{"gene":"RALY","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1997,"finding":"The human p542 gene (RALY/HNRPCL2) encodes a protein with RNA-binding motifs characteristic of heterogeneous nuclear ribonucleoproteins (hnRNPs), as determined by sequence homology analysis and RT-PCR confirming structural features including RNA recognition motifs.","method":"Anchored RT-PCR, sequence analysis, Northern blot","journal":"Journal of autoimmunity","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, sequence-based characterization without functional reconstitution","pmids":["9376072"],"is_preprint":false},{"year":2013,"finding":"RALY interacts with MATR3, PABP1, and ELAVL1 in an RNA-dependent manner, and with eIF4AIII, FMRP, and hnRNP-C in a protein-protein (RNA-independent) manner, as established by in vivo biotinylation pulldown with and without RNase treatment and quantitative mass spectrometry.","method":"In vivo biotinylation-pulldown (iBioPQ) with label-free quantitative MS, RNase treatment controls","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pulldown with RNase controls and MS quantification, single lab with two orthogonal methods","pmids":["23614458"],"is_preprint":false},{"year":2017,"finding":"RALY binds poly-U-rich elements within the 3′UTR of ANXA1 and H1FX mRNAs, regulating their stability and expression levels. Cells lacking RALY show altered H1FX and ANXA1 mRNA and protein levels, establishing RALY as a poly-U binding protein and post-transcriptional regulator.","method":"RIP-seq, knockdown, RT-qPCR, western blot, 3′UTR binding assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-seq plus loss-of-function with mRNA and protein readouts, single lab","pmids":["28379492"],"is_preprint":false},{"year":2017,"finding":"RALY down-regulation reduces E2F1 mRNA stability and E2F1 protein levels, impairs transcription and cell cycle progression in HeLa cells. RALY also interacts with transcriptionally active chromatin in both RNA-dependent and RNA-independent manners, an association abolished without active transcription.","method":"siRNA knockdown, RNA stability assays, chromatin association assays, gene expression profiling","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cellular assays with defined readouts (mRNA stability, cell cycle), single lab","pmids":["28972179"],"is_preprint":false},{"year":2017,"finding":"RALY binds the PRMT1 pre-mRNA and promotes inclusion of alternative exon 2, increasing abundance of the PRMT1v2 isoform. Knockdown of RALY decreases PRMT1v2 relative expression and reduces invasion in breast cancer cells; re-expression of PRMT1v2 rescues the invasion defect.","method":"RNAi screen, RT-PCR isoform analysis, RIP, invasion assays, rescue experiments","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirming pre-mRNA binding, functional rescue experiment, single lab","pmids":["28733251"],"is_preprint":false},{"year":2018,"finding":"RALY binds PRMT1 mRNA and regulates its expression; RALY down-regulation decreases PRMT1 protein levels, reducing arginine methylation of FUS. RALY knockout enhances nuclear translocation of FUS NLS mutants and decreases aggregate formation. RALY and FUS interact in an RNA-dependent manner in motor neurons; mutations in FUS NLS or RALY NLS reciprocally alter their localization and interaction with target mRNAs.","method":"RIP, western blot, immunofluorescence, RALY knockout, FUS localization assays in motor neurons","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RIP, KO, localization), single lab","pmids":["30354839"],"is_preprint":false},{"year":2020,"finding":"RALY acts as a regulatory component of the Drosha complex and promotes post-transcriptional processing of specific miRNAs (miR-483, miR-676, miR-877), which then downregulate mitochondrial metabolism genes (ATP5I, ATP5G1, ATP5G3, CYC1). This miRNA processing is facilitated by N6-methyladenosine (m6A) modification of pri-miRNA terminal loops under ROS stress; inhibition of m6A methylation abolishes RALY recognition of pri-miRNA terminal loops.","method":"Co-immunoprecipitation, pri-miRNA processing assays, m6A inhibition, cell line/xenograft/organoid models, metabolic assays","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP with Drosha complex, m6A functional abolishment, in vivo xenograft and organoid models), replicated across multiple model systems","pmids":["33219048"],"is_preprint":false},{"year":2011,"finding":"RALY physically interacts with YB-1 (identified by mass spectrometry after tagged-YB-1 pulldown). Depletion of RALY sensitizes colorectal cancer cells to oxaliplatin and counteracts YB-1-overexpression-mediated oxaliplatin resistance.","method":"Tagged pulldown with mass spectrometry, siRNA knockdown, drug dose-response assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction plus functional siRNA validation, single lab","pmids":["22118625"],"is_preprint":false},{"year":2021,"finding":"RALY binds to RNA polymerase II and the Ehmt2 gene promoter, enhancing Ehmt2 (G9a) transcription in dorsal root ganglion neurons. Downregulation of DS-lncRNA promotes increased RALY binding to these genomic elements, elevating G9a and consequently reducing opioid receptor and Kcna2 expression to cause neuropathic pain.","method":"ChIP, RIP, lncRNA rescue/overexpression in DRG neurons, behavioral assays in mice","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and RIP with in vivo rescue, single lab","pmids":["34383386"],"is_preprint":false},{"year":2022,"finding":"RALY cooperates with splicing factor SF3B3 to regulate the alternative splicing switch of MTA1 from MTA1-S to MTA1-L isoform in hepatocellular carcinoma, reducing MTA1-S levels and alleviating its inhibitory effect on cholesterol synthesis genes to promote cancer cell proliferation.","method":"Co-immunoprecipitation, splicing reporter assays, gain/loss-of-function, RT-PCR isoform analysis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus splicing analysis plus functional rescue, single lab","pmids":["35490918"],"is_preprint":false},{"year":2022,"finding":"RALY interacts with the E3 ubiquitin ligase MARCH8 and the cargo receptor NDP52, and promotes degradation of the PEDV nucleocapsid (N) protein via a RALY-MARCH8-NDP52-autophagosome pathway, thereby inhibiting viral replication.","method":"Co-immunoprecipitation, autophagy assays, viral replication assays, knockdown/overexpression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying interaction partners, functional viral replication readout, single lab","pmids":["35753351"],"is_preprint":false},{"year":2022,"finding":"RALY regulates alternative splicing of FOS pre-mRNA and negatively modulates expression of FOS and FOSB transcription factors, affecting immune/inflammatory response gene expression including suppression of IFIT1, IFIT2, IFIT3, IFI44, HERC4, and OASL in HeLa cells.","method":"RALY overexpression, RNA-seq transcriptome analysis, RT-qPCR validation, alternative splicing analysis","journal":"Genes and immunity","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression with transcriptomics, no direct binding assay for FOS pre-mRNA, single lab","pmids":["35941292"],"is_preprint":false},{"year":2023,"finding":"RALY stabilizes non-polyadenylated TERRA transcripts, and its depletion results in lower TERRA levels, impaired TERRA localization at telomeres, and telomere damage. RALY preferentially binds non-polyadenylated TERRA over polyadenylated TERRA. TERRA also interacts with poly(A)-binding protein nuclear 1 (PABPN1), and TERRA stability is regulated by interplay between RALY and PABPN1 defined by TERRA polyadenylation state.","method":"RALY depletion, RNA FISH, TERRA level quantification, polyadenylation-specific pulldown, co-immunoprecipitation","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (depletion, FISH, RIP with polyadenylation distinction), single