{"gene":"RRP9","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":2000,"finding":"U3-55k (RRP9) interaction with U3 snoRNA in vivo is mediated by the Box B/C motif unique to U3 snoRNA; mutation of Box B and Box C disrupted the interaction, while Box C appears to be the primary determinant in vitro. WD repeats and C-terminal sequences of U3-55k are required for U3 RNA association and nucleolar localization, suggesting protein-protein interactions also contribute.","method":"In vivo RNA binding assays (mutation of U3 Box B/C), in vitro RNA binding assays, cDNA cloning of Xenopus U3-55k, deletion mutagenesis of WD repeats","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis of both RNA and protein, replicated across multiple constructs and two species","pmids":["10982864"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of the WD repeat domain of yeast Rrp9 and its human ortholog U3-55K were determined, revealing a seven-bladed beta-propeller fold. A conserved '7bc loop' on the WD domain surface is crucial for specific recognition of U3 snoRNA, nucleolar localization of Rrp9, and yeast growth. Prior association of Snu13 with the B/C motif enhances specific binding of the WD domain. The N-terminal region contains a bipartite nuclear localization signal that is dispensable for nucleolar localization.","method":"X-ray crystallography, mutagenesis of conserved surface patches, yeast growth assays, biochemical binding assays","journal":"RNA","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and functional (yeast growth) validation, multiple orthogonal methods in one study","pmids":["23509373"],"is_preprint":false},{"year":2016,"finding":"SIRT7 deacetylates U3-55k (RRP9), a core component of the U3 snoRNP complex. Deacetylation of U3-55k by SIRT7 enhances U3-55k binding to U3 snoRNA, which is required for pre-rRNA processing (early cleavage steps for 18S rRNA generation). Under stress, SIRT7 is released from nucleoli, causing hyperacetylation of U3-55k and attenuation of pre-rRNA processing.","method":"Co-immunoprecipitation (SIRT7–U3-55k interaction), knockdown of SIRT7, acetylation/deacetylation assays, RNA binding assays, nucleolar localization experiments","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional KD with defined rRNA processing phenotype, biochemical deacetylation assay, stress-response validation; multiple orthogonal methods","pmids":["26867678"],"is_preprint":false},{"year":2020,"finding":"The R289A substitution in the Rrp9 beta-propeller domain (surface opposite to U3 snoRNA binding face) specifically reduced pre-rRNA cleavage at sites A1 and A2. A direct protein-protein interaction between the Rrp9 beta-propeller domain and Rrp36 was identified; the R289A mutation reduced this interaction, implicating it in the processing phenotype. Synergistic negative interactions were observed between R289A and U3 mutations that destabilize U3/pre-rRNA base-pairing, indicating cooperative function in SSU-processome stability.","method":"Site-directed mutagenesis (R289A), pre-rRNA processing assays, protein-protein interaction network mapping, genetic epistasis/synergy analysis with U3 variants","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis with defined processing phenotype, direct interaction mapping with Rrp36, genetic epistasis with U3 snoRNA variants; multiple orthogonal methods","pmids":["31996908"],"is_preprint":false},{"year":2021,"finding":"RRP9 is neddylated at Lys221 by the HECT-type E3 ligase Smurf1; this neddylation is removed by the NEDP1 deneddylase. RRP9 neddylation is required for pre-rRNA processing and ribosomal biogenesis; the unneddylated K221R mutant fails to promote pre-rRNA processing and does not support tumor cell proliferation, colony formation, or migration.","method":"In vivo and in vitro neddylation assays, Co-immunoprecipitation (Smurf1–RRP9), site-directed mutagenesis (K221R), pre-rRNA processing assays, functional cell proliferation/migration assays","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro neddylation reconstitution, site-specific mutagenesis, Co-IP, functional rescue experiments; multiple orthogonal methods in single study","pmids":["34662580"],"is_preprint":false},{"year":2022,"finding":"RRP9 interacts with the DNA-binding region of IGF2BP1 in pancreatic cancer cells, activating the AKT signaling pathway. This interaction promotes gemcitabine resistance by reducing DNA damage and inhibiting apoptosis. AKT inhibitor MK-2206 combined with gemcitabine reversed RRP9-overexpression-induced resistance.","method":"Immunoprecipitation (RRP9–IGF2BP1 interaction), immunofluorescence co-localization, RRP9 overexpression/siRNA knockdown, MTT assay, colony formation, FACS apoptosis, subcutaneous xenograft model","journal":"Cell Communication and Signaling","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and co-localization for interaction, functional KD/OE with defined phenotype and pathway rescue, single lab","pmids":["36434608"],"is_preprint":false},{"year":2024,"finding":"RRP9 interacts with JUN protein; RRP9 deletion decreases JUN protein stability by accelerating JUN ubiquitination via MDM2, leading to JUN degradation. Loss of JUN or AKT pathway activation (SC79) attenuated the regulatory effects of RRP9 on breast cancer cell phenotypes.","method":"Co-immunoprecipitation (RRP9–JUN), protein stability assay, ubiquitination assay, gene expression array (prime-view), shRNA knockdown, rescue