{"gene":"HNRNPR","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2002,"finding":"hnRNP-R physically interacts with SMN (survival motor neuron) protein via yeast two-hybrid and co-localization; interaction requires wild-type SMN and is abolished by truncated or SMA-associated mutant SMN forms. hnRNP-R is predominantly localized in axons of motor neurons where it co-localizes with SMN.","method":"Yeast two-hybrid, immunofluorescence co-localization","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus co-localization in axons, single lab, two orthogonal methods","pmids":["11773003"],"is_preprint":false},{"year":1998,"finding":"hnRNP R is a 633-amino acid protein with a modular structure: acidic N-terminal region (~150 aa), three RNA recognition motif (RRM) domains, a nuclear localization signal, an octapeptide (PPPRMPPP), and a C-terminal glycine- and arginine-rich RGG box. It was identified as a component of hnRNP complexes by immunoprecipitation and 2D gel co-migration of recombinant protein.","method":"cDNA cloning, sequence analysis, immunoprecipitation of hnRNP complexes, 2D gel electrophoresis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — primary structural characterization with recombinant protein, immunoprecipitation of native complexes, and sequence analysis; foundational paper replicated by subsequent studies","pmids":["9421497"],"is_preprint":false},{"year":2014,"finding":"Smn and hnRNP R are present in presynaptic compartments at neuromuscular endplates of embryonic and postnatal mice, and a direct interaction between Smn and hnRNP R was confirmed in vitro and in vivo, particularly in the cytosol of motoneurons.","method":"Immunofluorescence of neuromuscular endplates, co-immunoprecipitation (in vitro and in vivo)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus direct localization at presynaptic terminals in vivo, single lab, two orthogonal methods","pmids":["25338097"],"is_preprint":false},{"year":2018,"finding":"hnRNP R interacts with ~3,500 RNA targets in motoneurons (predominantly with functions in synaptic transmission and axon guidance) as determined by iCLIP. The noncoding RNA 7SK was identified as the top interactor. hnRNP R depletion reduces axonal 7SK levels and causes defective axon growth. 7SK function in axon elongation depends on its interaction with hnRNP R but not on its association with the P-TEFb complex.","method":"iCLIP (individual nucleotide-resolution cross-linking and immunoprecipitation), shRNA knockdown, axon growth assays, 7SK deletion mutant analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — iCLIP provides transcriptome-wide binding map, functional knockdown with specific phenotype, deletion mutant dissection of 7SK interaction, multiple orthogonal methods","pmids":["29507242"],"is_preprint":false},{"year":2016,"finding":"HNRNPR binds MHC class I mRNAs at their 3' UTRs and enhances their stability and expression. Knockdown of HNRNPR reduces classical and nonclassical MHC class I protein levels and consequently modulates NK cell cytotoxic activity.","method":"RNA immunoprecipitation, knockdown experiments, NK cell cytotoxicity assays, mRNA stability assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirms direct binding, KD with defined functional readout (NK cell killing), single lab, two orthogonal methods","pmids":["27194785"],"is_preprint":false},{"year":2019,"finding":"hnRNPR stabilizes CCNB1 and CENPF mRNAs, leading to increased expression of these oncoproteins. Knockdown of CCNB1 abolished hnRNPR-induced cell growth, and knockdown of CENPF abolished hnRNPR-induced invasion, placing hnRNPR upstream of these mRNA targets in gastric cancer.","method":"shRNA knockdown, mRNA stability assays, epistasis via double knockdown, xenograft tumor models","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with double knockdown rescue, in vivo models, single lab","pmids":["31527303"],"is_preprint":false},{"year":2021,"finding":"Full-length hnRNP R (containing the N-terminal acidic domain) interacts with the multifunctional protein Yb1 (top hit in proteomic interactome analysis). Upon DNA damage, full-length hnRNP R is required for Yb1 recruitment to chromatin, where Yb1 interacts with γ-H2AX. Motoneurons lacking full-length hnRNP R accumulate double-strand breaks and show impaired DNA damage response.","method":"Hnrnpr knockout mouse (Hnrnprtm1a/tm1a), proteomic interactome analysis (mass spectrometry), chromatin fractionation, co-IP with γ-H2AX, genotoxic stress assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse model, MS-based interactome, chromatin fractionation, multiple orthogonal methods in single rigorous study","pmids":["34850154"],"is_preprint":false},{"year":2022,"finding":"hnRNP R negatively regulates transcription elongation by modulating P-TEFb activity. Loss of hnRNP R promotes release of P-TEFb from the 7SK inhibitory complex, accompanied by enhanced hnRNP A1 binding to 7SK. Additionally, hnRNP R interacts with BRD4, and its depletion increases BRD4 binding to CDK9 and stabilizes CDK9 with enhanced association with Cyclin K, resulting in increased RNA polymerase II phosphorylation and transcription.","method":"hnRNP R knockdown/knockout cells, RNA Pol II phosphorylation assays, co-immunoprecipitation (BRD4, CDK9, 7SK complex), RNA immunoprecipitation","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO/KD with mechanistic dissection of P-TEFb complex, co-IP of multiple components, CDK9 stability assays, multiple orthogonal methods","pmids":["35856391"],"is_preprint":false},{"year":2023,"finding":"Cytosolic Ptbp2 binds the 3' UTR of Hnrnpr mRNA and is required for axonal localization of Hnrnpr mRNA and local synthesis of hnRNP R protein in motoneuron axons. This regulation occurs via Ptbp2-mediated association of Hnrnpr mRNA with ribosomes in an eIF5A2-dependent manner, and is necessary for axon growth.","method":"Ptbp2 conditional KO, RNA immunoprecipitation, ribosome association assays, axon growth assays, live imaging of mRNA localization","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with specific phenotypic rescue, RIP, ribosome fractionation, eIF5A2 epistasis, multiple orthogonal methods in single study","pmids":["37438340"],"is_preprint":false},{"year":2023,"finding":"hnRNPR binds an AU-rich element (ARE) towards the 3' end of SMN2 exon 7 via RNA-affinity chromatography and potently represses exon 7 inclusion. Both hnRNPR and Sam68 bind this ARE in a competitive manner, with hnRNPR showing stronger inhibitory effect. An exon 5-skipped hnRNPR isoform has minimal inhibitory effect. ASOs inducing hnRNPR exon 5 skipping promote SMN2 exon 7 inclusion.","method":"SMN2 minigene splicing assay, deletion analysis, RNA-affinity chromatography, co-overexpression analysis, tethering assay","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — minigene system with deletion mapping, RNA-affinity chromatography, and competitive binding assay, single lab","pmids":["37225410"],"is_preprint":false},{"year":2024,"finding":"hnRNP R is a component of translation initiation complexes in axons of motoneurons. Through interaction with O-GlcNAc transferase (Ogt), hnRNP R modulates O-GlcNAcylation of eIF4G. Loss of hnRNP R reduces axonal synthesis of cytoskeletal and synaptic components, and restoring axonal O-GlcNAc levels rescues local protein synthesis and axon growth defects.","method":"Hnrnpr knockout mice, ribosome/translation initiation complex fractionation, co-IP with Ogt, O-GlcNAc proteomics, axon growth assays, neuromuscular junction analysis, motor behavior tests","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic KO mouse with in vivo NMJ phenotype, biochemical reconstitution of translation complex, proteomic O-GlcNAc mapping, rescue experiment, multiple orthogonal methods","pmids":["39198412"],"is_preprint":false},{"year":2024,"finding":"hnRNPR binds to UPF3B pre-mRNA via its RRM2 domain to