lab","pmids":["37060569"],"is_preprint":false},{"year":2023,"finding":"RALY simultaneously binds Mdm2 and the deubiquitinase USP7, stimulating USP7 deubiquitinating activity toward Mdm2 (stabilizing Mdm2) and increasing Mdm2's trans-E3 ligase activity toward p53, resulting in enhanced p53 ubiquitination and degradation. RALY thereby promotes lung tumorigenesis through p53 inhibition.","method":"Co-immunoprecipitation, ubiquitination assays, USP7 activity assays, RALY knockdown/overexpression, in vivo tumor models","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro deubiquitination and ubiquitination assays plus Co-IP plus in vivo tumor model, multiple orthogonal methods in single rigorous study","pmids":["36952348"],"is_preprint":false},{"year":2023,"finding":"RALY can be SUMOylated by conjugation with SUMO1, facilitated by UBA2. SUMOylation of RALY at an identified site increases its protein stability, which in turn increases FOXD1 mRNA levels; FOXD1 then activates DKK1 transcription promoting glioma vasculogenic mimicry.","method":"SUMOylation assays, Co-immunoprecipitation, knockdown/overexpression, RALY stability assays, in vivo tumor models","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SUMOylation assay plus functional downstream pathway validation, single lab","pmids":["37906341"],"is_preprint":false},{"year":2024,"finding":"PTBP1 physically interacts with RALY and together they regulate exon 5 splicing of DNMT3B pre-mRNA, shifting the balance from DNMT3B-S to DNMT3B-L isoform. Upregulation of DNMT3B-L induces promoter methylation of DUSP2, suppressing DUSP2 expression and thereby increasing radioresistance in prostate cancer cells.","method":"Co-immunoprecipitation, RT-PCR isoform analysis, gain/loss-of-function, promoter methylation assay, in vitro and in vivo irradiation models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus splicing and methylation functional assays, single lab","pmids":["39287090"],"is_preprint":false},{"year":2024,"finding":"RALY directly interacts with phospholipase D2 (PLD2) protein and cooperates with RBM15b to control PLD2 mRNA stability in an m6A-dependent manner, promoting multivesicular body formation and exosome biogenesis to facilitate colorectal cancer metastasis.","method":"RIP, Co-IP, m6A-RIP, MVB formation assays, exosome quantification, in vivo metastasis model","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus Co-IP plus m6A-RIP with functional in vivo readout, single lab","pmids":["38880454"],"is_preprint":false},{"year":2024,"finding":"O-GlcNAcylation of RALY at Ser176 protects RALY from TRIM27-mediated ubiquitination and proteasomal degradation, enhancing RALY protein stability. O-GlcNAcylated RALY interacts with USP22 mRNA to increase its cytoplasmic localization and protein expression, promoting HCC cell proliferation.","method":"Site-directed mutagenesis (S176 mutation), co-immunoprecipitation, RIP, ubiquitination assays, subcellular fractionation, in vivo xenograft","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis identifying modification site plus RIP and ubiquitination assays, single lab","pmids":["38993567"],"is_preprint":false},{"year":2024,"finding":"RALY binds to domain 3 of the FMDV IRES via its RNA recognition motif, inhibiting IRES-driven translation by blocking 80S ribosome complex formation (rather than 40S ribosome assembly or translation initiation complex assembly). The viral 3C protease counteracts RALY's inhibitory effect via the ubiquitin-proteasome pathway.","method":"RRM mutagenesis, IRES binding assays, ribosome assembly assays, viral replication assays, proteasome inhibition experiments","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis plus mechanistic ribosome assembly assay, single lab","pmids":["38323828"],"is_preprint":false},{"year":2025,"finding":"The deubiquitinase USP11 interacts with RALY and reduces its ubiquitination level, stabilizing RALY protein. RALY in turn directly binds FXYD5 mRNA (confirmed by RIP) to promote its stability and expression, facilitating aerobic glycolysis and pancreatic cancer progression.","method":"Co-immunoprecipitation, ubiquitination assays, RIP, Seahorse metabolic assays, xenograft model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus RIP plus functional metabolic assay, single lab","pmids":["40972883"],"is_preprint":false},{"year":2026,"finding":"RALY homodimerizes and acts as a scaffold bridging the deubiquitinase USP22 to c-Myc, preventing c-Myc ubiquitination and proteasomal degradation. Akt phosphorylates RALY at S106 and T160, enabling ternary complex formation among RALY, USP22, and c-Myc to stabilize c-Myc. A synthetic peptide (RAMi) disrupting this complex destabilizes c-Myc.","method":"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (S106A/T160A), Akt kinase assay, peptide inhibitor experiments, in vivo tumor models","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — kinase assay, mutagenesis identifying phosphorylation sites, Co-IP of ternary complex, ubiquitination assay, functional rescue with peptide inhibitor, in vivo model","pmids":["42215722"],"is_preprint":false},{"year":2026,"finding":"RALY directly binds to the DSCR1 gene promoter region and suppresses DSCR1 transcriptional activity upon overexpression. Proteomic analysis by LC-MS/MS identified RALY as a direct promoter-binding protein. siRNA-mediated knockdown of RALY did not significantly alter DSCR1 levels, indicating complex regulatory dynamics.","method":"Bicistronic reporter assay, LC-MS/MS proteomics of promoter-binding proteins, RALY overexpression and siRNA knockdown","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (promoter-binding proteomics), negative result for knockdown weakens mechanistic claim","pmids":["41525744"],"is_preprint":false},{"year":2026,"finding":"RALY directly binds Snail mRNA to enhance its stability, and also modulates TGF-β signaling to promote Snail transcription, thereby driving epithelial-mesenchymal transition and promoting migration and invasion in hepatocellular carcinoma cell lines.","method":"RIP, mRNA stability assays, TGF-β signaling assays, knockdown/overexpression, migration/invasion assays","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic detail in abstract for TGF-β connection","pmids":["41650853"],"is_preprint":false},{"year":2026,"finding":"tRF-3005a binds RALY and enhances RALY's interaction with SPAG4 mRNA, suppressing exon 8 skipping of SPAG4 and increasing the SPAG4-L oncogenic isoform, thereby activating GRB14/PI3K/AKT signaling in gastric cancer.","method":"RIP, co-immunoprecipitation, splicing analysis, RNA-seq, gain/loss-of-function assays","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RIP-based interaction, limited mechanistic detail on how tRF-3005a modifies RALY activity","pmids":["41872130"],"is_preprint":false}],"current_model":"RALY is a poly-U-binding hnRNP family member that functions as a multi-level post-transcriptional and post-translational regulator: it stabilizes specific target mRNAs (including E2F1, PRMT1, ANXA1, H1FX, Snail, FXYD5, USP22) via 3′UTR U-rich elements, regulates alternative splicing of multiple pre-mRNAs (PRMT1, MTA1, DNMT3B, FOS, SPAG4), associates with the Drosha complex to promote m6A-facilitated miRNA processing, interacts with transcriptionally active chromatin, binds TERRA non-coding RNA to regulate telomere integrity, and acts as a protein scaffold to stabilize oncoproteins (Mdm2/c-Myc) by recruiting deubiquitinases (USP7, USP22); RALY's own activity is controlled post-translationally by Akt-mediated phosphorylation (S106/T160), SUMO1 conjugation (via UBA2), O-GlcNAcylation (S176), and ubiquitination/deubiquitination by TRIM27/USP11, collectively placing RALY as a central oncogenic hub in RNA metabolism and protein stability networks."