experiments","journal":"Biology Direct","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for interaction, ubiquitination assay, functional rescue; single lab with multiple methods","pmids":["39702367"],"is_preprint":false},{"year":2025,"finding":"RRP9 overexpression activates the AKT signaling pathway in prostate cancer, resulting in phosphorylation of GSK3β at Ser9, which prevents β-catenin degradation and promotes cell metastasis, invasion, and EMT. AKT activator SC79 reversed the inhibitory effects of RRP9 knockdown.","method":"RRP9 overexpression/knockdown, western blot for AKT/GSK3β/β-catenin phosphorylation, rescue experiments with SC79, Transwell invasion/migration assays","journal":"Discover Oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, signaling pathway placement by western blot with rescue, no direct binding partner identified for AKT pathway activation","pmids":["40526312"],"is_preprint":false},{"year":2025,"finding":"RRP9 interacts with the scaffolding protein SQSTM1 (p62) in prostate cancer cells, identified by FLAG-RRP9 pull-down followed by MALDI-TOF/TOF mass spectrometry and validated by co-immunoprecipitation. SQSTM1 overexpression rescued the anti-growth and anti-migration effects of RRP9 knockdown.","method":"FLAG-RRP9 pull-down, MALDI-TOF/TOF mass spectrometry, co-immunoprecipitation, shRNA knockdown, rescue experiments, in vivo xenograft","journal":"Advanced Biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pull-down + MS identification + Co-IP validation + functional rescue; single lab, multiple methods","pmids":["40994061"],"is_preprint":false},{"year":2025,"finding":"MYC transcriptionally regulates RRP9 expression. RRP9 knockdown impairs rRNA synthesis, reduces nucleolar size, and diminishes protein production in AML cells. Overexpression of RRP9 promotes AML cell proliferation and resistance to chidamide–cytarabine combination treatment.","method":"Transcriptomic analysis, binding assays (surface plasmon resonance for chidamide–MYC), RRP9 knockdown/overexpression, functional rRNA synthesis assays, nucleolar size measurement","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — transcriptomic pathway analysis plus direct rRNA synthesis/nucleolar assays, functional KD/OE with defined phenotype; single lab","pmids":["40781078"],"is_preprint":false},{"year":2025,"finding":"RRP9 promotes esophageal squamous cell carcinoma progression by enhancing E2F1-mediated transcriptional regulation of CDK1. RRP9 depletion reduced CDK1 expression and cell cycle progression.","method":"RRP9 knockdown/overexpression, luciferase or transcription reporter assays (E2F1-CDK1 axis implied), in vitro and in vivo functional assays","journal":"Advanced Biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic pathway placement inferred from transcriptional regulation assays without direct biochemical interaction between RRP9 and E2F1 demonstrated in abstract","pmids":["40937881"],"is_preprint":false},{"year":2025,"finding":"METTL1 promotes RRP9 mRNA stability through N7-methylguanosine (m7G) modification of RRP9 mRNA, as demonstrated by MeRIP assay and actinomycin D mRNA stability assay. This stabilization activates PI3K/AKT signaling via RRP9.","method":"MeRIP (methylated immunoprecipitation) assay, actinomycin D mRNA stability assay, METTL1 knockdown/overexpression, western blot for AKT pathway","journal":"Molecular Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP directly measures m7G modification of RRP9 mRNA, mRNA stability assay, functional rescue; single lab with two orthogonal methods","pmids":["39960239"],"is_preprint":false},{"year":2026,"finding":"RRP9 suppresses hepatocellular carcinoma by inhibiting the PI3K/AKT/mTOR pathway and downregulating cyclin A2 (CCNA2). Protein-protein interaction analysis and western blot identified an association between RRP9 and CCNA2; rescue experiments with PI3K activator 740Y-P and inhibitor PI3K/AKT/mTOR-IN-2 confirmed pathway involvement.","method":"Lentiviral KD/OE cell models, transcriptome sequencing, western blot, protein-protein interaction analysis, functional rescue with PI3K modulators, subcutaneous tumorigenesis in mice","journal":"International Journal of Oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement by transcriptomics + western blot with pharmacological rescue, RRP9-CCNA2 association not validated by direct binding assay in abstract","pmids":["41952494"],"is_preprint":false}],"current_model":"RRP9 (U3-55K) is a WD-repeat (seven-bladed beta-propeller) core component of the U3 snoRNP complex that binds specifically to the Box B/C motif of U3 snoRNA via its 7bc loop, facilitating SSU-processome assembly and early pre-rRNA cleavages (sites A0, A1, A2) required for 18S rRNA maturation; its activity is regulated by reversible acetylation (SIRT7-mediated deacetylation promotes U3 snoRNA binding) and by neddylation at Lys221 (catalyzed by Smurf1, reversed by NEDP1), both of which are required for productive pre-rRNA processing, while its expression is controlled at the mRNA level by METTL1-mediated m7G modification; beyond its canonical nucleolar role, RRP9 has been found to interact with IGF2BP1, SQSTM1, and JUN to activate AKT-dependent oncogenic signaling in multiple cancer contexts."