generate an exon 8 exclusion truncated splice variant UPF3B-S. UPF3B-S protein then targets the 3'-UTR of CDH1 mRNA to enhance CDH1 mRNA degradation, reducing E-cadherin and activating EMT. UPF3B-S also promotes dephosphorylation of LATS1 and nuclear accumulation of YAP1, activating Hippo signaling.","method":"RNA immunoprecipitation, RRM2 domain mutant analysis, in vitro and in vivo HCC invasion models, CDH1 mRNA stability assay, LATS1/YAP1 pathway analysis","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP with domain mutant, epistasis via UPF3B-S KD, in vivo models, single lab with multiple methods","pmids":["38402949"],"is_preprint":false},{"year":2024,"finding":"hnRNP R-deficient motoneurons show decreased anterograde and increased retrograde transport of mitochondria in axons, and exhibit mitochondrial hyperpolarization caused by decreased complex I and reversed complex V activity within the respiratory chain.","method":"Hnrnpr knockout motoneurons, live imaging of mitochondrial motility, mitochondrial membrane potential assays, respiratory chain complex activity assays","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with live imaging and biochemical readouts of respiratory chain, single lab","pmids":["38408684"],"is_preprint":false},{"year":2021,"finding":"hnRNPR uses its RNA recognition motif (RRM) to bind the 3' UTR of HMGCR mRNA, reducing its translation and lowering neuronal cholesterol levels. Knockdown of hnRNPR increases HMGCR expression and cholesterol levels; overexpression decreases them. RNA immunoprecipitation and luciferase reporter assays confirmed direct binding.","method":"RNA immunoprecipitation, luciferase reporter assay, knockdown/overexpression in N2a and MN1 cells, cholesterol measurement","journal":"Journal of integrative neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP plus reporter assay confirms binding, KD/OE with cholesterol phenotype, single lab, two methods","pmids":["34258925"],"is_preprint":false},{"year":2008,"finding":"hnRNP-R binds c-fos mRNA via its AU-rich element (ARE) in the 3' UTR, accelerating both the rise and decline phases of c-fos mRNA and protein in response to PMA. ARE-containing reporter assays showed hnRNP-R significantly reduces GFP expression driven by the c-fos ARE; co-immunoprecipitation-RT-PCR confirmed direct association with c-fos mRNA in retinal cells.","method":"Co-immunoprecipitation-RT-PCR, ARE-GFP reporter assay, overexpression in R28 cells","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP-RT-PCR plus reporter assay, single lab, two orthogonal methods","pmids":["18197392"],"is_preprint":false},{"year":2024,"finding":"HNRNPA2B1 and HNRNPR bind and stabilize ASCL1 mRNA in an m6A-dependent manner: HNRNPR binds the 3' UTR of ASCL1 mRNA, and METTL14-mediated m6A modification is required for this binding (mutations in m6A sites reduce HNRNPR binding). HNRNPR interacts with IGF2BP1, and knockdown of either impairs binding to ASCL1 mRNA.","method":"RNA immunoprecipitation, m6A site mutagenesis, RNA probe pulldown, METTL14 knockdown, co-IP of HNRNPR with IGF2BP1","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A site mutagenesis plus RIP, co-IP with IGF2BP1, single lab, multiple orthogonal methods","pmids":["38331110"],"is_preprint":false},{"year":2025,"finding":"The X-ray crystal structure (1.90 Å) and NMR studies of hnRNPR RRM1 reveal it is an extended RRM (eRRM) with a canonical RRM and a structured N-terminal extension (Next) motif that docks against the RRM and extends the β-sheet surface. A tryptophan cage in the adjoining loop positions the Next motif; mutagenesis of Next-RRM interface residues and loop residues impairs protein solubility, conformational ordering, and thermal stability.","method":"X-ray crystallography (1.90 Å), solution NMR spectroscopy, mutagenesis, thermal denaturation","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure at 1.90 Å with NMR and mutagenesis validation, single lab but multiple orthogonal structural and biophysical methods","pmids":["40247750"],"is_preprint":false},{"year":2025,"finding":"RRM3 of HNRNPR, together with a downstream C-terminal charged region, is required for RNA binding specificity. HNRNPR also binds RNA G-quadruplexes (rG4s) via RRM3 with the C-terminal charged region and RG-rich regions within the low complexity domain. rG4 binding depends on RNA folding and specific rG4 structural features.","method":"High-throughput biochemical RNA binding assays, domain deletion/mutant analysis, rG4-focused RNA pool SELEX-like assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — unbiased high-throughput biochemical domain mapping, single lab preprint, not yet peer-reviewed","pmids":["40654891"],"is_preprint":true},{"year":2025,"finding":"hnRNP R binds and stabilizes JUN mRNA in an O-GlcNAc glycosylation-dependent manner. Mannose suppresses OGT activity, reducing O-GlcNAcylation of hnRNP R, which then decreases JUN mRNA stability and subsequent IL-8 transcription in NSCLC cells.","method":"OGT inhibition/mannose treatment, O-GlcNAc proteomics, RNA immunoprecipitation, mRNA stability assay, in vitro and in vivo NSCLC models","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus O-GlcNAc modification directly linked to mRNA binding activity, functional readout in vivo, single lab","pmids":["39990658"],"is_preprint":false},{"year":2025,"finding":"hnRNPR protects XB130 mRNA from XRN1- and DIS3L2-mediated degradation by binding to specific regions within the XB130 3' UTR, thereby elevating XB130 expression and promoting NSCLC cell proliferation and EMT via Akt signaling.","method":"RNA pulldown, RNA immunoprecipitation, dual-luciferase reporter assay, XRN1/DIS3L2 knockdown epistasis, in vitro and in vivo NSCLC models","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown plus RIP confirm binding, epistasis with specific nucleases, in vivo model, single lab","pmids":["40268079"],"is_preprint":false},{"year":2026,"finding":"HNRNPR regulates Plcz1 (PLCζ) pre-mRNA splicing in an m6A-dependent manner in sperm. Pathogenic mutations in HNRNPR cause reduced expression and mislocalization of PLCζ in spermatozoa, impairing calcium oscillation induction in oocytes and resulting in fertilization failure.","method":"Whole-exome sequencing of patients, Hnrnpr knock-in mouse model, ICSI with calcium oscillation imaging, PLCζ localization by immunofluorescence, m6A-dependent splicing assay","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in mouse phenocopies human patients, calcium oscillation assay, m6A-splicing mechanism, single lab with multiple orthogonal methods","pmids":["41618099"],"is_preprint":false}],"current_model":"HNRNPR is a multi-domain RNA-binding protein (three RRMs with an extended eRRM1 structure, an RGG box, and an N-terminal acidic domain) that acts as a post-transcriptional regulator in both the nucleus and cytoplasm: it stabilizes or destabilizes specific mRNAs (including MHC class I, CCNB1, CENPF, HMGCR, ASCL1, JUN, XB130) by binding their 3' UTRs, regulates alternative splicing of SMN2 exon 7 and Plcz1 pre-mRNA via exonic AU-rich elements, controls axonal mRNA transport and local translation in motoneurons (including O-GlcNAcylation of eIF4G via Ogt interaction), negatively regulates P-TEFb-driven transcription elongation through 7SK and BRD4 interactions, supports DNA damage repair by recruiting Yb1 to chromatin in a manner dependent on its N-terminal acidic domain, and regulates axonal mitochondrial transport and respiratory function."