{"gene":"SNRPB2","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":1998,"finding":"Crystal structure at 2.4 Å of the ternary U2B\"/U2A'/U2 snRNA hairpin-loop IV complex revealed that U2A' leucine-rich repeats contact the RRM domain of U2B\" on the surface opposite its RNA-binding face, and the basic C-terminal region of U2A' interacts with the RNA stem; this protein-protein interaction is required for U2B\" to bind U2 snRNA specifically.","method":"X-ray crystallography at 2.4 Å resolution","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure with functional validation, replicated across multiple biochemical studies","pmids":["9716128"],"is_preprint":false},{"year":1990,"finding":"U2B'' binds specifically to U2 snRNA only in the presence of the accessory protein U2A'; exchange of two nucleotides between U1 and U2 snRNAs or of eight amino acids between U1A and U2B'' reverses binding specificity, identifying major RNA-binding determinants.","method":"In vitro RNA binding assays with recombinant proteins and mutant RNAs/proteins","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis, replicated by multiple independent studies","pmids":["2140872"],"is_preprint":false},{"year":1990,"finding":"U2B'' and U2A' form a stable protein-protein complex in the absence of RNA; the minimal U2B'' fragment (amino acids 1–88) required for specific U2 RNA binding is also the minimal region for U2A' interaction; U2B'' residues 37–46 permit U2 RNA binding when contacted by U2A', while residues 14–25 reduce non-specific U1 RNA binding.","method":"In vitro protein-protein and protein-RNA binding assays with deletion/hybrid mutants of U2B''","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with systematic mutagenesis, independently confirmed by structural data","pmids":["2145152"],"is_preprint":false},{"year":1991,"finding":"U2A' forms a weak but detectable interaction with U2 RNA (at the stem of hairpin IV) and a stable complex with U2B''; the U2A'-U2B''-U2 RNA ternary complex is stabilized by this weak U2A'-RNA contact; the region of U2A' essential for U2B'' binding spans amino acids 1–164.","method":"RNA-protein binding assays with wild-type and mutant U2A' proteins; mutant U2 RNA binding experiments","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, single lab but multiple orthogonal binding experiments","pmids":["1826350"],"is_preprint":false},{"year":1994,"finding":"U2B'' nuclear import can occur via two mechanisms: (1) an internal NLS (amino acids 90–146) related to U1A's NLS, and (2) a 'piggy-back' mechanism whereby interaction with U2A' mediates nuclear transport through sequences in the N-terminal RNP motif of U2B''; U2A' nuclear transport occurs independently of both U2B'' binding and U2 snRNA.","method":"Nuclear import assays in Xenopus oocytes and mammalian cells with deletion mutants and microinjection","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct nuclear localization experiments with deletion mutants showing functional consequence, single lab","pmids":["7983149"],"is_preprint":false},{"year":1998,"finding":"U2A' enables U2B'' to discriminate the loop sequence of U2 snRNA hairpin IV from U1 snRNA hairpin II but plays no role in stem sequence discrimination; a single leucine residue in U1A (Leu-44) accounts for much of the intrinsic RNA-binding specificity difference between U1A and U2B''; U2A' binds U2B'' with ~500-fold greater affinity than U1A.","method":"In vitro RNA-binding assays with purified recombinant proteins, site-directed mutagenesis","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, quantitative binding assays, single lab with multiple orthogonal experiments","pmids":["9814759"],"is_preprint":false},{"year":1998,"finding":"In yeast, the U2B'' counterpart Yib9p (Msl1p) requires the U2A' counterpart Lea1p for association with U2 snRNA in vivo, even though Yib9p can bind U2 snRNA stem-loop IV in vitro alone; deletion of LEA1 and/or YIB9 impairs pre-mRNA splicing and blocks spliceosome assembly prior to U2 snRNP addition.","method":"Yeast genetics (deletion strains), in vitro splicing/spliceosome assembly assays, recombinant protein rescue","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis combined with in vitro spliceosome assembly rescue, yeast