},"narrative":{"mechanistic_narrative":"RRP9 (U3-55K) is a WD-repeat core component of the U3 snoRNP that organizes early steps of small-subunit ribosome biogenesis by binding U3 snoRNA and promoting pre-rRNA cleavage required for 18S rRNA maturation [PMID:10982864, PMID:31996908]. Its WD-repeat domain folds into a seven-bladed beta-propeller whose conserved '7bc loop' surface specifically recognizes the Box B/C motif unique to U3 snoRNA; this recognition, together with C-terminal sequences, drives both U3 association and nucleolar localization, and is enhanced by prior loading of Snu13 on the B/C motif [PMID:10982864, PMID:23509373]. A surface opposite the RNA-binding face mediates a direct protein-protein contact with Rrp36 and cooperates with U3/pre-rRNA base-pairing to stabilize the SSU processome and support cleavage at sites A1 and A2 [PMID:31996908]. RRP9 function in pre-rRNA processing is regulated by post-translational modification: SIRT7-mediated deacetylation enhances U3 snoRNA binding and is reversed under stress by nucleolar release of SIRT7 [PMID:26867678], and Smurf1-catalyzed neddylation at Lys221 (reversed by NEDP1) is required for productive processing, with the K221R mutant failing to support pre-rRNA processing or tumor cell proliferation [PMID:34662580]. Beyond its nucleolar role, RRP9 has been linked to oncogenic AKT signaling through physical interactions with IGF2BP1 [PMID:36434608], SQSTM1 [PMID:40994061], and JUN [PMID:39702367], and its expression is controlled transcriptionally by MYC and post-transcriptionally by METTL1-mediated m7G mRNA modification [PMID:40781078, PMID:39960239].","teleology":[{"year":2000,"claim":"Established how RRP9 is recruited to its specific RNA target, answering whether U3-55K associates with U3 snoRNA directly and which RNA elements confer specificity.","evidence":"In vivo and in vitro RNA binding with Box B/C mutagenesis and WD-repeat deletion analysis in Xenopus U3-55k","pmids":["10982864"],"confidence":"High","gaps":["Atomic basis of the WD/U3 contact not resolved","Contribution of protein partners to recruitment not quantified"]},{"year":2013,"claim":"Defined the structural basis of U3 recognition, showing the WD domain forms a beta-propeller and identifying the specific surface loop responsible for RNA binding and nucleolar targeting.","evidence":"X-ray crystallography of yeast and human WD domains with surface-patch mutagenesis and yeast growth assays","pmids":["23509373"],"confidence":"High","gaps":["No structure of the full RRP9/U3/Snu13 assembly","Role of N-terminal NLS in context of intact processome unresolved"]},{"year":2016,"claim":"Showed RRP9's RNA-binding activity is acetylation-regulated, linking pre-rRNA processing to stress signaling via SIRT7.","evidence":"Reciprocal Co-IP, SIRT7 knockdown, deacetylation and RNA-binding assays with stress-response validation","pmids":["26867678"],"confidence":"High","gaps":["Specific acetylated lysines not mapped","Acetyltransferase responsible not identified"]},{"year":2020,"claim":"Identified a second functional surface on the propeller that contacts Rrp36 and cooperates with U3/pre-rRNA base-pairing, explaining how RRP9 stabilizes the SSU processome for A1/A2 cleavage.","evidence":"R289A site-directed mutagenesis, pre-rRNA processing assays, interaction mapping, and genetic epistasis with U3 variants in yeast","pmids":["31996908"],"confidence":"High","gaps":["Structural detail of the Rrp36 contact unknown","Human ortholog interaction with RRP36 not directly tested"]},{"year":2021,"claim":"Revealed a neddylation switch (Smurf1/NEDP1 at Lys221) controlling RRP9 processing activity and tying it to tumor cell proliferation.","evidence":"In vitro/in vivo neddylation reconstitution, Co-IP, K221R mutagenesis, and processing/proliferation rescue assays","pmids":["34662580"],"confidence":"High","gaps":["How neddylation alters RRP9 conformation or partner binding unresolved","Interplay between neddylation and acetylation not addressed"]},{"year":2022,"claim":"Began defining a non-canonical role, showing RRP9 binds IGF2BP1 to activate AKT signaling and confer chemoresistance in pancreatic cancer.","evidence":"Co-IP, co-localization, KD/OE with apoptosis and xenograft assays plus AKT-inhibitor rescue","pmids":["36434608"],"confidence":"Medium","gaps":["Whether this role is independent of ribosome biogenesis unclear","Direct mechanism linking IGF2BP1 binding to AKT not defined"]},{"year":2024,"claim":"Extended the oncogenic interaction network, showing RRP9 stabilizes JUN by limiting MDM2-mediated ubiquitination.","evidence":"Co-IP, ubiquitination and protein stability assays, shRNA knockdown with rescue in breast cancer cells","pmids":["39702367"],"confidence":"Medium","gaps":["Single lab without reciprocal validation across systems","Direct vs indirect effect of RRP9 on MDM2 not separated"]},{"year":2025,"claim":"Mapped upstream regulation of RRP9 expression, identifying MYC transcriptional control and METTL1 m7G-dependent mRNA stabilization, and tied RRP9 to nucleolar size and rRNA synthesis in cancer cells.","evidence":"Transcriptomics, MeRIP and actinomycin D mRNA stability assays, KD/OE with rRNA synthesis and nucleolar measurements in AML cells","pmids":["40781078","39960239"],"confidence":"Medium","gaps":["Direct MYC binding to RRP9 promoter not shown","m7G reader linking modification to translation/stability not identified"]},{"year":2025,"claim":"Reported additional cancer-context partners (SQSTM1) and downstream signaling outputs (AKT/GSK3β/β-catenin, E2F1/CDK1), broadening the proposed oncogenic functions.","evidence":"FLAG pull-down/MS with Co-IP for SQSTM1; western blot pathway placement