},"narrative":{"mechanistic_narrative":"HNRNPR is a modular RNA-binding protein of the hnRNP complex, built from an N-terminal acidic domain, three RNA recognition motifs (including an extended eRRM1 with a structured Next motif), an NLS, and a C-terminal RGG box, that functions as a post-transcriptional regulator in both nucleus and cytoplasm [PMID:9421497, PMID:40247750]. Through 3' UTR binding it controls the stability of numerous mRNAs, stabilizing MHC class I transcripts to set NK-cell cytotoxicity [PMID:27194785], the oncogenic CCNB1 and CENPF mRNAs [PMID:31527303], JUN [PMID:39990658] and XB130 (the latter by shielding it from XRN1/DIS3L2 nucleases) [PMID:40268079], stabilizing ASCL1 mRNA cooperatively with HNRNPA2B1/IGF2BP1 in an m6A-dependent manner [PMID:38331110], and repressing HMGCR translation to lower neuronal cholesterol [PMID:34258925]. It also regulates alternative splicing, repressing SMN2 exon 7 inclusion via an exonic AU-rich element in competition with Sam68 [PMID:37225410], generating a truncated UPF3B-S variant through RRM2-dependent binding [PMID:38402949], and controlling m6A-dependent Plcz1 splicing required for sperm PLCζ function—pathogenic HNRNPR mutations cause fertilization failure [PMID:41618099]. In motoneurons HNRNPR binds thousands of synaptic and axon-guidance transcripts, with the noncoding 7SK RNA as its top partner, and supports axon growth [PMID:29507242]; its own axonal localization and local translation depend on Ptbp2 [PMID:37438340]. There it is a component of axonal translation initiation complexes that modulates eIF4G O-GlcNAcylation through OGT, and it additionally governs axonal mitochondrial transport and respiratory chain activity [PMID:39198412, PMID:38408684]. In the nucleus, full-length HNRNPR negatively regulates P-TEFb-driven transcription elongation via 7SK and BRD4/CDK9 interactions [PMID:35856391], and its N-terminal acidic domain recruits Yb1 to chromatin to support the DNA damage response [PMID:34850154].","teleology":[{"year":1998,"claim":"Established HNRNPR as a bona fide hnRNP complex component and defined its modular domain architecture, providing the structural framework for all later functional work.","evidence":"cDNA cloning, sequence analysis, and immunoprecipitation of native hnRNP complexes with 2D gel co-migration","pmids":["9421497"],"confidence":"High","gaps":["No RNA targets or binding specificity defined","Functional role of individual domains untested"]},{"year":2002,"claim":"Linked HNRNPR to motoneuron biology by showing a direct, SMA-mutation-sensitive interaction with SMN in axons, raising the question of an RNA-handling role in motoneurons.","evidence":"Yeast two-hybrid and immunofluorescence co-localization in motor neuron axons","pmids":["11773003"],"confidence":"Medium","gaps":["Functional consequence of SMN interaction unknown","Y2H interaction not validated biochemically at this stage"]},{"year":2008,"claim":"First demonstrated 3' UTR ARE-mediated mRNA regulation, showing HNRNPR shapes c-fos transcript dynamics.","evidence":"Co-IP-RT-PCR and ARE-GFP reporter assay in retinal R28 cells","pmids":["18197392"],"confidence":"Medium","gaps":["Mechanism of accelerated turnover not resolved","Generality across other AREs untested at the time"]},{"year":2014,"claim":"Confirmed the SMN-HNRNPR interaction reciprocally in vivo at presynaptic terminals, localizing the partnership to the cytosol of motoneurons.","evidence":"Reciprocal co-IP and immunofluorescence at neuromuscular endplates in mice","pmids":["25338097"],"confidence":"Medium","gaps":["RNA cargo of the complex not identified","Whether interaction drives axonal mRNA transport untested"]},{"year":2016,"claim":"Showed HNRNPR stabilizes MHC class I mRNAs via 3' UTR binding, connecting its mRNA-stabilizing activity to immune effector outcomes.","evidence":"RNA immunoprecipitation, knockdown, mRNA stability and NK cytotoxicity assays","pmids":["27194785"],"confidence":"Medium","gaps":["Binding site within 3' UTR not mapped","Co-factors for stabilization unknown"]},{"year":2018,"claim":"Provided a transcriptome-wide binding map identifying ~3,500 motoneuron targets and 7SK as the top interactor, establishing HNRNPR as a regulator of axon growth genes.","evidence":"iCLIP, shRNA knockdown with axon growth assays, and 7SK deletion-mutant dissection","pmids":["29507242"],"confidence":"High","gaps":["How 7SK binding promotes axon elongation mechanistically unresolved","Direct vs indirect regulation of individual targets not separated"]},{"year":2019,"claim":"Placed HNRNPR upstream of oncogenic CCNB1 and CENPF mRNAs in gastric cancer through stabilization, separating its growth- versus invasion-promoting outputs.","evidence":"shRNA knockdown, mRNA stability, double-knockdown epistasis, and xenograft models","pmids":["31527303"],"confidence":"Medium","gaps":["Binding determinants on target 3' UTRs not defined","Single tumor context"]},{"year":2021,"claim":"Defined a nuclear DNA-repair function in which the N-terminal acidic domain of full-length HNRNPR recruits Yb1 to chromatin, protecting motoneurons from double-strand breaks.","evidence":"Hnrnpr knockout mouse, MS interactome, chromatin fractionation, and co-IP with γ-H2AX","pmids":["34850154"],"confidence":"High","gaps":["How acidic domain mediates Yb1 chromatin loading mechanistically unknown","Relationship to RNA-binding functions unclear"]},{"year":2021,"claim":"Extended translational repression to HMGCR, showing RRM-mediated 3' UTR binding lowers neuronal cholesterol.","evidence":"RIP, luciferase reporter, knockdown/overexpression, and cholesterol measurement in N2a/MN1 cells","pmids":["34258925"],"confidence":"Medium","gaps":["Mechanism linking binding to translational suppression not detailed","Physiological relevance in vivo untested"]},{"year":2022,"claim":"Established a nuclear role in transcription elongation control, with HNRNPR restraining P-TEFb release from 7SK and limiting BRD4/CDK9-driven Pol II phosphorylation.","evidence":"Knockdown/knockout cells, Pol II phosphorylation assays, and co-IP of BRD4, CDK9, and 7SK complex components","pmids":["35856391"],"confidence":"High","gaps":["Whether this elongation control intersects with cytoplasmic functions unknown","Gene-specific consequences of derepression not catalogued"]},{"year":2023,"claim":"Resolved how HNRNPR reaches the axon, showing Ptbp2 binds its mRNA 3' UTR to drive ribosome association and local synthesis required for axon growth.","evidence":"Ptbp2 conditional KO, RIP, ribosome association, eIF5A2 epistasis, and live mRNA imaging","pmids":["37438340"],"confidence":"High","gaps":["Signals triggering local translation not defined","Generality to other neuron types untested"]},{"year":2023,"claim":"Demonstrated direct splicing repression of SMN2 exon 7 via an exonic ARE, with HNRNPR competing with Sam68 and an isoform-dependent activity exploitable by ASOs.","evidence":"SMN2 minigene splicing, deletion mapping, RNA-affinity chromatography, competitive binding and tethering assays","pmids":["37225410"],"confidence":"Medium","gaps":["Structural basis of ARE recognition not resolved","In vivo SMN2 splicing effect of exon-5-skipping ASOs untested"]},{"year":2024,"claim":"Connected HNRNPR to axonal translational control by showing it modulates eIF4G O-GlcNAcylation through OGT, with O-GlcNAc restoration rescuing local synthesis and axon growth.","evidence":"Hnrnpr KO mice, translation-initiation complex fractionation, OGT co-IP, O-GlcNAc proteomics, NMJ and behavior analysis","pmids":["39198412"],"confidence":"High","gaps":["How HNRNPR targets OGT to eIF4G mechanistically unknown","Direct enzyme regulation vs scaffolding not distinguished"]},{"year":2024,"claim":"Revealed a metabolic/transport role, with HNRNPR loss skewing axonal mitochondrial trafficking and impairing respiratory chain function.","evidence":"Hnrnpr KO motoneurons, live mitochondrial motility imaging, membrane potential and complex activity assays","pmids":["38408684"],"confidence":"Medium","gaps":["RNA targets driving the mitochondrial phenotype not identified","Direct vs downstream cause unresolved"]},{"year":2024,"claim":"Expanded HNRNPR's mRNA repertoire to ASCL1 and UPF3B, showing m6A-dependent cooperative stabilization with IGF2BP1 and RRM2-dependent generation of an EMT-promoting UPF3B