},"narrative":{"mechanistic_narrative":"RALY is a poly-U-binding hnRNP-family RNA-binding protein that operates as a multi-level post-transcriptional regulator and protein-stability scaffold [PMID:9376072, PMID:28379492]. Through its RNA recognition motifs it binds U-rich elements in 3′UTRs to stabilize specific target mRNAs—including ANXA1, H1FX, and E2F1, the last coupling RALY to transcription and cell-cycle progression [PMID:28379492, PMID:28972179]. RALY also controls alternative splicing of multiple pre-mRNAs, promoting oncogenic isoform switches by cooperating with partner splicing factors: it drives PRMT1 exon 2 inclusion, partners with SF3B3 to shift MTA1 splicing, and with PTBP1 to alter DNMT3B exon 5 usage [PMID:28733251, PMID:35490918, PMID:39287090]. It associates with the Drosha complex and recognizes m6A-modified pri-miRNA terminal loops to promote processing of specific miRNAs under ROS stress [PMID:33219048]. Beyond RNA metabolism, RALY functions as a deubiquitinase-recruiting scaffold that stabilizes oncoproteins: it bridges USP7 to Mdm2 to promote p53 degradation, and homodimerizes to bridge USP22 to c-Myc, an assembly licensed by Akt phosphorylation at S106/T160 [PMID:36952348, PMID:42215722]. RALY's own abundance is governed post-translationally by SUMO1 conjugation via UBA2, by O-GlcNAcylation at Ser176 that antagonizes TRIM27-mediated ubiquitination, and by USP11-mediated deubiquitination [PMID:37906341, PMID:38993567, PMID:40972883]. It additionally binds non-polyadenylated TERRA to maintain telomere integrity and acts in antiviral defense by promoting autophagic degradation of viral nucleocapsid protein and by blocking IRES-driven translation [PMID:37060569, PMID:35753351, PMID:38323828]. Collectively these activities position RALY as an oncogenic hub linking RNA processing to protein stability across multiple cancers.","teleology":[{"year":1997,"claim":"Established RALY as an hnRNP-family member by identifying canonical RNA-binding motifs, framing it as a candidate post-transcriptional regulator.","evidence":"Anchored RT-PCR and sequence/Northern analysis of the human p542 gene","pmids":["9376072"],"confidence":"Low","gaps":["sequence-based only, no functional reconstitution","no RNA targets identified","no cellular role demonstrated"]},{"year":2011,"claim":"Connected RALY to chemoresistance by showing it physically partners with YB-1 and modulates oxaliplatin sensitivity.","evidence":"Tagged YB-1 pulldown with MS and siRNA drug-response assays in colorectal cancer cells","pmids":["22118625"],"confidence":"Medium","gaps":["mechanism linking YB-1 interaction to resistance unresolved","no RNA target of the RALY-YB-1 axis defined"]},{"year":2013,"claim":"Defined the RALY interactome and distinguished RNA-dependent from direct protein partners, placing it within mRNP and splicing-associated complexes.","evidence":"In vivo biotinylation-pulldown with RNase controls and quantitative MS","pmids":["23614458"],"confidence":"Medium","gaps":["functional consequence of each interaction not tested","no structural basis for direct binding"]},{"year":2017,"claim":"Demonstrated RALY is a poly-U binding protein that stabilizes 3′UTR target mRNAs and couples to transcription/cell cycle, establishing its core post-transcriptional function.","evidence":"RIP-seq, knockdown with mRNA/protein readouts, and chromatin association and RNA-stability assays for ANXA1, H1FX, and E2F1","pmids":["28379492","28972179"],"confidence":"Medium","gaps":["binding-element consensus not fully defined","mechanism of mRNA stabilization (decay factor competition) not resolved"]},{"year":2017,"claim":"Extended RALY's repertoire to alternative splicing by showing it promotes a pro-invasive PRMT1 isoform switch with functional rescue.","evidence":"RNAi screen, RIP, isoform RT-PCR, and invasion rescue in breast cancer cells","pmids":["28733251"],"confidence":"Medium","gaps":["splicing-factor cofactors not yet identified","direct exon-binding site mapping incomplete"]},{"year":2018,"claim":"Linked RALY to motor-neuron RNA biology via PRMT1 regulation and RNA-dependent interaction with FUS, affecting FUS localization and aggregation.","evidence":"RIP, RALY knockout, and FUS localization assays in motor neurons","pmids":["30354839"],"confidence":"Medium","gaps":["disease relevance to ALS not established by causative genetics","NLS-dependent co-trafficking mechanism only partly defined"]},{"year":2020,"claim":"Revealed RALY as a Drosha-complex regulatory component that reads m6A on pri-miRNA loops to direct miRNA processing controlling mitochondrial metabolism.","evidence":"Co-IP, pri-miRNA processing and m6A-inhibition assays in cell, xenograft and organoid models","pmids":["33219048"],"confidence":"High","gaps":["direct m6A-reader biochemistry vs. recruited reader not distinguished","structural basis of terminal-loop recognition unknown"]},{"year":2021,"claim":"Showed RALY can act at chromatin/promoters by binding RNA Pol II and the Ehmt2 promoter to drive G9a transcription in a pain model.","evidence":"ChIP, RIP, and lncRNA rescue with behavioral assays in DRG neurons and mice","pmids":["34383386"],"confidence":"Medium","gaps":["direct vs. lncRNA-bridged promoter binding unresolved","generality of transcriptional role beyond DRG unclear"]},{"year":2022,"claim":"Broadened the splicing function (MTA1 via SF3B3; FOS) and added antiviral roles, showing RALY routes a viral nucleocapsid to autophagic degradation.","evidence":"Co-IP, splicing reporters, RNA-seq, and autophagy/viral replication assays","pmids":["35490918","35941292","35753351"],"confidence":"Medium","gaps":["FOS pre-mRNA binding not directly demonstrated (#11 Low)","MARCH8/NDP52 pathway directionality vs. RALY's RNA roles not integrated"]},{"year":2023,"claim":"Identified RALY as a deubiquitinase scaffold and SUMO-regulated protein, recruiting USP7 to stabilize Mdm2 (degrading p53) and being stabilized by SUMO1 to amplify oncogenic output.","evidence":"In vitro deubiquitination/ubiquitination assays, Co-IP, SUMOylation assays, and in vivo tumor models","pmids":["36952348","37906341"],"confidence":"High","gaps":["structural basis of the RALY-USP7-Mdm2 ternary complex unknown","SUMO acceptor-site requirement for scaffold function untested"]},{"year":2023,"claim":"Established a non-coding RNA role at telomeres by showing RALY preferentially stabilizes non-polyadenylated TERRA in interplay with PABPN1 to maintain telomere integrity.","evidence":"RALY depletion, RNA FISH, and polyadenylation-specific pulldown/Co-IP","pmids":["37060569"],"confidence":"Medium","gaps":["how RALY discriminates polyadenylation state mechanistically unclear","telomere-damage causality vs. correlation not fully resolved"]},{"year":2024,"claim":"Mapped post-translational control of RALY (O-GlcNAc at Ser176 vs. TRIM27 ubiquitination) and expanded its m6A-coupled mRNA-stabilizing and splicing functions across cancers.","evidence":"Site-directed mutagenesis, RIP, m6A-RIP, ubiquitination assays, and in vivo models for USP22, DNMT3B, PLD2 targets","pmids":["38993567","39287090","38880454","38323828"],"confidence":"Medium","gaps":["crosstalk among SUMO, O-GlcNAc, and ubiquitin modifications not integrated","stoichiometry of m6A-reader cooperation with RBM15b undefined"]},{"year":2026,"claim":"Resolved the c-Myc-stabilizing mechanism: RALY homodimerizes and, when Akt-phosphorylated at S106/T160, bridges USP22 to c-Myc, a complex druggable by a disrupting peptide.","evidence":"Akt kinase assay, S106A/T160A mutagenesis, ternary-complex Co-IP, ubiquitination assays, and peptide-inhibitor tumor models","pmids":["42215722"],"confidence":"High","gaps":["structural model of the RALY dimer-USP22-c-Myc assembly absent","selectivity of phospho-control across other RALY scaffold targets untested"]},{"year":2026,"claim":"Added further mRNA-stability and splicing targets (USP11-stabilized RALY→FXYD5; Snail; tRF-guided SPAG4 splicing; DSCR1 promoter repression) linking RALY to metabolism, EMT and tumor