ortholog study","pmids":["9799242"],"is_preprint":false},{"year":2014,"finding":"U2A' binds U2B'' with nanomolar affinity but binds U1A with only micromolar affinity; RNA-dependent cooperativity (thermodynamic linkage) between protein-protein and protein-RNA interactions ensures partitioning of the U2A'/U2B'' complex exclusively to the U2 snRNP.","method":"Fluorescence binding assays and isothermal titration calorimetry (ITC) with purified recombinant proteins","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative in vitro reconstitution with two orthogonal biophysical methods (fluorescence + ITC), single lab","pmids":["24866816"],"is_preprint":false},{"year":2011,"finding":"Human U2B'' binds not only U2 snRNA stem-loop IV but also U1 snRNA stem-loop II and Drosophila U2 snRNA SLIV in vitro with similar thermodynamics, indicating a relaxed RNA-binding specificity compared to U1A.","method":"In vitro RNA-protein binding assays and thermodynamic measurements","journal":"Biophysical chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — quantitative in vitro binding, single lab, single method type","pmids":["21684671"],"is_preprint":false},{"year":2007,"finding":"In C. elegans, RNP-3 (U2B'') is U2 snRNP-associated and binds U2 snRNA even in the absence of U2A'; knockout of both rnp-2 (U1A) and rnp-3 (U2B'') is required for lethality, demonstrating functional redundancy; U1A can associate with U2 RNA when U2B'' is deleted.","method":"Co-immunoprecipitation, genetic knockouts, RNA co-precipitation in C. elegans","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and double knockout genetics in C. elegans with defined phenotypic readout","pmids":["17535930"],"is_preprint":false},{"year":2024,"finding":"SNRPB2 knockdown in TNBC cells causes skipping of exon 6 in MDM4 pre-mRNA generating the MDM4-S transcript, reducing MDM4 protein levels, which decreases Rb1 protein expression and inactivates E2F1 signaling, suppressing cell proliferation and invasion.","method":"siRNA knockdown, transcriptome/alternative splicing analysis, Western blot, cell proliferation and invasion assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined molecular pathway (splicing → MDM4 → Rb1 → E2F1) validated by multiple assays, single lab","pmids":["39329452"],"is_preprint":false},{"year":2025,"finding":"SNRPB2 stabilizes E2F4 protein by preventing its proteasomal degradation; SNRPB2 knockdown in esophageal squamous cell carcinoma cells reduces E2F4 levels and suppresses proliferation, migration, and invasion, which is rescued by E2F4 overexpression.","method":"siRNA knockdown, cycloheximide chase assay, rescue overexpression, in vitro and in vivo functional assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CHX chase assay demonstrating protein stability mechanism with rescue experiment, single lab","pmids":["40612943"],"is_preprint":false},{"year":2026,"finding":"SNRPB2 knockdown in breast cancer cells induces G2/M cell cycle arrest and alters alternative splicing events including HMGA2 splicing; proposed mechanism is that SNRPB2 regulates cell cycle progression partly through HMGA2 splicing modulation.","method":"siRNA knockdown, RNA-seq, RT-qPCR, cell cycle analysis","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD phenotype with splicing readout but HMGA2 mechanism not directly validated","pmids":["42068395"],"is_preprint":false}],"current_model":"SNRPB2 (U2B'') is an RRM-domain protein that associates with stem-loop IV of U2 snRNA as part of the U2 snRNP; its specific RNA binding requires cooperative interaction with U2A', whose leucine-rich repeat domain contacts the opposite face of U2B'''s RRM while U2A'''s basic C-terminus contacts the RNA stem—a mechanism revealed by X-ray crystallography—and nanomolar U2A'/U2B'' affinity combined with RNA-dependent cooperativity ensures exclusive partitioning to the U2 snRNP; in mammalian cancer cells SNRPB2 additionally regulates alternative splicing of pre-mRNAs (e.g., MDM4) to control cell cycle progression and can stabilize cell cycle transcription factors (E2F4) against proteasomal degradation."