splice variant.","evidence":"RIP, m6A site mutagenesis, RRM2 mutant analysis, co-IP with IGF2BP1, and HCC invasion models","pmids":["38331110","38402949"],"confidence":"Medium","gaps":["How m6A reading is partitioned among HNRNPR/IGF2BP1 unclear","Domain requirements for ASCL1 binding not mapped"]},{"year":2025,"claim":"Provided high-resolution structural insight into the eRRM1 Next motif and mapped RRM3/C-terminal regions as determinants of RNA and rG4 binding specificity.","evidence":"X-ray crystallography (1.90 Å), NMR, mutagenesis, thermal denaturation, and high-throughput RNA binding/rG4 assays (one preprint)","pmids":["40247750","40654891"],"confidence":"High","gaps":["Structural basis of full-length multi-RRM RNA engagement not solved","rG4 binding role in cellular targets untested"]},{"year":2025,"claim":"Tied HNRNPR mRNA-stabilizing activity to O-GlcNAcylation and nuclease protection, with O-GlcNAc modulating JUN stability and HNRNPR shielding XB130 from XRN1/DIS3L2 to drive NSCLC phenotypes.","evidence":"OGT inhibition/mannose, O-GlcNAc proteomics, RIP, RNA pulldown, nuclease knockdown epistasis, and in vivo NSCLC models","pmids":["39990658","40268079"],"confidence":"Medium","gaps":["O-GlcNAc sites on HNRNPR controlling RNA binding not fully mapped","Generality of nuclease-protection mechanism to other targets unknown"]},{"year":2026,"claim":"Established HNRNPR as a disease gene, with mutations causing m6A-dependent Plcz1 mis-splicing and PLCζ mislocalization that yields fertilization failure.","evidence":"Whole-exome sequencing of patients, Hnrnpr knock-in mouse, ICSI calcium oscillation imaging, and m6A-splicing assay","pmids":["41618099"],"confidence":"Medium","gaps":["How m6A directs HNRNPR to Plcz1 splice sites unknown","Spectrum of human phenotypes from HNRNPR mutations not fully defined"]},{"year":null,"claim":"How HNRNPR's many activities—mRNA stability, splicing, axonal transport/translation, transcription elongation, and DNA repair—are coordinated and partitioned across domains, post-translational modifications, and subcellular compartments remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model integrating nuclear and cytoplasmic roles","Domain/modification logic selecting among target classes undefined","Structure of full-length protein on RNA not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,3,4,9,13,16,17,19]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[9,11,20]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[10,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,6,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,8,10]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,5,9,11,19]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[6]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,8]}],"complexes":["hnRNP complex","7SK snRNP / P-TEFb complex","axonal translation initiation complex"],"partners":["SMN","YBX1","BRD4","CDK9","OGT","PTBP2","IGF2BP1","HNRNPA2B1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43390","full_name":"Heterogeneous nuclear ribonucleoprotein R","aliases":[],"length_aa":633,"mass_kda":70.9,"function":"Component of ribonucleosomes, which are complexes of at least 20 other different heterogeneous nuclear ribonucleoproteins (hnRNP). hnRNP play an important role in processing of precursor mRNA in the nucleus","subcellular_location":"Nucleus; Microsome; Nucleus, nucleoplasm; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O43390/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HNRNPR","classification":"Not Classified","n_dependent_lines":303,"n_total_lines":1208,"dependency_fraction":0.2508278145695364},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDX21","stoichiometry":4.0},{"gene":"HNRNPL","stoichiometry":4.0},{"gene":"IGF2BP1","stoichiometry":4.0},{"gene":"TOP1","stoichiometry":4.0},{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX5","stoichiometry":0.2},{"gene":"DDX6","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HNRNPR","total_profiled":1310},"omim":[{"mim_id":"620073","title":"NEURODEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES AND SKELETAL AND BRAIN ABNORMALITIES; NEDDFSB","url":"https://www.omim.org/entry/620073"},{"mim_id":"616686","title":"SYNAPTOTAGMIN-BINDING CYTOPLASMIC RNA-INTERACTING PROTEIN; SYNCRIP","url":"https://www.omim.org/entry/616686"},{"mim_id":"607201","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN R; HNRNPR","url":"https://www.omim.org/entry/607201"},{"mim_id":"600354","title":"SURVIVAL OF MOTOR NEURON 1; SMN1","url":"https://www.omim.org/entry/600354"},{"mim_id":"301136","title":"RBMX-LIKE PROTEIN 3; RBMXL3","url":"https://www.omim.org/entry/301136"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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interaction of Smn, the spinal muscular atrophy determining gene product, with hnRNP-R and gry-rbp/hnRNP-Q: a role for Smn in RNA processing in motor axons?","date":"2002","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11773003","citation_count":242,"is_preprint":false},{"pmid":"31527303","id":"PMC_31527303","title":"HnRNPR-CCNB1/CENPF axis contributes to gastric cancer proliferation and metastasis.","date":"2019","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/31527303","citation_count":93,"is_preprint":false},{"pmid":"25338097","id":"PMC_25338097","title":"Presynaptic localization of Smn and hnRNP R in axon terminals of embryonic and postnatal mouse motoneurons.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25338097","citation_count":59,"is_preprint":false},{"pmid":"9421497","id":"PMC_9421497","title":"Molecular definition of heterogeneous nuclear ribonucleoprotein R (hnRNP R) using autoimmune antibody: immunological relationship with hnRNP P.","date":"1998","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/9421497","citation_count":56,"is_preprint":false},{"pmid":"29507242","id":"PMC_29507242","title":"hnRNP R and its main interactor, the noncoding RNA 7SK, coregulate the axonal transcriptome of motoneurons.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29507242","citation_count":47,"is_preprint":false},{"pmid":"27194785","id":"PMC_27194785","title":"HNRNPR Regulates the Expression of Classical and Nonclassical MHC Class I Proteins.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/27194785","citation_count":46,"is_preprint":false},{"pmid":"34850154","id":"PMC_34850154","title":"Loss of full-length hnRNP R isoform impairs DNA damage response in motoneurons by inhibiting Yb1 recruitment to chromatin.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/34850154","citation_count":23,"is_preprint":false},{"pmid":"38402949","id":"PMC_38402949","title":"HnRNPR-mediated UPF3B mRNA splicing drives hepatocellular carcinoma metastasis.","date":"2024","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/38402949","citation_count":16,"is_preprint":false},{"pmid":"37438340","id":"PMC_37438340","title":"Cytosolic Ptbp2 modulates axon growth in motoneurons through axonal localization and translation of Hnrnpr.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37438340","citation_count":15,"is_preprint":false},{"pmid":"18197392","id":"PMC_18197392","title":"hnRNP-R regulates the PMA-induced c-fos expression in retinal cells.","date":"2008","source":"Cellular & molecular biology 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Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38331110","citation_count":12,"is_preprint":false},{"pmid":"39198412","id":"PMC_39198412","title":"hnRNP R promotes O-GlcNAcylation of eIF4G and facilitates axonal protein synthesis.