signaling.","evidence":"Co-IP, RIP, splicing/stability assays, metabolic and migration assays across pancreatic, hepatic and gastric cancer models","pmids":["40972883","41650853","41872130","41525744"],"confidence":"Low","gaps":["several targets rest on single-method RIP without reciprocal validation","DSCR1 knockdown gave no effect, weakening the repression model","tRF-3005a mechanism of modifying RALY activity undefined"]},{"year":null,"claim":"How RALY's distinct activities—mRNA stabilization, splicing, miRNA processing, chromatin/promoter binding, and deubiquitinase scaffolding—are coordinated and partitioned within the cell remains unresolved.","evidence":"No integrating structural or systems-level study in the corpus","pmids":[],"confidence":"Low","gaps":["no structure of RALY bound to RNA or to scaffold partners","no unified model for how PTMs switch RALY between RNA and protein-scaffold modes","determinants of target selectivity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,3,4,5,12,16,18,19,22]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[13,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,13,20]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[8,21]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,5,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,4,6,9,12,15]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[13,17,19,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,20,22]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,8]}],"complexes":["Drosha microprocessor complex"],"partners":["USP7","USP22","MDM2","MYC","SF3B3","PTBP1","FUS","USP11"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UKM9","full_name":"RNA-binding protein Raly","aliases":["Autoantigen p542","Heterogeneous nuclear ribonucleoprotein C-like 2","hnRNP core protein C-like 2","hnRNP associated with lethal yellow protein homolog"],"length_aa":306,"mass_kda":32.5,"function":"RNA-binding protein that acts as a transcriptional cofactor for cholesterol biosynthetic genes in the liver. Binds the lipid-responsive non-coding RNA LeXis and is required for LeXis-mediated effect on cholesterogenesis (By similarity). May be a heterogeneous nuclear ribonucleoprotein (hnRNP) (PubMed:9376072)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UKM9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RALY","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"COPB2","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2},{"gene":"HNRNPL","stoichiometry":0.2},{"gene":"ILF3","stoichiometry":0.2},{"gene":"MAP4","stoichiometry":0.2},{"gene":"RBM14","stoichiometry":0.2},{"gene":"SF3A1","stoichiometry":0.2},{"gene":"SF3B1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RALY","total_profiled":1310},"omim":[{"mim_id":"618575","title":"E2F1 mRNA STABILIZING LONG NONCODING RNA; EMSLR","url":"https://www.omim.org/entry/618575"},{"mim_id":"614663","title":"RALY HETEROGENEOUS NUCLEAR RIBONUCLEAR PROTEIN; RALY","url":"https://www.omim.org/entry/614663"},{"mim_id":"614648","title":"RALY-LIKE PROTEIN; RALYL","url":"https://www.omim.org/entry/614648"},{"mim_id":"603908","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 2, SUBUNIT 2; EIF2S2","url":"https://www.omim.org/entry/603908"},{"mim_id":"600201","title":"AGOUTI SIGNALING PROTEIN; ASIP","url":"https://www.omim.org/entry/600201"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RALY"},"hgnc":{"alias_symbol":["P542","HNRPCL2"],"prev_symbol":[]},"alphafold":{"accession":"Q9UKM9","domains":[{"cath_id":"3.30.70.330","chopping":"17-90","consensus_level":"high","plddt":92.7355,"start":17,"end":90}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKM9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKM9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKM9-F1-predicted_aligned_error_v6.png","plddt_mean":69.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RALY","jax_strain_url":"https://www.jax.org/strain/search?query=RALY"},"sequence":{"accession":"Q9UKM9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKM9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKM9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKM9"}},"corpus_meta":[{"pmid":"33219048","id":"PMC_33219048","title":"RNA-binding protein RALY reprogrammes mitochondrial metabolism via mediating miRNA processing in colorectal cancer.","date":"2020","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/33219048","citation_count":95,"is_preprint":false},{"pmid":"34383386","id":"PMC_34383386","title":"Downregulation of a Dorsal Root Ganglion-Specifically Enriched Long Noncoding RNA is Required for Neuropathic Pain by Negatively Regulating RALY-Triggered Ehmt2 Expression.","date":"2021","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/34383386","citation_count":67,"is_preprint":false},{"pmid":"22118625","id":"PMC_22118625","title":"NONO and RALY proteins are required for YB-1 oxaliplatin induced resistance in colon adenocarcinoma cell lines.","date":"2011","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22118625","citation_count":48,"is_preprint":false},{"pmid":"23614458","id":"PMC_23614458","title":"Proteome-wide characterization of the RNA-binding protein RALY-interactome using the in vivo-biotinylation-pulldown-quant (iBioPQ) approach.","date":"2013","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/23614458","citation_count":48,"is_preprint":false},{"pmid":"35490918","id":"PMC_35490918","title":"RNA binding protein RALY activates the cholesterol synthesis pathway through an MTA1 splicing switch in hepatocellular carcinoma.","date":"2022","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/35490918","citation_count":29,"is_preprint":false},{"pmid":"28379492","id":"PMC_28379492","title":"Identification and dynamic changes of RNAs isolated from RALY-containing ribonucleoprotein complexes.","date":"2017","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/28379492","citation_count":29,"is_preprint":false},{"pmid":"28733251","id":"PMC_28733251","title":"RNA binding protein RALY promotes Protein Arginine Methyltransferase 1 alternatively spliced isoform v2 relative expression and metastatic potential in breast cancer cells.","date":"2017","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28733251","citation_count":29,"is_preprint":false},{"pmid":"28972179","id":"PMC_28972179","title":"The hnRNP RALY regulates transcription and cell proliferation by modulating the expression of specific factors including the proliferation marker E2F1.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28972179","citation_count":27,"is_preprint":false},{"pmid":"9376072","id":"PMC_9376072","title":"The p542 gene encodes an autoantigen that cross-reacts with EBNA-1 of the Epstein Barr virus and which may be a heterogeneous nuclear ribonucleoprotein.","date":"1997","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/9376072","citation_count":25,"is_preprint":false},{"pmid":"31781561","id":"PMC_31781561","title":"The Long Non-coding RNA ZFAS1 Sponges miR-193a-3p to Modulate Hepatoblastoma Growth by Targeting RALY via HGF/c-Met Pathway.","date":"2019","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/31781561","citation_count":25,"is_preprint":false},{"pmid":"35941292","id":"PMC_35941292","title":"RALY regulate the proliferation and expression of immune/inflammatory response genes via alternative splicing of FOS.","date":"2022","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/35941292","citation_count":20,"is_preprint":false},{"pmid":"37060569","id":"PMC_37060569","title":"TERRA stability is regulated by RALY and polyadenylation in a telomere-specific manner.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37060569","citation_count":18,"is_preprint":false},{"pmid":"35753351","id":"PMC_35753351","title":"Nuclear ribonucleoprotein RALY targets virus nucleocapsid protein and induces autophagy to restrict porcine epidemic diarrhea virus replication.