},"narrative":{"mechanistic_narrative":"SNRPB2 (U2B'') is an RRM-domain protein that functions as a sequence-specific RNA-binding component of the U2 snRNP, where its association with U2 snRNA stem-loop IV is the molecular basis for incorporating this protein into the spliceosomal U2 particle [PMID:9716128, PMID:2140872]. On its own U2B'' binds RNA only weakly and non-specifically; specific recognition of U2 snRNA requires the accessory protein U2A', whose leucine-rich repeats contact the face of the U2B'' RRM opposite the RNA-binding surface while its basic C-terminus contacts the RNA stem, an arrangement resolved by crystallography that explains why protein-protein interaction is a prerequisite for specific RNA binding [PMID:9716128, PMID:2145152, PMID:1826350]. U2A' binds U2B'' with nanomolar affinity, far tighter than its interaction with the paralogous U1A protein, and RNA-dependent cooperativity (thermodynamic linkage between the protein-protein and protein-RNA contacts) ensures the U2A'/U2B'' complex partitions exclusively to the U2 snRNP rather than to U1 [PMID:9814759, PMID:24866816]. The functional importance of this interaction is conserved: in yeast the U2B''/U2A' counterparts Yib9p/Lea1p are required for U2 snRNP association with snRNA in vivo, and their loss blocks spliceosome assembly prior to U2 addition and impairs pre-mRNA splicing [PMID:9799242]. In mammalian cancer cells SNRPB2 additionally shapes alternative splicing of specific pre-mRNAs to control proliferation: its depletion drives skipping of MDM4 exon 6 to generate MDM4-S, lowering MDM4 and Rb1 and inactivating E2F1 signaling [PMID:39329452], and it stabilizes the transcription factor E2F4 against proteasomal degradation, with E2F4 re-expression rescuing the proliferative defect [PMID:40612943].","teleology":[{"year":1990,"claim":"Established the central rule of U2B'' biology: that it cannot recognize U2 snRNA on its own but requires the accessory protein U2A', and pinpointed the RNA and protein determinants of binding specificity.","evidence":"in vitro RNA binding assays with recombinant proteins and reciprocal nucleotide/amino-acid swaps between the U1 and U2 systems","pmids":["2140872","2145152"],"confidence":"High","gaps":["Atomic geometry of the U2B''/U2A'/RNA contacts not yet resolved","In vivo requirement in a cellular splicing context not addressed"]},{"year":1991,"claim":"Showed the ternary complex is stabilized by a direct, if weak, U2A'-RNA contact at the hairpin IV stem, refining the model from a purely protein-bridged one to a tripartite assembly.","evidence":"RNA-protein binding assays with wild-type and mutant U2A' and mutant U2 RNA","pmids":["1826350"],"confidence":"High","gaps":["Quantitative affinities of each pairwise contact not measured","Structural basis still inferred rather than observed"]},{"year":1994,"claim":"Addressed how U2B'' reaches its site of action, showing it can enter the nucleus via its own internal NLS or by piggy-backing on U2A'.","evidence":"nuclear import assays in Xenopus oocytes and mammalian cells using deletion mutants and microinjection","pmids":["7983149"],"confidence":"Medium","gaps":["Relative contribution of each import route in normal cells unknown","Import receptors mediating either pathway not identified"]},{"year":1998,"claim":"Resolved the ternary complex at atomic resolution and dissected the chemical origin of U2 versus U1 specificity, converting the genetic/biochemical model into a structural mechanism.","evidence":"2.4 Å X-ray crystal structure of the U2B''/U2A'/U2 hairpin IV complex plus in vitro binding with single-residue mutants","pmids":["9716128","9814759"],"confidence":"High","gaps":["Dynamics and kinetics of complex assembly not captured by a static structure","Did not quantify the thermodynamic linkage driving snRNP partitioning"]},{"year":1998,"claim":"Demonstrated the in vivo functional consequence of the interaction in a whole organism, showing the accessory protein is needed for U2 snRNP assembly and splicing.","evidence":"yeast deletion genetics of LEA1/YIB9 with in vitro spliceosome assembly and recombinant rescue","pmids":["9799242"],"confidence":"High","gaps":["Discrepancy between in vitro RNA binding by Yib9p alone and in vivo dependence on Lea1p not fully reconciled","Direct extension to human cells not tested"]},{"year":2007,"claim":"Revealed evolutionary flexibility in the