and reporter/functional assays for AKT and E2F1-CDK1 axes","pmids":["40994061","40526312","40937881"],"confidence":"Low","gaps":["AKT and E2F1 axes placed by western blot/rescue without direct RRP9 binding to pathway components","Single-lab observations not independently confirmed"]},{"year":2026,"claim":"Reported a context-dependent tumor-suppressive role in hepatocellular carcinoma via PI3K/AKT/mTOR inhibition and CCNA2 downregulation, contrasting the oncogenic AKT activation seen in other cancers.","evidence":"Lentiviral KD/OE, transcriptomics, western blot, PI3K modulator rescue, and xenograft in mice","pmids":["41952494"],"confidence":"Low","gaps":["RRP9-CCNA2 association not validated by direct binding assay","Reconciliation of opposing AKT effects across tissues unresolved"]},{"year":null,"claim":"How RRP9's conserved nucleolar pre-rRNA processing function mechanistically connects to its reported cytoplasmic/oncogenic AKT-modulating interactions, and why effects on AKT signaling differ across cancer types, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical link between ribosome-biogenesis role and signaling partners","Opposing oncogenic vs tumor-suppressive outcomes not mechanistically reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,1,2,9]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,3,4]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[3,4,9]}],"complexes":["U3 snoRNP","SSU processome"],"partners":["SNU13","RRP36","SIRT7","SMURF1","IGF2BP1","SQSTM1","JUN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43818","full_name":"U3 small nucleolar RNA-interacting protein 2","aliases":["RRP9 homolog","U3 small nucleolar ribonucleoprotein-associated 55 kDa protein","U3 snoRNP-associated 55 kDa protein","U3-55K"],"length_aa":475,"mass_kda":51.8,"function":"Component of a nucleolar small nuclear ribonucleoprotein particle (snoRNP) thought to participate in the processing and modification of pre-ribosomal RNA (pre-rRNA) (PubMed:26867678). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797)","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/O43818/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RRP9","classification":"Common Essential","n_dependent_lines":1084,"n_total_lines":1208,"dependency_fraction":0.8973509933774835},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FBL","stoichiometry":0.2},{"gene":"NOP58","stoichiometry":0.2},{"gene":"SSB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RRP9","total_profiled":1310},"omim":[{"mim_id":"620013","title":"RIBOSOMAL RNA-PROCESSING 9, U3 SMALL NUCLEOLAR RNA-BINDING PROTEIN; RRP9","url":"https://www.omim.org/entry/620013"},{"mim_id":"614514","title":"THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL RECESSIVE; THPH6","url":"https://www.omim.org/entry/614514"},{"mim_id":"612336","title":"THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL DOMINANT; THPH5","url":"https://www.omim.org/entry/612336"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RRP9"},"hgnc":{"alias_symbol":["U3-55K"],"prev_symbol":["RNU3IP2"]},"alphafold":{"accession":"O43818","domains":[{"cath_id":"2.130.10.10","chopping":"143-189_196-467","consensus_level":"medium","plddt":96.1397,"start":143,"end":467}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43818","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43818-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43818-F1-predicted_aligned_error_v6.png","plddt_mean":83.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RRP9","jax_strain_url":"https://www.jax.org/strain/search?query=RRP9"},"sequence":{"accession":"O43818","fasta_url":"https://rest.uniprot.org/uniprotkb/O43818.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43818/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43818"}},"corpus_meta":[{"pmid":"26867678","id":"PMC_26867678","title":"SIRT7-dependent deacetylation of the U3-55k protein controls pre-rRNA processing.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26867678","citation_count":114,"is_preprint":false},{"pmid":"36434608","id":"PMC_36434608","title":"RRP9 promotes gemcitabine resistance in pancreatic cancer via activating AKT signaling pathway.","date":"2022","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/36434608","citation_count":39,"is_preprint":false},{"pmid":"10982864","id":"PMC_10982864","title":"Interaction of the U3-55k protein with U3 snoRNA is mediated by the box B/C motif of U3 and the WD repeats of U3-55k.","date":"2000","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/10982864","citation_count":38,"is_preprint":false},{"pmid":"23509373","id":"PMC_23509373","title":"Structural and functional analysis of the U3 snoRNA binding protein Rrp9.","date":"2013","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23509373","citation_count":26,"is_preprint":false},{"pmid":"34662580","id":"PMC_34662580","title":"Neddylation modification of the U3 snoRNA-binding protein RRP9 by Smurf1 promotes tumorigenesis.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34662580","citation_count":25,"is_preprint":false},{"pmid":"31996908","id":"PMC_31996908","title":"Synergistic defects in pre-rRNA processing from mutations in the U3-specific protein Rrp9 and U3 snoRNA.