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39198412","citation_count":11,"is_preprint":false},{"pmid":"35856391","id":"PMC_35856391","title":"hnRNP R negatively regulates transcription by modulating the association of P-TEFb with 7SK and BRD4.","date":"2022","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/35856391","citation_count":11,"is_preprint":false},{"pmid":"36195940","id":"PMC_36195940","title":"High expression of HNRNPR in ESCA combined with 18F-FDG PET/CT metabolic parameters are novel biomarkers for preoperative diagnosis of ESCA.","date":"2022","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36195940","citation_count":9,"is_preprint":false},{"pmid":"34258925","id":"PMC_34258925","title":"RNA-binding protein hnRNPR reduces neuronal cholesterol levels by binding to and suppressing HMGCR.","date":"2021","source":"Journal of integrative neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34258925","citation_count":8,"is_preprint":false},{"pmid":"37077028","id":"PMC_37077028","title":"Pan-cancer analysis of the oncogenic role of HNRNPR in human tumors.","date":"2023","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/37077028","citation_count":8,"is_preprint":false},{"pmid":"39990658","id":"PMC_39990658","title":"Mannose Inhibits NSCLC Growth and Inflammatory Microenvironment by Regulating Gut Microbiota and Targeting OGT/hnRNP R/JUN/IL-8 Axis.","date":"2025","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39990658","citation_count":8,"is_preprint":false},{"pmid":"38408684","id":"PMC_38408684","title":"hnRNP R regulates mitochondrial movement and membrane potential in axons of motoneurons.","date":"2024","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38408684","citation_count":3,"is_preprint":false},{"pmid":"37225410","id":"PMC_37225410","title":"HnRNPR strongly represses splicing of a critical exon associated with spinal muscular atrophy through binding to an exonic AU-rich element.","date":"2023","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37225410","citation_count":2,"is_preprint":false},{"pmid":"40247750","id":"PMC_40247750","title":"An evolutionarily conserved tryptophan cage promotes folding of the extended RNA recognition motif in the hnRNPR-like protein family.","date":"2025","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/40247750","citation_count":2,"is_preprint":false},{"pmid":"41618099","id":"PMC_41618099","title":"Characterization and therapy of fertilization failure in murine and human models with HNRNPR mutations.","date":"2026","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41618099","citation_count":1,"is_preprint":false},{"pmid":"40268079","id":"PMC_40268079","title":"HnRNPR promotes non-small cell lung cancer progression by protecting XB130 mRNA from XRN1- and DIS3L2-mediated degradation.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40268079","citation_count":0,"is_preprint":false},{"pmid":"40654891","id":"PMC_40654891","title":"Contributions of Folded and Disordered Domains to RNA Binding by HNRNPR.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40654891","citation_count":0,"is_preprint":false},{"pmid":"41659252","id":"PMC_41659252","title":"circ-UBR5 in hypoxia-induced exosomes may mediate lung adenocarcinoma metastasis via the targeting of HNRNPR.","date":"2026","source":"Translational lung cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41659252","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14465,"output_tokens":5643,"usd":0.06402,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14047,"output_tokens":5559,"usd":0.104605,"stage2_stop_reason":"end_turn"},"total_usd":0.168625,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"hnRNP-R physically interacts with SMN (survival motor neuron) protein via yeast two-hybrid and co-localization; interaction requires wild-type SMN and is abolished by truncated or SMA-associated mutant SMN forms. hnRNP-R is predominantly localized in axons of motor neurons where it co-localizes with SMN.\",\n      \"method\": \"Yeast two-hybrid, immunofluorescence co-localization\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus co-localization in axons, single lab, two orthogonal methods\",\n      \"pmids\": [\"11773003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"hnRNP R is a 633-amino acid protein with a modular structure: acidic N-terminal region (~150 aa), three RNA recognition motif (RRM) domains, a nuclear localization signal, an octapeptide (PPPRMPPP), and a C-terminal glycine- and arginine-rich RGG box. It was identified as a component of hnRNP complexes by immunoprecipitation and 2D gel co-migration of recombinant protein.\",\n      \"method\": \"cDNA cloning, sequence analysis, immunoprecipitation of hnRNP complexes, 2D gel electrophoresis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — primary structural characterization with recombinant protein, immunoprecipitation of native complexes, and sequence analysis; foundational paper replicated by subsequent studies\",\n      \"pmids\": [\"9421497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Smn and hnRNP R are present in presynaptic compartments at neuromuscular endplates of embryonic and postnatal mice, and a direct interaction between Smn and hnRNP R was confirmed in vitro and in vivo, particularly in the cytosol of motoneurons.\",\n      \"method\": \"Immunofluorescence of neuromuscular endplates, co-immunoprecipitation (in vitro and in vivo)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus direct localization at presynaptic terminals in vivo, single lab, two orthogonal methods\",\n      \"pmids\": [\"25338097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"hnRNP R interacts with ~3,500 RNA targets in motoneurons (predominantly with functions in synaptic transmission and axon guidance) as determined by iCLIP. The noncoding RNA 7SK was identified as the top interactor. hnRNP R depletion reduces axonal 7SK levels and causes defective axon growth. 7SK function in axon elongation depends on its interaction with hnRNP R but not on its association with the P-TEFb complex.\",\n      \"method\": \"iCLIP (individual nucleotide-resolution cross-linking and immunoprecipitation), shRNA knockdown, axon growth assays, 7SK deletion mutant analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — iCLIP provides transcriptome-wide binding map, functional knockdown with specific phenotype, deletion mutant dissection of 7SK interaction, multiple orthogonal methods\",\n      \"pmids\": [\"29507242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HNRNPR binds MHC class I mRNAs at their 3' UTRs and enhances their stability and expression. Knockdown of HNRNPR reduces classical and nonclassical MHC class I protein levels and consequently modulates NK cell cytotoxic activity.\",\n      \"method\": \"RNA immunoprecipitation, knockdown experiments, NK cell cytotoxicity assays, mRNA stability assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirms direct binding, KD with defined functional readout (NK cell killing), single lab, two orthogonal methods\",\n      \"pmids\": [\"27194785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"hnRNPR stabilizes CCNB1 and CENPF mRNAs, leading to increased expression of these oncoproteins. Knockdown of CCNB1 abolished hnRNPR-induced cell growth, and knockdown of CENPF abolished hnRNPR-induced invasion, placing hnRNPR upstream of these mRNA targets in gastric cancer.\",\n      \"method\": \"shRNA knockdown, mRNA stability assays, epistasis via double knockdown, xenograft tumor models\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with double knockdown rescue, in vivo models, single lab\",\n      \"pmids\": [\"31527303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Full-length hnRNP R (containing the N-terminal acidic domain) interacts with the multifunctional protein Yb1 (top hit in proteomic interactome analysis). Upon DNA damage, full-length hnRNP R is required for Yb1 recruitment to chromatin, where Yb1 interacts with γ-H2AX. Motoneurons lacking full-length hnRNP R accumulate double-strand breaks and show impaired DNA damage response.