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35753351","citation_count":17,"is_preprint":false},{"pmid":"39287090","id":"PMC_39287090","title":"PTBP1 Regulates DNMT3B Alternative Splicing by Interacting With RALY to Enhance the Radioresistance of Prostate Cancer.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39287090","citation_count":16,"is_preprint":false},{"pmid":"30354839","id":"PMC_30354839","title":"The hnRNP RALY regulates PRMT1 expression and interacts with the ALS-linked protein FUS: implication for reciprocal cellular localization.","date":"2018","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/30354839","citation_count":16,"is_preprint":false},{"pmid":"36952348","id":"PMC_36952348","title":"The RNA binding protein RALY suppresses p53 activity and promotes lung tumorigenesis.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36952348","citation_count":12,"is_preprint":false},{"pmid":"38880454","id":"PMC_38880454","title":"RNA binding protein RALY facilitates colorectal cancer metastasis via enhancing exosome biogenesis in m6A dependent manner.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/38880454","citation_count":11,"is_preprint":false},{"pmid":"37906341","id":"PMC_37906341","title":"SUMOylation of RALY promotes vasculogenic mimicry in glioma cells via the FOXD1/DKK1 pathway.","date":"2023","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/37906341","citation_count":11,"is_preprint":false},{"pmid":"38993567","id":"PMC_38993567","title":"O-GlcNAcylated RALY Contributes to Hepatocellular Carcinoma Cells Proliferation by Regulating USP22 mRNA Nuclear Export.","date":"2024","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38993567","citation_count":9,"is_preprint":false},{"pmid":"10500250","id":"PMC_10500250","title":"Alternative processing of the human and mouse raly genes(1).","date":"1999","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/10500250","citation_count":7,"is_preprint":false},{"pmid":"37371543","id":"PMC_37371543","title":"Effects of the Combination of the C1473G Mutation in the Tph2 Gene and Lethal Yellow Mutations in the Raly-Agouti Locus on Behavior, Brain 5-HT and Melanocortin Systems in Mice.","date":"2023","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/37371543","citation_count":7,"is_preprint":false},{"pmid":"38323828","id":"PMC_38323828","title":"Nuclear ribonucleoprotein RALY downregulates foot-and-mouth disease virus replication but antagonized by viral 3C protease.","date":"2024","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/38323828","citation_count":6,"is_preprint":false},{"pmid":"41449865","id":"PMC_41449865","title":"Astragaloside IV Alleviates Colorectal Cancer Metastases by Regulating RALY/PLD2 Axis and Inhibiting Tumoral Exosome Biogenesis.","date":"2025","source":"Phytotherapy research : PTR","url":"https://pubmed.ncbi.nlm.nih.gov/41449865","citation_count":2,"is_preprint":false},{"pmid":"40972883","id":"PMC_40972883","title":"USP11 stabilizes RALY to promote FXYD5-mediated aerobic glycolysis and aggravate pancreatic cancer progression.","date":"2025","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/40972883","citation_count":1,"is_preprint":false},{"pmid":"41525744","id":"PMC_41525744","title":"Identification of RALY as a novel regulator of DSCR1 transcription.","date":"2026","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41525744","citation_count":1,"is_preprint":false},{"pmid":"42100402","id":"PMC_42100402","title":"The regulatory mechanisms and clinical translation potential of RNA-binding protein RALY in tumors.","date":"2026","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42100402","citation_count":0,"is_preprint":false},{"pmid":"41650853","id":"PMC_41650853","title":"RALY promotes Epithelial-mesenchymal transition in Hepatocellular carcinoma by regulating Snail.","date":"2026","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41650853","citation_count":0,"is_preprint":false},{"pmid":"40912352","id":"PMC_40912352","title":"Lethal yellow mutation in the Raly-Agouti locus reduces the energy expenditure in male mice.","date":"2025","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/40912352","citation_count":0,"is_preprint":false},{"pmid":"42215722","id":"PMC_42215722","title":"Akt-mediated RALY phosphorylation functions as a molecular switch governing c-Myc stability.","date":"2026","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/42215722","citation_count":0,"is_preprint":false},{"pmid":"41872130","id":"PMC_41872130","title":"tRF-3005a regulates exon skipping of SPAG4 by interacting with RALY to drive gastric cancer progression.","date":"2026","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/41872130","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16227,"output_tokens":5798,"usd":0.067825,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14299,"output_tokens":4583,"usd":0.093035,"stage2_stop_reason":"end_turn"},"total_usd":0.16086,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"The human p542 gene (RALY/HNRPCL2) encodes a protein with RNA-binding motifs characteristic of heterogeneous nuclear ribonucleoproteins (hnRNPs), as determined by sequence homology analysis and RT-PCR confirming structural features including RNA recognition motifs.\",\n      \"method\": \"Anchored RT-PCR, sequence analysis, Northern blot\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, sequence-based characterization without functional reconstitution\",\n      \"pmids\": [\"9376072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RALY interacts with MATR3, PABP1, and ELAVL1 in an RNA-dependent manner, and with eIF4AIII, FMRP, and hnRNP-C in a protein-protein (RNA-independent) manner, as established by in vivo biotinylation pulldown with and without RNase treatment and quantitative mass spectrometry.\",\n      \"method\": \"In vivo biotinylation-pulldown (iBioPQ) with label-free quantitative MS, RNase treatment controls\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pulldown with RNase controls and MS quantification, single lab with two orthogonal methods\",\n      \"pmids\": [\"23614458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RALY binds poly-U-rich elements within the 3′UTR of ANXA1 and H1FX mRNAs, regulating their stability and expression levels. Cells lacking RALY show altered H1FX and ANXA1 mRNA and protein levels, establishing RALY as a poly-U binding protein and post-transcriptional regulator.\",\n      \"method\": \"RIP-seq, knockdown, RT-qPCR, western blot, 3′UTR binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq plus loss-of-function with mRNA and protein readouts, single lab\",\n      \"pmids\": [\"28379492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RALY down-regulation reduces E2F1 mRNA stability and E2F1 protein levels, impairs transcription and cell cycle progression in HeLa cells. RALY also interacts with transcriptionally active chromatin in both RNA-dependent and RNA-independent manners, an association abolished without active transcription.\",\n      \"method\": \"siRNA knockdown, RNA stability assays, chromatin association assays, gene expression profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cellular assays with defined readouts (mRNA stability, cell cycle), single lab\",\n      \"pmids\": [\"28972179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RALY binds the PRMT1 pre-mRNA and promotes inclusion of alternative exon 2, increasing abundance of the PRMT1v2 isoform. Knockdown of RALY decreases PRMT1v2 relative expression and reduces invasion in breast cancer cells; re-expression of PRMT1v2 rescues the invasion defect.