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/31996908","citation_count":22,"is_preprint":false},{"pmid":"12448766","id":"PMC_12448766","title":"Cloning and expression of PARP-3 (Adprt3) and U3-55k, two genes closely linked on mouse chromosome 9.","date":"2002","source":"Folia biologica","url":"https://pubmed.ncbi.nlm.nih.gov/12448766","citation_count":13,"is_preprint":false},{"pmid":"39395773","id":"PMC_39395773","title":"Regulation of microglia inflammation and oligodendrocyte demyelination by Engeletin via the TLR4/RRP9/NF-κB pathway after spinal cord injury.","date":"2024","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/39395773","citation_count":10,"is_preprint":false},{"pmid":"39960239","id":"PMC_39960239","title":"METTL1 Enhances RRP9 mRNA Stability Through m7G Modification to Drive Colorectal Tumorigenesis.","date":"2025","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/39960239","citation_count":9,"is_preprint":false},{"pmid":"39702367","id":"PMC_39702367","title":"The RRP9-JUN axis promotes breast cancer progression via the AKT signalling pathway.","date":"2024","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/39702367","citation_count":6,"is_preprint":false},{"pmid":"37904456","id":"PMC_37904456","title":"RRP9 and DDX21 as new biomarkers of colorectal cancer.","date":"2023","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37904456","citation_count":4,"is_preprint":false},{"pmid":"37988222","id":"PMC_37988222","title":"Joint effect of RRP9 and DDX21 on development of colorectal cancer and keloid.","date":"2023","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/37988222","citation_count":3,"is_preprint":false},{"pmid":"40781078","id":"PMC_40781078","title":"Chidamide and cytarabine synergistically treat acute myeloid leukemia: inhibiting ribosome biogenesis via the MYC-RRP9 pathway.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/40781078","citation_count":1,"is_preprint":false},{"pmid":"40937881","id":"PMC_40937881","title":"RRP9 Promotes Esophageal Squamous Cell Carcinoma Progression through E2F1 Transcriptional Regulation of CDK1.","date":"2025","source":"Advanced biology","url":"https://pubmed.ncbi.nlm.nih.gov/40937881","citation_count":1,"is_preprint":false},{"pmid":"40526312","id":"PMC_40526312","title":"RRP9 promotes prostate cancer metastasis and epithelial-mesenchymal transition through activation of the AKT/GSK3β/β-Catenin signaling pathway.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40526312","citation_count":0,"is_preprint":false},{"pmid":"40994061","id":"PMC_40994061","title":"snoRNP RRP9 Promotes Prostate Cancer Cell Proliferation and Migration via SQSTM1.","date":"2025","source":"Advanced biology","url":"https://pubmed.ncbi.nlm.nih.gov/40994061","citation_count":0,"is_preprint":false},{"pmid":"41952494","id":"PMC_41952494","title":"RRP9 suppresses hepatocellular carcinoma progression by inhibiting the PI3K/AKT/mTOR pathway.","date":"2026","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41952494","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11364,"output_tokens":3672,"usd":0.044586,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11347,"output_tokens":3396,"usd":0.070818,"stage2_stop_reason":"end_turn"},"total_usd":0.115404,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"U3-55k (RRP9) interaction with U3 snoRNA in vivo is mediated by the Box B/C motif unique to U3 snoRNA; mutation of Box B and Box C disrupted the interaction, while Box C appears to be the primary determinant in vitro. WD repeats and C-terminal sequences of U3-55k are required for U3 RNA association and nucleolar localization, suggesting protein-protein interactions also contribute.\",\n      \"method\": \"In vivo RNA binding assays (mutation of U3 Box B/C), in vitro RNA binding assays, cDNA cloning of Xenopus U3-55k, deletion mutagenesis of WD repeats\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis of both RNA and protein, replicated across multiple constructs and two species\",\n      \"pmids\": [\"10982864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of the WD repeat domain of yeast Rrp9 and its human ortholog U3-55K were determined, revealing a seven-bladed beta-propeller fold. A conserved '7bc loop' on the WD domain surface is crucial for specific recognition of U3 snoRNA, nucleolar localization of Rrp9, and yeast growth. Prior association of Snu13 with the B/C motif enhances specific binding of the WD domain. The N-terminal region contains a bipartite nuclear localization signal that is dispensable for nucleolar localization.\",\n      \"method\": \"X-ray crystallography, mutagenesis of conserved surface patches, yeast growth assays, biochemical binding assays\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and functional (yeast growth) validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23509373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SIRT7 deacetylates U3-55k (RRP9), a core component of the U3 snoRNP complex. Deacetylation of U3-55k by SIRT7 enhances U3-55k binding to U3 snoRNA, which is required for pre-rRNA processing (early cleavage steps for 18S rRNA generation). Under stress, SIRT7 is released from nucleoli, causing hyperacetylation of U3-55k and attenuation of pre-rRNA processing.