partnership, showing functional redundancy between U1A and U2B'' orthologs and U2A'-independent U2 binding in nematodes.","evidence":"reciprocal co-IP, RNA co-precipitation and double knockouts in C. elegans","pmids":["17535930"],"confidence":"Medium","gaps":["Whether the human protein shares this redundancy not established","Molecular basis of U2A'-independent binding in worm not defined"]},{"year":2014,"claim":"Provided the thermodynamic explanation for exclusive U2 snRNP targeting, showing RNA-dependent cooperativity and nanomolar U2A'/U2B'' affinity bias the complex away from U1.","evidence":"fluorescence binding and isothermal titration calorimetry with purified recombinant proteins","pmids":["24866816"],"confidence":"High","gaps":["Cooperativity demonstrated in vitro; partitioning not measured in living cells","Role of additional snRNP factors in vivo unaddressed"]},{"year":2011,"claim":"Characterized the intrinsic RNA-binding promiscuity of human U2B'', which binds U1 and Drosophila U2 hairpins with similar thermodynamics, underscoring why U2A' is needed for fidelity.","evidence":"in vitro RNA-protein binding and thermodynamic measurements","pmids":["21684671"],"confidence":"Medium","gaps":["Single method type, single lab","Cellular relevance of relaxed specificity not tested"]},{"year":2024,"claim":"Extended SNRPB2 beyond core snRNP assembly to a regulator of specific alternative splicing events controlling proliferation, defining an MDM4-Rb1-E2F1 axis in cancer cells.","evidence":"siRNA knockdown, splicing/transcriptome analysis, Western blot and proliferation/invasion assays in TNBC cells","pmids":["39329452"],"confidence":"Medium","gaps":["Direct binding of SNRPB2 to MDM4 pre-mRNA not shown","Specificity for MDM4 versus global U2 snRNP function not separated"]},{"year":2025,"claim":"Identified a non-splicing role in which SNRPB2 stabilizes the transcription factor E2F4 against proteasomal turnover, broadening its proliferative function.","evidence":"siRNA knockdown, cycloheximide chase, E2F4 rescue and in vitro/in vivo functional assays in esophageal squamous cell carcinoma","pmids":["40612943"],"confidence":"Medium","gaps":["Whether SNRPB2 acts directly on E2F4 or via an intermediate not resolved","Connection to its RNA-binding/splicing activity unclear"]},{"year":2026,"claim":"Linked SNRPB2 depletion to G2/M arrest and altered HMGA2 splicing, proposing an additional splicing-dependent route to cell cycle control.","evidence":"siRNA knockdown, RNA-seq, RT-qPCR and cell cycle analysis in breast cancer cells","pmids":["42068395"],"confidence":"Low","gaps":["HMGA2 mechanism not directly validated","Causality between HMGA2 splicing and G2/M arrest not established","Single lab, descriptive readout"]},{"year":null,"claim":"How SNRPB2's core U2 snRNP function mechanistically connects to its reported gene-specific splicing and protein-stabilization activities in cancer cells remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct in vivo CLIP/binding map of SNRPB2 target transcripts","Mechanism linking a core snRNP subunit to E2F4 protein stability undefined","Whether splicing changes are direct or secondary to perturbed U2 snRNP function unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,5,7,8]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[6,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[6,10]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[10,11]}],"complexes":["U2 snRNP"],"partners":["SNRPA1","U2 SNRNA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P08579","full_name":"U2 small nuclear ribonucleoprotein B''","aliases":[],"length_aa":225,"mass_kda":25.5,"function":"Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:28076346, PubMed:28502770, PubMed:28781166, PubMed:32494006). Associated with sn-RNP U2, where it contributes to the binding of stem loop IV of U2 snRNA (PubMed:32494006, PubMed:9716128)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P08579/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNRPB2","classification":"Not