\",\n      \"method\": \"RNAi screen, RT-PCR isoform analysis, RIP, invasion assays, rescue experiments\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirming pre-mRNA binding, functional rescue experiment, single lab\",\n      \"pmids\": [\"28733251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RALY binds PRMT1 mRNA and regulates its expression; RALY down-regulation decreases PRMT1 protein levels, reducing arginine methylation of FUS. RALY knockout enhances nuclear translocation of FUS NLS mutants and decreases aggregate formation. RALY and FUS interact in an RNA-dependent manner in motor neurons; mutations in FUS NLS or RALY NLS reciprocally alter their localization and interaction with target mRNAs.\",\n      \"method\": \"RIP, western blot, immunofluorescence, RALY knockout, FUS localization assays in motor neurons\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RIP, KO, localization), single lab\",\n      \"pmids\": [\"30354839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RALY acts as a regulatory component of the Drosha complex and promotes post-transcriptional processing of specific miRNAs (miR-483, miR-676, miR-877), which then downregulate mitochondrial metabolism genes (ATP5I, ATP5G1, ATP5G3, CYC1). This miRNA processing is facilitated by N6-methyladenosine (m6A) modification of pri-miRNA terminal loops under ROS stress; inhibition of m6A methylation abolishes RALY recognition of pri-miRNA terminal loops.\",\n      \"method\": \"Co-immunoprecipitation, pri-miRNA processing assays, m6A inhibition, cell line/xenograft/organoid models, metabolic assays\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP with Drosha complex, m6A functional abolishment, in vivo xenograft and organoid models), replicated across multiple model systems\",\n      \"pmids\": [\"33219048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RALY physically interacts with YB-1 (identified by mass spectrometry after tagged-YB-1 pulldown). Depletion of RALY sensitizes colorectal cancer cells to oxaliplatin and counteracts YB-1-overexpression-mediated oxaliplatin resistance.\",\n      \"method\": \"Tagged pulldown with mass spectrometry, siRNA knockdown, drug dose-response assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction plus functional siRNA validation, single lab\",\n      \"pmids\": [\"22118625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RALY binds to RNA polymerase II and the Ehmt2 gene promoter, enhancing Ehmt2 (G9a) transcription in dorsal root ganglion neurons. Downregulation of DS-lncRNA promotes increased RALY binding to these genomic elements, elevating G9a and consequently reducing opioid receptor and Kcna2 expression to cause neuropathic pain.\",\n      \"method\": \"ChIP, RIP, lncRNA rescue/overexpression in DRG neurons, behavioral assays in mice\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and RIP with in vivo rescue, single lab\",\n      \"pmids\": [\"34383386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RALY cooperates with splicing factor SF3B3 to regulate the alternative splicing switch of MTA1 from MTA1-S to MTA1-L isoform in hepatocellular carcinoma, reducing MTA1-S levels and alleviating its inhibitory effect on cholesterol synthesis genes to promote cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, splicing reporter assays, gain/loss-of-function, RT-PCR isoform analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus splicing analysis plus functional rescue, single lab\",\n      \"pmids\": [\"35490918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RALY interacts with the E3 ubiquitin ligase MARCH8 and the cargo receptor NDP52, and promotes degradation of the PEDV nucleocapsid (N) protein via a RALY-MARCH8-NDP52-autophagosome pathway, thereby inhibiting viral replication.\",\n      \"method\": \"Co-immunoprecipitation, autophagy assays, viral replication assays, knockdown/overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying interaction partners, functional viral replication readout, single lab\",\n      \"pmids\": [\"35753351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RALY regulates alternative splicing of FOS pre-mRNA and negatively modulates expression of FOS and FOSB transcription factors, affecting immune/inflammatory response gene expression including suppression of IFIT1, IFIT2, IFIT3, IFI44, HERC4, and OASL in HeLa cells.\",\n      \"method\": \"RALY overexpression, RNA-seq transcriptome analysis, RT-qPCR validation, alternative splicing analysis\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression with transcriptomics, no direct binding assay for FOS pre-mRNA, single lab\",\n      \"pmids\": [\"35941292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RALY stabilizes non-polyadenylated TERRA transcripts, and its depletion results in lower TERRA levels, impaired TERRA localization at telomeres, and telomere damage. RALY preferentially binds non-polyadenylated TERRA over polyadenylated TERRA. TERRA also interacts with poly(A)-binding protein nuclear 1 (PABPN1), and TERRA stability is regulated by interplay between RALY and PABPN1 defined by TERRA polyadenylation state.\",\n      \"method\": \"RALY depletion, RNA FISH, TERRA level quantification, polyadenylation-specific pulldown, co-immunoprecipitation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (depletion, FISH, RIP with polyadenylation distinction), single lab\",\n      \"pmids\": [\"37060569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RALY simultaneously binds Mdm2 and the deubiquitinase USP7, stimulating USP7 deubiquitinating activity toward Mdm2 (stabilizing Mdm2) and increasing Mdm2's trans-E3 ligase activity toward p53, resulting in enhanced p53 ubiquitination and degradation. RALY thereby promotes lung tumorigenesis through p53 inhibition.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, USP7 activity assays, RALY knockdown/overexpression, in vivo tumor models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro deubiquitination and ubiquitination assays plus Co-IP plus in vivo tumor model, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"36952348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RALY can be SUMOylated by conjugation with SUMO1, facilitated by UBA2. SUMOylation of RALY at an identified site increases its protein stability, which in turn increases FOXD1 mRNA levels; FOXD1 then activates DKK1 transcription promoting glioma vasculogenic mimicry.\",\n      \"method\": \"SUMOylation assays, Co-immunoprecipitation, knockdown/overexpression, RALY stability assays, in vivo tumor models\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SUMOylation assay plus functional downstream pathway validation, single lab\",\n      \"pmids\": [\"37906341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTBP1 physically interacts with RALY and together they regulate exon 5 splicing of DNMT3B pre-mRNA, shifting the balance from DNMT3B-S to DNMT3B-L isoform. Upregulation of DNMT3B-L induces promoter methylation of DUSP2, suppressing DUSP2 expression and thereby increasing radioresistance in prostate cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, RT-PCR isoform analysis, gain/loss-of-function, promoter methylation assay, in vitro and in vivo irradiation models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus splicing and methylation functional assays, single lab\",\n      \"pmids\": [\"39287090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RALY directly interacts with phospholipase D2 (PLD2) protein and cooperates with RBM15b to control PLD2 mRNA stability in an m6A-dependent manner, promoting multivesicular body formation and exosome biogenesis to facilitate colorectal cancer metastasis.\",\n      \"method\": \"RIP, Co-IP, m6A-RIP, MVB formation assays, exosome quantification, in vivo metastasis model\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus Co-IP plus m6A-RIP with functional in vivo readout, single lab\",\n      \"pmids\": [\"38880454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"O-GlcNAcylation of RALY at Ser176 protects RALY from TRIM27-mediated ubiquitination and proteasomal degradation, enhancing RALY protein stability. O-GlcNAcylated RALY interacts with USP22 mRNA to increase its cytoplasmic localization and protein expression, promoting HCC cell proliferation.