\",\n      \"method\": \"Co-immunoprecipitation (SIRT7–U3-55k interaction), knockdown of SIRT7, acetylation/deacetylation assays, RNA binding assays, nucleolar localization experiments\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional KD with defined rRNA processing phenotype, biochemical deacetylation assay, stress-response validation; multiple orthogonal methods\",\n      \"pmids\": [\"26867678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The R289A substitution in the Rrp9 beta-propeller domain (surface opposite to U3 snoRNA binding face) specifically reduced pre-rRNA cleavage at sites A1 and A2. A direct protein-protein interaction between the Rrp9 beta-propeller domain and Rrp36 was identified; the R289A mutation reduced this interaction, implicating it in the processing phenotype. Synergistic negative interactions were observed between R289A and U3 mutations that destabilize U3/pre-rRNA base-pairing, indicating cooperative function in SSU-processome stability.\",\n      \"method\": \"Site-directed mutagenesis (R289A), pre-rRNA processing assays, protein-protein interaction network mapping, genetic epistasis/synergy analysis with U3 variants\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis with defined processing phenotype, direct interaction mapping with Rrp36, genetic epistasis with U3 snoRNA variants; multiple orthogonal methods\",\n      \"pmids\": [\"31996908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RRP9 is neddylated at Lys221 by the HECT-type E3 ligase Smurf1; this neddylation is removed by the NEDP1 deneddylase. RRP9 neddylation is required for pre-rRNA processing and ribosomal biogenesis; the unneddylated K221R mutant fails to promote pre-rRNA processing and does not support tumor cell proliferation, colony formation, or migration.\",\n      \"method\": \"In vivo and in vitro neddylation assays, Co-immunoprecipitation (Smurf1–RRP9), site-directed mutagenesis (K221R), pre-rRNA processing assays, functional cell proliferation/migration assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro neddylation reconstitution, site-specific mutagenesis, Co-IP, functional rescue experiments; multiple orthogonal methods in single study\",\n      \"pmids\": [\"34662580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RRP9 interacts with the DNA-binding region of IGF2BP1 in pancreatic cancer cells, activating the AKT signaling pathway. This interaction promotes gemcitabine resistance by reducing DNA damage and inhibiting apoptosis. AKT inhibitor MK-2206 combined with gemcitabine reversed RRP9-overexpression-induced resistance.\",\n      \"method\": \"Immunoprecipitation (RRP9–IGF2BP1 interaction), immunofluorescence co-localization, RRP9 overexpression/siRNA knockdown, MTT assay, colony formation, FACS apoptosis, subcutaneous xenograft model\",\n      \"journal\": \"Cell Communication and Signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and co-localization for interaction, functional KD/OE with defined phenotype and pathway rescue, single lab\",\n      \"pmids\": [\"36434608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RRP9 interacts with JUN protein; RRP9 deletion decreases JUN protein stability by accelerating JUN ubiquitination via MDM2, leading to JUN degradation. Loss of JUN or AKT pathway activation (SC79) attenuated the regulatory effects of RRP9 on breast cancer cell phenotypes.\",\n      \"method\": \"Co-immunoprecipitation (RRP9–JUN), protein stability assay, ubiquitination assay, gene expression array (prime-view), shRNA knockdown, rescue experiments\",\n      \"journal\": \"Biology Direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for interaction, ubiquitination assay, functional rescue; single lab with multiple methods\",\n      \"pmids\": [\"39702367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RRP9 overexpression activates the AKT signaling pathway in prostate cancer, resulting in phosphorylation of GSK3β at Ser9, which prevents β-catenin degradation and promotes cell metastasis, invasion, and EMT. AKT activator SC79 reversed the inhibitory effects of RRP9 knockdown.\",\n      \"method\": \"RRP9 overexpression/knockdown, western blot for AKT/GSK3β/β-catenin phosphorylation, rescue experiments with SC79, Transwell invasion/migration assays\",\n      \"journal\": \"Discover Oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, signaling pathway placement by western blot with rescue, no direct binding partner identified for AKT pathway activation\",\n      \"pmids\": [\"40526312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RRP9 interacts with the scaffolding protein SQSTM1 (p62) in prostate cancer cells, identified by FLAG-RRP9 pull-down followed by MALDI-TOF/TOF mass spectrometry and validated by co-immunoprecipitation. SQSTM1 overexpression rescued the anti-growth and anti-migration effects of RRP9 knockdown.\",\n      \"method\": \"FLAG-RRP9 pull-down, MALDI-TOF/TOF mass spectrometry, co-immunoprecipitation, shRNA knockdown, rescue experiments, in vivo xenograft\",\n      \"journal\": \"Advanced Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pull-down + MS identification + Co-IP validation + functional rescue; single lab, multiple methods\",\n      \"pmids\": [\"40994061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYC transcriptionally regulates RRP9 expression. RRP9 knockdown impairs rRNA synthesis, reduces nucleolar size, and diminishes protein production in AML cells. Overexpression of RRP9 promotes AML cell proliferation and resistance to chidamide–cytarabine combination treatment.