Classified","n_dependent_lines":824,"n_total_lines":1208,"dependency_fraction":0.6821192052980133},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000125870","cell_line_id":"CID001456","localizations":[{"compartment":"chromatin","grade":3},{"compartment":"nuclear_punctae","grade":2}],"interactors":[{"gene":"SF3A2","stoichiometry":10.0},{"gene":"SF3A3","stoichiometry":10.0},{"gene":"SF3B1","stoichiometry":10.0},{"gene":"SF3B2","stoichiometry":10.0},{"gene":"SF3B6","stoichiometry":10.0},{"gene":"SNRPA1","stoichiometry":10.0},{"gene":"RBM17","stoichiometry":4.0},{"gene":"SF3A1","stoichiometry":4.0},{"gene":"SF3B3","stoichiometry":4.0},{"gene":"SF3B5","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001456","total_profiled":1310},"omim":[{"mim_id":"604981","title":"WW DOMAIN-CONTAINING BINDING PROTEIN 4; WBP4","url":"https://www.omim.org/entry/604981"},{"mim_id":"603521","title":"SMALL NUCLEAR RIBONUCLEOPROTEIN POLYPEPTIDE A-PRIME; SNRPA1","url":"https://www.omim.org/entry/603521"},{"mim_id":"603520","title":"SMALL NUCLEAR RIBONUCLEOPROTEIN POLYPEPTIDE B-DOUBLE PRIME; SNRPB2","url":"https://www.omim.org/entry/603520"},{"mim_id":"182285","title":"SMALL NUCLEAR RIBONUCLEOPROTEIN POLYPEPTIDE A; SNRPA","url":"https://www.omim.org/entry/182285"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Cytoplasmic bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNRPB2"},"hgnc":{"alias_symbol":["Msl1","U2B''"],"prev_symbol":[]},"alphafold":{"accession":"P08579","domains":[{"cath_id":"3.30.70.330","chopping":"7-88","consensus_level":"high","plddt":94.8315,"start":7,"end":88},{"cath_id":"3.30.70.330","chopping":"151-221","consensus_level":"high","plddt":91.152,"start":151,"end":221}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08579","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08579-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08579-F1-predicted_aligned_error_v6.png","plddt_mean":82.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNRPB2","jax_strain_url":"https://www.jax.org/strain/search?query=SNRPB2"},"sequence":{"accession":"P08579","fasta_url":"https://rest.uniprot.org/uniprotkb/P08579.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08579/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08579"}},"corpus_meta":[{"pmid":"9716128","id":"PMC_9716128","title":"Crystal structure of the spliceosomal U2B\"-U2A' protein complex bound to a fragment of U2 small nuclear RNA.","date":"1998","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9716128","citation_count":313,"is_preprint":false},{"pmid":"2140872","id":"PMC_2140872","title":"Major determinants of the specificity of interaction between small nuclear ribonucleoproteins U1A and U2B'' and their cognate RNAs.","date":"1990","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/2140872","citation_count":262,"is_preprint":false},{"pmid":"2145152","id":"PMC_2145152","title":"The U2B'' RNP motif as a site of protein-protein interaction.","date":"1990","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/2145152","citation_count":91,"is_preprint":false},{"pmid":"12091724","id":"PMC_12091724","title":"Center for Synchrotron Biosciences' U2B beamline: an international resource for biological infrared spectroscopy.","date":"2002","source":"Journal of synchrotron 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affinity and cooperativity control U2B″/snRNA/U2A' RNP formation.","date":"2014","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24866816","citation_count":13,"is_preprint":false},{"pmid":"11816027","id":"PMC_11816027","title":"Involvement of Nst1p/YNL091w and Msl1p, a U2B'' splicing factor, in Saccharomyces cerevisiae salt tolerance.","date":"2002","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/11816027","citation_count":10,"is_preprint":false},{"pmid":"24840944","id":"PMC_24840944","title":"Climbing the vertebrate branch of U1A/U2B″ protein evolution.","date":"2014","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/24840944","citation_count":9,"is_preprint":false},{"pmid":"39329452","id":"PMC_39329452","title":"SNRPB2 promotes triple-negative breast cancer progression by controlling alternative splicing of MDM4 pre-mRNA.","date":"2024","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/39329452","citation_count":5,"is_preprint":false},{"pmid":"39366532","id":"PMC_39366532","title":"SNRPB2 in the pan-cancer landscape: A bioinformatics exploration and validation in hepatocellular carcinoma.","date":"2024","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/39366532","citation_count":4,"is_preprint":false},{"pmid":"40612943","id":"PMC_40612943","title":"SNRPB2 facilitates esophageal squamous cell carcinoma oncogenesis and progression via E2F4 stabilization.