\",\n      \"method\": \"Hnrnpr knockout mouse (Hnrnprtm1a/tm1a), proteomic interactome analysis (mass spectrometry), chromatin fractionation, co-IP with γ-H2AX, genotoxic stress assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse model, MS-based interactome, chromatin fractionation, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"34850154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"hnRNP R negatively regulates transcription elongation by modulating P-TEFb activity. Loss of hnRNP R promotes release of P-TEFb from the 7SK inhibitory complex, accompanied by enhanced hnRNP A1 binding to 7SK. Additionally, hnRNP R interacts with BRD4, and its depletion increases BRD4 binding to CDK9 and stabilizes CDK9 with enhanced association with Cyclin K, resulting in increased RNA polymerase II phosphorylation and transcription.\",\n      \"method\": \"hnRNP R knockdown/knockout cells, RNA Pol II phosphorylation assays, co-immunoprecipitation (BRD4, CDK9, 7SK complex), RNA immunoprecipitation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO/KD with mechanistic dissection of P-TEFb complex, co-IP of multiple components, CDK9 stability assays, multiple orthogonal methods\",\n      \"pmids\": [\"35856391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cytosolic Ptbp2 binds the 3' UTR of Hnrnpr mRNA and is required for axonal localization of Hnrnpr mRNA and local synthesis of hnRNP R protein in motoneuron axons. This regulation occurs via Ptbp2-mediated association of Hnrnpr mRNA with ribosomes in an eIF5A2-dependent manner, and is necessary for axon growth.\",\n      \"method\": \"Ptbp2 conditional KO, RNA immunoprecipitation, ribosome association assays, axon growth assays, live imaging of mRNA localization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with specific phenotypic rescue, RIP, ribosome fractionation, eIF5A2 epistasis, multiple orthogonal methods in single study\",\n      \"pmids\": [\"37438340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"hnRNPR binds an AU-rich element (ARE) towards the 3' end of SMN2 exon 7 via RNA-affinity chromatography and potently represses exon 7 inclusion. Both hnRNPR and Sam68 bind this ARE in a competitive manner, with hnRNPR showing stronger inhibitory effect. An exon 5-skipped hnRNPR isoform has minimal inhibitory effect. ASOs inducing hnRNPR exon 5 skipping promote SMN2 exon 7 inclusion.\",\n      \"method\": \"SMN2 minigene splicing assay, deletion analysis, RNA-affinity chromatography, co-overexpression analysis, tethering assay\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — minigene system with deletion mapping, RNA-affinity chromatography, and competitive binding assay, single lab\",\n      \"pmids\": [\"37225410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNP R is a component of translation initiation complexes in axons of motoneurons. Through interaction with O-GlcNAc transferase (Ogt), hnRNP R modulates O-GlcNAcylation of eIF4G. Loss of hnRNP R reduces axonal synthesis of cytoskeletal and synaptic components, and restoring axonal O-GlcNAc levels rescues local protein synthesis and axon growth defects.\",\n      \"method\": \"Hnrnpr knockout mice, ribosome/translation initiation complex fractionation, co-IP with Ogt, O-GlcNAc proteomics, axon growth assays, neuromuscular junction analysis, motor behavior tests\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic KO mouse with in vivo NMJ phenotype, biochemical reconstitution of translation complex, proteomic O-GlcNAc mapping, rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"39198412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPR binds to UPF3B pre-mRNA via its RRM2 domain to generate an exon 8 exclusion truncated splice variant UPF3B-S. UPF3B-S protein then targets the 3'-UTR of CDH1 mRNA to enhance CDH1 mRNA degradation, reducing E-cadherin and activating EMT. UPF3B-S also promotes dephosphorylation of LATS1 and nuclear accumulation of YAP1, activating Hippo signaling.\",\n      \"method\": \"RNA immunoprecipitation, RRM2 domain mutant analysis, in vitro and in vivo HCC invasion models, CDH1 mRNA stability assay, LATS1/YAP1 pathway analysis\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP with domain mutant, epistasis via UPF3B-S KD, in vivo models, single lab with multiple methods\",\n      \"pmids\": [\"38402949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNP R-deficient motoneurons show decreased anterograde and increased retrograde transport of mitochondria in axons, and exhibit mitochondrial hyperpolarization caused by decreased complex I and reversed complex V activity within the respiratory chain.\",\n      \"method\": \"Hnrnpr knockout motoneurons, live imaging of mitochondrial motility, mitochondrial membrane potential assays, respiratory chain complex activity assays\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with live imaging and biochemical readouts of respiratory chain, single lab\",\n      \"pmids\": [\"38408684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"hnRNPR uses its RNA recognition motif (RRM) to bind the 3' UTR of HMGCR mRNA, reducing its translation and lowering neuronal cholesterol levels. Knockdown of hnRNPR increases HMGCR expression and cholesterol levels; overexpression decreases them. RNA immunoprecipitation and luciferase reporter assays confirmed direct binding.\",\n      \"method\": \"RNA immunoprecipitation, luciferase reporter assay, knockdown/overexpression in N2a and MN1 cells, cholesterol measurement\",\n      \"journal\": \"Journal of integrative neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP plus reporter assay confirms binding, KD/OE with cholesterol phenotype, single lab, two methods\",\n      \"pmids\": [\"34258925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"hnRNP-R binds c-fos mRNA via its AU-rich element (ARE) in the 3' UTR, accelerating both the rise and decline phases of c-fos mRNA and protein in response to PMA. ARE-containing reporter assays showed hnRNP-R significantly reduces GFP expression driven by the c-fos ARE; co-immunoprecipitation-RT-PCR confirmed direct association with c-fos mRNA in retinal cells.\",\n      \"method\": \"Co-immunoprecipitation-RT-PCR, ARE-GFP reporter assay, overexpression in R28 cells\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP-RT-PCR plus reporter assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"18197392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HNRNPA2B1 and HNRNPR bind and stabilize ASCL1 mRNA in an m6A-dependent manner: HNRNPR binds the 3' UTR of ASCL1 mRNA, and METTL14-mediated m6A modification is required for this binding (mutations in m6A sites reduce HNRNPR binding). HNRNPR interacts with IGF2BP1, and knockdown of either impairs binding to ASCL1 mRNA.\",\n      \"method\": \"RNA immunoprecipitation, m6A site mutagenesis, RNA probe pulldown, METTL14 knockdown, co-IP of HNRNPR with IGF2BP1\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A site mutagenesis plus RIP, co-IP with IGF2BP1, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38331110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The X-ray crystal structure (1.90 Å) and NMR studies of hnRNPR RRM1 reveal it is an extended RRM (eRRM) with a canonical RRM and a structured N-terminal extension (Next) motif that docks against the RRM and extends the β-sheet surface. A tryptophan cage in the adjoining loop positions the Next motif; mutagenesis of Next-RRM interface residues and loop residues impairs protein solubility, conformational ordering, and thermal stability.\",\n      \"method\": \"X-ray crystallography (1.90 Å), solution NMR spectroscopy, mutagenesis, thermal denaturation\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure at 1.90 Å with NMR and mutagenesis validation, single lab but multiple orthogonal structural and biophysical methods\",\n      \"pmids\": [\"40247750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RRM3 of HNRNPR, together with a downstream C-terminal charged region, is required for RNA binding specificity. HNRNPR also binds RNA G-quadruplexes (rG4s) via RRM3 with the C-terminal charged region and RG-rich regions within the low complexity domain. rG4 binding depends on RNA folding and specific rG4 structural features.