\",\n      \"method\": \"Transcriptomic analysis, binding assays (surface plasmon resonance for chidamide–MYC), RRP9 knockdown/overexpression, functional rRNA synthesis assays, nucleolar size measurement\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — transcriptomic pathway analysis plus direct rRNA synthesis/nucleolar assays, functional KD/OE with defined phenotype; single lab\",\n      \"pmids\": [\"40781078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RRP9 promotes esophageal squamous cell carcinoma progression by enhancing E2F1-mediated transcriptional regulation of CDK1. RRP9 depletion reduced CDK1 expression and cell cycle progression.\",\n      \"method\": \"RRP9 knockdown/overexpression, luciferase or transcription reporter assays (E2F1-CDK1 axis implied), in vitro and in vivo functional assays\",\n      \"journal\": \"Advanced Biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic pathway placement inferred from transcriptional regulation assays without direct biochemical interaction between RRP9 and E2F1 demonstrated in abstract\",\n      \"pmids\": [\"40937881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL1 promotes RRP9 mRNA stability through N7-methylguanosine (m7G) modification of RRP9 mRNA, as demonstrated by MeRIP assay and actinomycin D mRNA stability assay. This stabilization activates PI3K/AKT signaling via RRP9.\",\n      \"method\": \"MeRIP (methylated immunoprecipitation) assay, actinomycin D mRNA stability assay, METTL1 knockdown/overexpression, western blot for AKT pathway\",\n      \"journal\": \"Molecular Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP directly measures m7G modification of RRP9 mRNA, mRNA stability assay, functional rescue; single lab with two orthogonal methods\",\n      \"pmids\": [\"39960239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RRP9 suppresses hepatocellular carcinoma by inhibiting the PI3K/AKT/mTOR pathway and downregulating cyclin A2 (CCNA2). Protein-protein interaction analysis and western blot identified an association between RRP9 and CCNA2; rescue experiments with PI3K activator 740Y-P and inhibitor PI3K/AKT/mTOR-IN-2 confirmed pathway involvement.\",\n      \"method\": \"Lentiviral KD/OE cell models, transcriptome sequencing, western blot, protein-protein interaction analysis, functional rescue with PI3K modulators, subcutaneous tumorigenesis in mice\",\n      \"journal\": \"International Journal of Oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement by transcriptomics + western blot with pharmacological rescue, RRP9-CCNA2 association not validated by direct binding assay in abstract\",\n      \"pmids\": [\"41952494\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RRP9 (U3-55K) is a WD-repeat (seven-bladed beta-propeller) core component of the U3 snoRNP complex that binds specifically to the Box B/C motif of U3 snoRNA via its 7bc loop, facilitating SSU-processome assembly and early pre-rRNA cleavages (sites A0, A1, A2) required for 18S rRNA maturation; its activity is regulated by reversible acetylation (SIRT7-mediated deacetylation promotes U3 snoRNA binding) and by neddylation at Lys221 (catalyzed by Smurf1, reversed by NEDP1), both of which are required for productive pre-rRNA processing, while its expression is controlled at the mRNA level by METTL1-mediated m7G modification; beyond its canonical nucleolar role, RRP9 has been found to interact with IGF2BP1, SQSTM1, and JUN to activate AKT-dependent oncogenic signaling in multiple cancer contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RRP9 (U3-55K) is a WD-repeat core component of the U3 snoRNP that organizes early steps of small-subunit ribosome biogenesis by binding U3 snoRNA and promoting pre-rRNA cleavage required for 18S rRNA maturation [#0, #3]. Its WD-repeat domain folds into a seven-bladed beta-propeller whose conserved '7bc loop' surface specifically recognizes the Box B/C motif unique to U3 snoRNA; this recognition, together with C-terminal sequences, drives both U3 association and nucleolar localization, and is enhanced by prior loading of Snu13 on the B/C motif [#0, #1]. A surface opposite the RNA-binding face mediates a direct protein-protein contact with Rrp36 and cooperates with U3/pre-rRNA base-pairing to stabilize the SSU processome and support cleavage at sites A1 and A2 [#3]. RRP9 function in pre-rRNA processing is regulated by post-translational modification: SIRT7-mediated deacetylation enhances U3 snoRNA binding and is reversed under stress by nucleolar release of SIRT7 [#2], and Smurf1-catalyzed neddylation at Lys221 (reversed by NEDP1) is required for productive processing, with the K221R mutant failing to support pre-rRNA processing or tumor cell proliferation [#4]. Beyond its nucleolar role, RRP9 has been linked to oncogenic AKT signaling through physical interactions with IGF2BP1 [#5], SQSTM1 [#8], and JUN [#6], and its expression is controlled transcriptionally by MYC and post-transcriptionally by METTL1-mediated m7G mRNA modification [#9, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established how RRP9 is recruited to its specific RNA target, answering whether U3-55K associates with U3 snoRNA directly and which RNA elements confer specificity.\",\n      \"evidence\": \"In vivo and in vitro RNA binding with Box B/C mutagenesis and WD-repeat deletion analysis in Xenopus U3-55k\",\n      \"pmids\": [\"10982864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic basis of the WD/U3 contact not resolved\", \"Contribution of protein partners to recruitment not quantified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the structural basis of U3 recognition, showing the WD domain forms a beta-propeller and identifying the specific surface loop responsible for RNA binding and nucleolar targeting.