNA export via THOC4.\",\n      \"evidence\": \"NFAT-NF45/NF90 co-IP and rDNA-promoter ChIP with mouse transplant models; ILF2-THOC4 co-IP, RIP, export and stability assays\",\n      \"pmids\": [\"33555115\", \"33975879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ARRE2-like rDNA recognition occurs structurally unknown\", \"Selectivity of pluripotency-mRNA export incompletely explained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended ILF2's RNA-related functions to APOBEC3B deaminase modulation, pri-miRNA m6A regulation, and beta-cell metabolic compensation via p53 suppression.\",\n      \"evidence\": \"A3B interactome MS and deaminase assays; in vitro m6A modification assay; beta-cell conditional KO with dominant-negative p53 rescue\",\n      \"pmids\": [\"35145187\", \"41351330\", \"35614067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs RNA-bridged A3B interaction partly unresolved\", \"Mechanism of p53 suppression in beta cells not molecularly defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established ILF2 as a regulator of R-loop homeostasis acting with NUSAP1 to limit DNA-damage-induced R-loop accumulation.\",\n      \"evidence\": \"AP-MS, co-IP with domain mapping, confocal colocalization, S9.6 R-loop immunostaining with NUSAP1 epistasis\",\n      \"pmids\": [\"37047232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ILF2 acts via helicase recruitment here not yet shown\", \"Single-lab functional epistasis\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Refined the structural model of dsRNA recognition (oligomeric coating of long dsRNA, Alu-inverted-repeat targeting) and defined post-translational control of ILF2 stability by USP5, alongside cancer-relevant CDK4 mRNA stabilization.\",\n      \"evidence\": \"SAXS/CLMS/EM integrative modeling with Alu-IR functional annotation; USP5 co-IP, catalytic-mutant ubiquitination assay, WP1130 rescue; DYNLL1-ILF2-CDK4 mRNA RIP and stability assays\",\n      \"pmids\": [\"40156862\", \"41523258\", \"38824222\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"High-resolution dsRNA-bound structure still lacking\", \"USP5 and DYNLL1 axes each rest on single-lab data\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed that endogenous dsRNAs (ICAM1/ICAM1-AS) can entrap and inactivate the ILF2/ILF3 complex to repress EIF4E and global translation, revealing a sensing/sequestration mode of regulation.\",\n      \"evidence\": \"dsRNA pulldown of ILF2/ILF3, CRISPR KO vs shRNA comparison, EIF4E transcription and global protein synthesis assays\",\n      \"pmids\": [\"41512856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of dsRNA entrapment beyond ICAM1 unknown\", \"Single-lab mechanism\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single scaffold partner integrates and switches between transcription, miRNA/splicing/editing control, ribosome biogenesis, DSB repair, and R-loop resolution—and what determines target selection in each context—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking distinct molecular activities\", \"No high-resolution structure of nucleic-acid-bound functional states\", \"Determinants of context-specific target choice unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6, 7, 20, 21, 38]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 9, 17, 25, 30]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 17, 24, 30]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [7, 14]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [39]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 24, 30]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [16, 30]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 11, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 9, 17, 24, 30]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [6, 18, 19, 31, 38]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 10, 35]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 36]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [16, 30]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 9, 30]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 14, 39]}\n    ],\n    \"complexes\": [\n      \"NF90-NF45 (ILF3-ILF2) heterodimer\",\n      \"NF110-NF45 heterodimer\",\n      \"DNA-PK complex (DNA-PKcs-Ku70-Ku80)\",\n      \"NF-AT/purine-box DNA-binding complex\"\n    ],\n    \"partners\": [\n      \"ILF3\",\n      \"DNA-PKcs\",\n      \"Ku70\",\n      \"Ku80\",\n      \"THOC4\",\n      \"YB-1\",\n      \"USP5\",\n      \"NUSAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}