\",\n      \"method\": \"High-throughput biochemical RNA binding assays, domain deletion/mutant analysis, rG4-focused RNA pool SELEX-like assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — unbiased high-throughput biochemical domain mapping, single lab preprint, not yet peer-reviewed\",\n      \"pmids\": [\"40654891\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"hnRNP R binds and stabilizes JUN mRNA in an O-GlcNAc glycosylation-dependent manner. Mannose suppresses OGT activity, reducing O-GlcNAcylation of hnRNP R, which then decreases JUN mRNA stability and subsequent IL-8 transcription in NSCLC cells.\",\n      \"method\": \"OGT inhibition/mannose treatment, O-GlcNAc proteomics, RNA immunoprecipitation, mRNA stability assay, in vitro and in vivo NSCLC models\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus O-GlcNAc modification directly linked to mRNA binding activity, functional readout in vivo, single lab\",\n      \"pmids\": [\"39990658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"hnRNPR protects XB130 mRNA from XRN1- and DIS3L2-mediated degradation by binding to specific regions within the XB130 3' UTR, thereby elevating XB130 expression and promoting NSCLC cell proliferation and EMT via Akt signaling.\",\n      \"method\": \"RNA pulldown, RNA immunoprecipitation, dual-luciferase reporter assay, XRN1/DIS3L2 knockdown epistasis, in vitro and in vivo NSCLC models\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown plus RIP confirm binding, epistasis with specific nucleases, in vivo model, single lab\",\n      \"pmids\": [\"40268079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"HNRNPR regulates Plcz1 (PLCζ) pre-mRNA splicing in an m6A-dependent manner in sperm. Pathogenic mutations in HNRNPR cause reduced expression and mislocalization of PLCζ in spermatozoa, impairing calcium oscillation induction in oocytes and resulting in fertilization failure.\",\n      \"method\": \"Whole-exome sequencing of patients, Hnrnpr knock-in mouse model, ICSI with calcium oscillation imaging, PLCζ localization by immunofluorescence, m6A-dependent splicing assay\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in mouse phenocopies human patients, calcium oscillation assay, m6A-splicing mechanism, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41618099\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HNRNPR is a multi-domain RNA-binding protein (three RRMs with an extended eRRM1 structure, an RGG box, and an N-terminal acidic domain) that acts as a post-transcriptional regulator in both the nucleus and cytoplasm: it stabilizes or destabilizes specific mRNAs (including MHC class I, CCNB1, CENPF, HMGCR, ASCL1, JUN, XB130) by binding their 3' UTRs, regulates alternative splicing of SMN2 exon 7 and Plcz1 pre-mRNA via exonic AU-rich elements, controls axonal mRNA transport and local translation in motoneurons (including O-GlcNAcylation of eIF4G via Ogt interaction), negatively regulates P-TEFb-driven transcription elongation through 7SK and BRD4 interactions, supports DNA damage repair by recruiting Yb1 to chromatin in a manner dependent on its N-terminal acidic domain, and regulates axonal mitochondrial transport and respiratory function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HNRNPR is a modular RNA-binding protein of the hnRNP complex, built from an N-terminal acidic domain, three RNA recognition motifs (including an extended eRRM1 with a structured Next motif), an NLS, and a C-terminal RGG box, that functions as a post-transcriptional regulator in both nucleus and cytoplasm [#1, #16]. Through 3' UTR binding it controls the stability of numerous mRNAs, stabilizing MHC class I transcripts to set NK-cell cytotoxicity [#4], the oncogenic CCNB1 and CENPF mRNAs [#5], JUN [#18] and XB130 (the latter by shielding it from XRN1/DIS3L2 nucleases) [#19], stabilizing ASCL1 mRNA cooperatively with HNRNPA2B1/IGF2BP1 in an m6A-dependent manner [#15], and repressing HMGCR translation to lower neuronal cholesterol [#13]. It also regulates alternative splicing, repressing SMN2 exon 7 inclusion via an exonic AU-rich element in competition with Sam68 [#9], generating a truncated UPF3B-S variant through RRM2-dependent binding [#11], and controlling m6A-dependent Plcz1 splicing required for sperm PLCζ function—pathogenic HNRNPR mutations cause fertilization failure [#20]. In motoneurons HNRNPR binds thousands of synaptic and axon-guidance transcripts, with the noncoding 7SK RNA as its top partner, and supports axon growth [#3]; its own axonal localization and local translation depend on Ptbp2 [#8]. There it is a component of axonal translation initiation complexes that modulates eIF4G O-GlcNAcylation through OGT, and it additionally governs axonal mitochondrial transport and respiratory chain activity [#10, #12]. In the nucleus, full-length HNRNPR negatively regulates P-TEFb-driven transcription elongation via 7SK and BRD4/CDK9 interactions [#7], and its N-terminal acidic domain recruits Yb1 to chromatin to support the DNA damage response [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established HNRNPR as a bona fide hnRNP complex component and defined its modular domain architecture, providing the structural framework for all later functional work.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and immunoprecipitation of native hnRNP complexes with 2D gel co-migration\",\n      \"pmids\": [\"9421497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No RNA targets or binding specificity defined\", \"Functional role of individual domains untested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linked HNRNPR to motoneuron biology by showing a direct, SMA-mutation-sensitive interaction with SMN in axons, raising the question of an RNA-handling role in motoneurons.\",\n      \"evidence\": \"Yeast two-hybrid and immunofluorescence co-localization in motor neuron axons\",\n      \"pmids\": [\"11773003\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of SMN interaction unknown\", \"Y2H interaction not validated biochemically at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"First demonstrated 3' UTR ARE-mediated mRNA regulation, showing HNRNPR shapes c-fos transcript dynamics.\",\n      \"evidence\": \"Co-IP-RT-PCR and ARE-GFP reporter assay in retinal R28 cells\",\n      \"pmids\": [\"18197392\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of accelerated turnover not resolved\", \"Generality across other AREs untested at the time\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Confirmed the SMN-HNRNPR interaction reciprocally in vivo at presynaptic terminals, localizing the partnership to the cytosol of motoneurons.\",\n      \"evidence\": \"Reciprocal co-IP and immunofluorescence at neuromuscular endplates in mice\",\n      \"pmids\": [\"25338097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA cargo of the complex not identified\", \"Whether interaction drives axonal mRNA transport untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed HNRNPR stabilizes MHC class I mRNAs via 3' UTR binding, connecting its mRNA-stabilizing activity to immune effector outcomes.\",\n      \"evidence\": \"RNA immunoprecipitation, knockdown, mRNA stability and NK cytotoxicity assays\",\n      \"pmids\": [\"27194785\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site within 3' UTR not mapped\", \"Co-factors for stabilization unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided a transcriptome-wide binding map identifying ~3,500 motoneuron targets and 7SK as the top interactor, establishing HNRNPR as a regulator of axon growth genes.