\",\n      \"evidence\": \"X-ray crystallography of yeast and human WD domains with surface-patch mutagenesis and yeast growth assays\",\n      \"pmids\": [\"23509373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the full RRP9/U3/Snu13 assembly\", \"Role of N-terminal NLS in context of intact processome unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed RRP9's RNA-binding activity is acetylation-regulated, linking pre-rRNA processing to stress signaling via SIRT7.\",\n      \"evidence\": \"Reciprocal Co-IP, SIRT7 knockdown, deacetylation and RNA-binding assays with stress-response validation\",\n      \"pmids\": [\"26867678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific acetylated lysines not mapped\", \"Acetyltransferase responsible not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a second functional surface on the propeller that contacts Rrp36 and cooperates with U3/pre-rRNA base-pairing, explaining how RRP9 stabilizes the SSU processome for A1/A2 cleavage.\",\n      \"evidence\": \"R289A site-directed mutagenesis, pre-rRNA processing assays, interaction mapping, and genetic epistasis with U3 variants in yeast\",\n      \"pmids\": [\"31996908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the Rrp36 contact unknown\", \"Human ortholog interaction with RRP36 not directly tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a neddylation switch (Smurf1/NEDP1 at Lys221) controlling RRP9 processing activity and tying it to tumor cell proliferation.\",\n      \"evidence\": \"In vitro/in vivo neddylation reconstitution, Co-IP, K221R mutagenesis, and processing/proliferation rescue assays\",\n      \"pmids\": [\"34662580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How neddylation alters RRP9 conformation or partner binding unresolved\", \"Interplay between neddylation and acetylation not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Began defining a non-canonical role, showing RRP9 binds IGF2BP1 to activate AKT signaling and confer chemoresistance in pancreatic cancer.\",\n      \"evidence\": \"Co-IP, co-localization, KD/OE with apoptosis and xenograft assays plus AKT-inhibitor rescue\",\n      \"pmids\": [\"36434608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this role is independent of ribosome biogenesis unclear\", \"Direct mechanism linking IGF2BP1 binding to AKT not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the oncogenic interaction network, showing RRP9 stabilizes JUN by limiting MDM2-mediated ubiquitination.\",\n      \"evidence\": \"Co-IP, ubiquitination and protein stability assays, shRNA knockdown with rescue in breast cancer cells\",\n      \"pmids\": [\"39702367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without reciprocal validation across systems\", \"Direct vs indirect effect of RRP9 on MDM2 not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped upstream regulation of RRP9 expression, identifying MYC transcriptional control and METTL1 m7G-dependent mRNA stabilization, and tied RRP9 to nucleolar size and rRNA synthesis in cancer cells.\",\n      \"evidence\": \"Transcriptomics, MeRIP and actinomycin D mRNA stability assays, KD/OE with rRNA synthesis and nucleolar measurements in AML cells\",\n      \"pmids\": [\"40781078\", \"39960239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MYC binding to RRP9 promoter not shown\", \"m7G reader linking modification to translation/stability not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reported additional cancer-context partners (SQSTM1) and downstream signaling outputs (AKT/GSK3β/β-catenin, E2F1/CDK1), broadening the proposed oncogenic functions.\",\n      \"evidence\": \"FLAG pull-down/MS with Co-IP for SQSTM1; western blot pathway placement and reporter/functional assays for AKT and E2F1-CDK1 axes\",\n      \"pmids\": [\"40994061\", \"40526312\", \"40937881\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"AKT and E2F1 axes placed by western blot/rescue without direct RRP9 binding to pathway components\", \"Single-lab observations not independently confirmed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Reported a context-dependent tumor-suppressive role in hepatocellular carcinoma via PI3K/AKT/mTOR inhibition and CCNA2 downregulation, contrasting the oncogenic AKT activation seen in other cancers.\",\n      \"evidence\": \"Lentiviral KD/OE, transcriptomics, western blot, PI3K modulator rescue, and xenograft in mice\",\n      \"pmids\": [\"41952494\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"RRP9-CCNA2 association not validated by direct binding assay\", \"Reconciliation of opposing AKT effects across tissues unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RRP9's conserved nucleolar pre-rRNA processing function mechanistically connects to its reported cytoplasmic/oncogenic AKT-modulating interactions, and why effects on AKT signaling differ across cancer types, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or biochemical link between ribosome-biogenesis role and signaling partners\", \"Opposing oncogenic vs tumor-suppressive outcomes not mechanistically reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 1, 2, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [3, 4, 9]}\n    ],\n    \"complexes\": [\"U3 snoRNP\", \"SSU processome\"],\n    \"partners\": [\"Snu13\", \"RRP36\", \"SIRT7\", \"Smurf1\", \"IGF2BP1\", \"SQSTM1\", \"JUN\", \"IGF2BP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}