\",\n      \"method\": \"Site-directed mutagenesis (S176 mutation), co-immunoprecipitation, RIP, ubiquitination assays, subcellular fractionation, in vivo xenograft\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis identifying modification site plus RIP and ubiquitination assays, single lab\",\n      \"pmids\": [\"38993567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RALY binds to domain 3 of the FMDV IRES via its RNA recognition motif, inhibiting IRES-driven translation by blocking 80S ribosome complex formation (rather than 40S ribosome assembly or translation initiation complex assembly). The viral 3C protease counteracts RALY's inhibitory effect via the ubiquitin-proteasome pathway.\",\n      \"method\": \"RRM mutagenesis, IRES binding assays, ribosome assembly assays, viral replication assays, proteasome inhibition experiments\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis plus mechanistic ribosome assembly assay, single lab\",\n      \"pmids\": [\"38323828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The deubiquitinase USP11 interacts with RALY and reduces its ubiquitination level, stabilizing RALY protein. RALY in turn directly binds FXYD5 mRNA (confirmed by RIP) to promote its stability and expression, facilitating aerobic glycolysis and pancreatic cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, RIP, Seahorse metabolic assays, xenograft model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus RIP plus functional metabolic assay, single lab\",\n      \"pmids\": [\"40972883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RALY homodimerizes and acts as a scaffold bridging the deubiquitinase USP22 to c-Myc, preventing c-Myc ubiquitination and proteasomal degradation. Akt phosphorylates RALY at S106 and T160, enabling ternary complex formation among RALY, USP22, and c-Myc to stabilize c-Myc. A synthetic peptide (RAMi) disrupting this complex destabilizes c-Myc.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (S106A/T160A), Akt kinase assay, peptide inhibitor experiments, in vivo tumor models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — kinase assay, mutagenesis identifying phosphorylation sites, Co-IP of ternary complex, ubiquitination assay, functional rescue with peptide inhibitor, in vivo model\",\n      \"pmids\": [\"42215722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RALY directly binds to the DSCR1 gene promoter region and suppresses DSCR1 transcriptional activity upon overexpression. Proteomic analysis by LC-MS/MS identified RALY as a direct promoter-binding protein. siRNA-mediated knockdown of RALY did not significantly alter DSCR1 levels, indicating complex regulatory dynamics.\",\n      \"method\": \"Bicistronic reporter assay, LC-MS/MS proteomics of promoter-binding proteins, RALY overexpression and siRNA knockdown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (promoter-binding proteomics), negative result for knockdown weakens mechanistic claim\",\n      \"pmids\": [\"41525744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RALY directly binds Snail mRNA to enhance its stability, and also modulates TGF-β signaling to promote Snail transcription, thereby driving epithelial-mesenchymal transition and promoting migration and invasion in hepatocellular carcinoma cell lines.\",\n      \"method\": \"RIP, mRNA stability assays, TGF-β signaling assays, knockdown/overexpression, migration/invasion assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic detail in abstract for TGF-β connection\",\n      \"pmids\": [\"41650853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"tRF-3005a binds RALY and enhances RALY's interaction with SPAG4 mRNA, suppressing exon 8 skipping of SPAG4 and increasing the SPAG4-L oncogenic isoform, thereby activating GRB14/PI3K/AKT signaling in gastric cancer.\",\n      \"method\": \"RIP, co-immunoprecipitation, splicing analysis, RNA-seq, gain/loss-of-function assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RIP-based interaction, limited mechanistic detail on how tRF-3005a modifies RALY activity\",\n      \"pmids\": [\"41872130\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RALY is a poly-U-binding hnRNP family member that functions as a multi-level post-transcriptional and post-translational regulator: it stabilizes specific target mRNAs (including E2F1, PRMT1, ANXA1, H1FX, Snail, FXYD5, USP22) via 3′UTR U-rich elements, regulates alternative splicing of multiple pre-mRNAs (PRMT1, MTA1, DNMT3B, FOS, SPAG4), associates with the Drosha complex to promote m6A-facilitated miRNA processing, interacts with transcriptionally active chromatin, binds TERRA non-coding RNA to regulate telomere integrity, and acts as a protein scaffold to stabilize oncoproteins (Mdm2/c-Myc) by recruiting deubiquitinases (USP7, USP22); RALY's own activity is controlled post-translationally by Akt-mediated phosphorylation (S106/T160), SUMO1 conjugation (via UBA2), O-GlcNAcylation (S176), and ubiquitination/deubiquitination by TRIM27/USP11, collectively placing RALY as a central oncogenic hub in RNA metabolism and protein stability networks.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RALY is a poly-U-binding hnRNP-family RNA-binding protein that operates as a multi-level post-transcriptional regulator and protein-stability scaffold [#0, #2]. Through its RNA recognition motifs it binds U-rich elements in 3′UTRs to stabilize specific target mRNAs—including ANXA1, H1FX, and E2F1, the last coupling RALY to transcription and cell-cycle progression [#2, #3]. RALY also controls alternative splicing of multiple pre-mRNAs, promoting oncogenic isoform switches by cooperating with partner splicing factors: it drives PRMT1 exon 2 inclusion, partners with SF3B3 to shift MTA1 splicing, and with PTBP1 to alter DNMT3B exon 5 usage [#4, #9, #15]. It associates with the Drosha complex and recognizes m6A-modified pri-miRNA terminal loops to promote processing of specific miRNAs under ROS stress [#6]. Beyond RNA metabolism, RALY functions as a deubiquitinase-recruiting scaffold that stabilizes oncoproteins: it bridges USP7 to Mdm2 to promote p53 degradation, and homodimerizes to bridge USP22 to c-Myc, an assembly licensed by Akt phosphorylation at S106/T160 [#13, #20]. RALY's own abundance is governed post-translationally by SUMO1 conjugation via UBA2, by O-GlcNAcylation at Ser176 that antagonizes TRIM27-mediated ubiquitination, and by USP11-mediated deubiquitination [#14, #17, #19]. It additionally binds non-polyadenylated TERRA to maintain telomere integrity and acts in antiviral defense by promoting autophagic degradation of viral nucleocapsid protein and by blocking IRES-driven translation [#12, #10, #18]. Collectively these activities position RALY as an oncogenic hub linking RNA processing to protein stability across multiple cancers.\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established RALY as an hnRNP-family member by identifying canonical RNA-binding motifs, framing it as a candidate post-transcriptional regulator.\",\n      \"evidence\": \"Anchored RT-PCR and sequence/Northern analysis of the human p542 gene\",\n      \"pmids\": [\"9376072\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"sequence-based only, no functional reconstitution\", \"no RNA targets identified\", \"no cellular role demonstrated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected RALY to chemoresistance by showing it physically partners with YB-1 and modulates oxaliplatin sensitivity.\",\n      \"evidence\": \"Tagged YB-1 pulldown with MS and siRNA drug-response assays in colorectal cancer cells\",\n      \"pmids\": [\"22118625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism linking YB-1 interaction to resistance unresolved\", \"no RNA target of the RALY-YB-1 axis defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the RALY interactome and distinguished RNA-dependent from direct protein partners, placing it within mRNP and splicing-associated complexes.