\",\n      \"evidence\": \"iCLIP, shRNA knockdown with axon growth assays, and 7SK deletion-mutant dissection\",\n      \"pmids\": [\"29507242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How 7SK binding promotes axon elongation mechanistically unresolved\", \"Direct vs indirect regulation of individual targets not separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed HNRNPR upstream of oncogenic CCNB1 and CENPF mRNAs in gastric cancer through stabilization, separating its growth- versus invasion-promoting outputs.\",\n      \"evidence\": \"shRNA knockdown, mRNA stability, double-knockdown epistasis, and xenograft models\",\n      \"pmids\": [\"31527303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding determinants on target 3' UTRs not defined\", \"Single tumor context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a nuclear DNA-repair function in which the N-terminal acidic domain of full-length HNRNPR recruits Yb1 to chromatin, protecting motoneurons from double-strand breaks.\",\n      \"evidence\": \"Hnrnpr knockout mouse, MS interactome, chromatin fractionation, and co-IP with γ-H2AX\",\n      \"pmids\": [\"34850154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How acidic domain mediates Yb1 chromatin loading mechanistically unknown\", \"Relationship to RNA-binding functions unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended translational repression to HMGCR, showing RRM-mediated 3' UTR binding lowers neuronal cholesterol.\",\n      \"evidence\": \"RIP, luciferase reporter, knockdown/overexpression, and cholesterol measurement in N2a/MN1 cells\",\n      \"pmids\": [\"34258925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking binding to translational suppression not detailed\", \"Physiological relevance in vivo untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a nuclear role in transcription elongation control, with HNRNPR restraining P-TEFb release from 7SK and limiting BRD4/CDK9-driven Pol II phosphorylation.\",\n      \"evidence\": \"Knockdown/knockout cells, Pol II phosphorylation assays, and co-IP of BRD4, CDK9, and 7SK complex components\",\n      \"pmids\": [\"35856391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this elongation control intersects with cytoplasmic functions unknown\", \"Gene-specific consequences of derepression not catalogued\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved how HNRNPR reaches the axon, showing Ptbp2 binds its mRNA 3' UTR to drive ribosome association and local synthesis required for axon growth.\",\n      \"evidence\": \"Ptbp2 conditional KO, RIP, ribosome association, eIF5A2 epistasis, and live mRNA imaging\",\n      \"pmids\": [\"37438340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals triggering local translation not defined\", \"Generality to other neuron types untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated direct splicing repression of SMN2 exon 7 via an exonic ARE, with HNRNPR competing with Sam68 and an isoform-dependent activity exploitable by ASOs.\",\n      \"evidence\": \"SMN2 minigene splicing, deletion mapping, RNA-affinity chromatography, competitive binding and tethering assays\",\n      \"pmids\": [\"37225410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of ARE recognition not resolved\", \"In vivo SMN2 splicing effect of exon-5-skipping ASOs untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected HNRNPR to axonal translational control by showing it modulates eIF4G O-GlcNAcylation through OGT, with O-GlcNAc restoration rescuing local synthesis and axon growth.\",\n      \"evidence\": \"Hnrnpr KO mice, translation-initiation complex fractionation, OGT co-IP, O-GlcNAc proteomics, NMJ and behavior analysis\",\n      \"pmids\": [\"39198412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HNRNPR targets OGT to eIF4G mechanistically unknown\", \"Direct enzyme regulation vs scaffolding not distinguished\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a metabolic/transport role, with HNRNPR loss skewing axonal mitochondrial trafficking and impairing respiratory chain function.\",\n      \"evidence\": \"Hnrnpr KO motoneurons, live mitochondrial motility imaging, membrane potential and complex activity assays\",\n      \"pmids\": [\"38408684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA targets driving the mitochondrial phenotype not identified\", \"Direct vs downstream cause unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded HNRNPR's mRNA repertoire to ASCL1 and UPF3B, showing m6A-dependent cooperative stabilization with IGF2BP1 and RRM2-dependent generation of an EMT-promoting UPF3B splice variant.\",\n      \"evidence\": \"RIP, m6A site mutagenesis, RRM2 mutant analysis, co-IP with IGF2BP1, and HCC invasion models\",\n      \"pmids\": [\"38331110\", \"38402949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How m6A reading is partitioned among HNRNPR/IGF2BP1 unclear\", \"Domain requirements for ASCL1 binding not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided high-resolution structural insight into the eRRM1 Next motif and mapped RRM3/C-terminal regions as determinants of RNA and rG4 binding specificity.\",\n      \"evidence\": \"X-ray crystallography (1.90 Å), NMR, mutagenesis, thermal denaturation, and high-throughput RNA binding/rG4 assays (one preprint)\",\n      \"pmids\": [\"40247750\", \"40654891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of full-length multi-RRM RNA engagement not solved\", \"rG4 binding role in cellular targets untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Tied HNRNPR mRNA-stabilizing activity to O-GlcNAcylation and nuclease protection, with O-GlcNAc modulating JUN stability and HNRNPR shielding XB130 from XRN1/DIS3L2 to drive NSCLC phenotypes.\",\n      \"evidence\": \"OGT inhibition/mannose, O-GlcNAc proteomics, RIP, RNA pulldown, nuclease knockdown epistasis, and in vivo NSCLC models\",\n      \"pmids\": [\"39990658\", \"40268079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"O-GlcNAc sites on HNRNPR controlling RNA binding not fully mapped\", \"Generality of nuclease-protection mechanism to other targets unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established HNRNPR as a disease gene, with mutations causing m6A-dependent Plcz1 mis-splicing and PLCζ mislocalization that yields fertilization failure.\",\n      \"evidence\": \"Whole-exome sequencing of patients, Hnrnpr knock-in mouse, ICSI calcium oscillation imaging, and m6A-splicing assay\",\n      \"pmids\": [\"41618099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How m6A directs HNRNPR to Plcz1 splice sites unknown\", \"Spectrum of human phenotypes from HNRNPR mutations not fully defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HNRNPR's many activities—mRNA stability, splicing, axonal transport/translation, transcription elongation, and DNA repair—are coordinated and partitioned across domains, post-translational modifications, and subcellular compartments remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model integrating nuclear and cytoplasmic roles\", \"Domain/modification logic selecting among target classes undefined\", \"Structure of full-length protein on RNA not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 3, 4, 9, 13, 16, 17, 19]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [9, 11, 20]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [10, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 6, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 8, 10]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 5, 9, 11, 19]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"complexes\": [\n      \"hnRNP complex\",\n      \"7SK snRNP / P-TEFb complex\",\n      \"axonal translation initiation complex\"\n    ],\n    \"partners\": [\n      \"SMN\",\n      \"YBX1\",\n      \"BRD4\",\n      \"CDK9\",\n      \"OGT\",\n      \"PTBP2\",\n      \"IGF2BP1\",\n      \"HNRNPA2B1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}