\",\n      \"evidence\": \"In vivo biotinylation-pulldown with RNase controls and quantitative MS\",\n      \"pmids\": [\"23614458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional consequence of each interaction not tested\", \"no structural basis for direct binding\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated RALY is a poly-U binding protein that stabilizes 3′UTR target mRNAs and couples to transcription/cell cycle, establishing its core post-transcriptional function.\",\n      \"evidence\": \"RIP-seq, knockdown with mRNA/protein readouts, and chromatin association and RNA-stability assays for ANXA1, H1FX, and E2F1\",\n      \"pmids\": [\"28379492\", \"28972179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"binding-element consensus not fully defined\", \"mechanism of mRNA stabilization (decay factor competition) not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended RALY's repertoire to alternative splicing by showing it promotes a pro-invasive PRMT1 isoform switch with functional rescue.\",\n      \"evidence\": \"RNAi screen, RIP, isoform RT-PCR, and invasion rescue in breast cancer cells\",\n      \"pmids\": [\"28733251\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"splicing-factor cofactors not yet identified\", \"direct exon-binding site mapping incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked RALY to motor-neuron RNA biology via PRMT1 regulation and RNA-dependent interaction with FUS, affecting FUS localization and aggregation.\",\n      \"evidence\": \"RIP, RALY knockout, and FUS localization assays in motor neurons\",\n      \"pmids\": [\"30354839\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"disease relevance to ALS not established by causative genetics\", \"NLS-dependent co-trafficking mechanism only partly defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed RALY as a Drosha-complex regulatory component that reads m6A on pri-miRNA loops to direct miRNA processing controlling mitochondrial metabolism.\",\n      \"evidence\": \"Co-IP, pri-miRNA processing and m6A-inhibition assays in cell, xenograft and organoid models\",\n      \"pmids\": [\"33219048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"direct m6A-reader biochemistry vs. recruited reader not distinguished\", \"structural basis of terminal-loop recognition unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed RALY can act at chromatin/promoters by binding RNA Pol II and the Ehmt2 promoter to drive G9a transcription in a pain model.\",\n      \"evidence\": \"ChIP, RIP, and lncRNA rescue with behavioral assays in DRG neurons and mice\",\n      \"pmids\": [\"34383386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct vs. lncRNA-bridged promoter binding unresolved\", \"generality of transcriptional role beyond DRG unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Broadened the splicing function (MTA1 via SF3B3; FOS) and added antiviral roles, showing RALY routes a viral nucleocapsid to autophagic degradation.\",\n      \"evidence\": \"Co-IP, splicing reporters, RNA-seq, and autophagy/viral replication assays\",\n      \"pmids\": [\"35490918\", \"35941292\", \"35753351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FOS pre-mRNA binding not directly demonstrated (#11 Low)\", \"MARCH8/NDP52 pathway directionality vs. RALY's RNA roles not integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified RALY as a deubiquitinase scaffold and SUMO-regulated protein, recruiting USP7 to stabilize Mdm2 (degrading p53) and being stabilized by SUMO1 to amplify oncogenic output.\",\n      \"evidence\": \"In vitro deubiquitination/ubiquitination assays, Co-IP, SUMOylation assays, and in vivo tumor models\",\n      \"pmids\": [\"36952348\", \"37906341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural basis of the RALY-USP7-Mdm2 ternary complex unknown\", \"SUMO acceptor-site requirement for scaffold function untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a non-coding RNA role at telomeres by showing RALY preferentially stabilizes non-polyadenylated TERRA in interplay with PABPN1 to maintain telomere integrity.\",\n      \"evidence\": \"RALY depletion, RNA FISH, and polyadenylation-specific pulldown/Co-IP\",\n      \"pmids\": [\"37060569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"how RALY discriminates polyadenylation state mechanistically unclear\", \"telomere-damage causality vs. correlation not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped post-translational control of RALY (O-GlcNAc at Ser176 vs. TRIM27 ubiquitination) and expanded its m6A-coupled mRNA-stabilizing and splicing functions across cancers.\",\n      \"evidence\": \"Site-directed mutagenesis, RIP, m6A-RIP, ubiquitination assays, and in vivo models for USP22, DNMT3B, PLD2 targets\",\n      \"pmids\": [\"38993567\", \"39287090\", \"38880454\", \"38323828\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"crosstalk among SUMO, O-GlcNAc, and ubiquitin modifications not integrated\", \"stoichiometry of m6A-reader cooperation with RBM15b undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved the c-Myc-stabilizing mechanism: RALY homodimerizes and, when Akt-phosphorylated at S106/T160, bridges USP22 to c-Myc, a complex druggable by a disrupting peptide.\",\n      \"evidence\": \"Akt kinase assay, S106A/T160A mutagenesis, ternary-complex Co-IP, ubiquitination assays, and peptide-inhibitor tumor models\",\n      \"pmids\": [\"42215722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural model of the RALY dimer-USP22-c-Myc assembly absent\", \"selectivity of phospho-control across other RALY scaffold targets untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Added further mRNA-stability and splicing targets (USP11-stabilized RALY→FXYD5; Snail; tRF-guided SPAG4 splicing; DSCR1 promoter repression) linking RALY to metabolism, EMT and tumor signaling.\",\n      \"evidence\": \"Co-IP, RIP, splicing/stability assays, metabolic and migration assays across pancreatic, hepatic and gastric cancer models\",\n      \"pmids\": [\"40972883\", \"41650853\", \"41872130\", \"41525744\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"several targets rest on single-method RIP without reciprocal validation\", \"DSCR1 knockdown gave no effect, weakening the repression model\", \"tRF-3005a mechanism of modifying RALY activity undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RALY's distinct activities—mRNA stabilization, splicing, miRNA processing, chromatin/promoter binding, and deubiquitinase scaffolding—are coordinated and partitioned within the cell remains unresolved.\",\n      \"evidence\": \"No integrating structural or systems-level study in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"no structure of RALY bound to RNA or to scaffold partners\", \"no unified model for how PTMs switch RALY between RNA and protein-scaffold modes\", \"determinants of target selectivity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5, 12, 16, 18, 19, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [13, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 13, 20]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [8, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 5, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 4, 6, 9, 12, 15]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [13, 17, 19, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 20, 22]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"complexes\": [\"Drosha microprocessor complex\"],\n    \"partners\": [\"USP7\", \"USP22\", \"MDM2\", \"MYC\", \"SF3B3\", \"PTBP1\", \"FUS\", \"USP11\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}