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40612943","citation_count":1,"is_preprint":false},{"pmid":"42068395","id":"PMC_42068395","title":"Emerging roles for SNRPB2 in governing the cell cycle and steering tumor immune modulation in breast cancer.","date":"2026","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/42068395","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13479,"output_tokens":3073,"usd":0.043266,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10509,"output_tokens":3599,"usd":0.07126,"stage2_stop_reason":"end_turn"},"total_usd":0.114526,"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\": 1998,\n      \"finding\": \"Crystal structure at 2.4 Å of the ternary U2B\\\"/U2A'/U2 snRNA hairpin-loop IV complex revealed that U2A' leucine-rich repeats contact the RRM domain of U2B\\\" on the surface opposite its RNA-binding face, and the basic C-terminal region of U2A' interacts with the RNA stem; this protein-protein interaction is required for U2B\\\" to bind U2 snRNA specifically.\",\n      \"method\": \"X-ray crystallography at 2.4 Å resolution\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structure with functional validation, replicated across multiple biochemical studies\",\n      \"pmids\": [\"9716128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"U2B'' binds specifically to U2 snRNA only in the presence of the accessory protein U2A'; exchange of two nucleotides between U1 and U2 snRNAs or of eight amino acids between U1A and U2B'' reverses binding specificity, identifying major RNA-binding determinants.\",\n      \"method\": \"In vitro RNA binding assays with recombinant proteins and mutant RNAs/proteins\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis, replicated by multiple independent studies\",\n      \"pmids\": [\"2140872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"U2B'' and U2A' form a stable protein-protein complex in the absence of RNA; the minimal U2B'' fragment (amino acids 1–88) required for specific U2 RNA binding is also the minimal region for U2A' interaction; U2B'' residues 37–46 permit U2 RNA binding when contacted by U2A', while residues 14–25 reduce non-specific U1 RNA binding.\",\n      \"method\": \"In vitro protein-protein and protein-RNA binding assays with deletion/hybrid mutants of U2B''\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with systematic mutagenesis, independently confirmed by structural data\",\n      \"pmids\": [\"2145152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"U2A' forms a weak but detectable interaction with U2 RNA (at the stem of hairpin IV) and a stable complex with U2B''; the U2A'-U2B''-U2 RNA ternary complex is stabilized by this weak U2A'-RNA contact; the region of U2A' essential for U2B'' binding spans amino acids 1–164.\",\n      \"method\": \"RNA-protein binding assays with wild-type and mutant U2A' proteins; mutant U2 RNA binding experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, single lab but multiple orthogonal binding experiments\",\n      \"pmids\": [\"1826350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"U2B'' nuclear import can occur via two mechanisms: (1) an internal NLS (amino acids 90–146) related to U1A's NLS, and (2) a 'piggy-back' mechanism whereby interaction with U2A' mediates nuclear transport through sequences in the N-terminal RNP motif of U2B''; U2A' nuclear transport occurs independently of both U2B'' binding and U2 snRNA.\",\n      \"method\": \"Nuclear import assays in Xenopus oocytes and mammalian cells with deletion mutants and microinjection\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct nuclear localization experiments with deletion mutants showing functional consequence, single lab\",\n      \"pmids\": [\"7983149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"U2A' enables U2B'' to discriminate the loop sequence of U2 snRNA hairpin IV from U1 snRNA hairpin II but plays no role in stem sequence discrimination; a single leucine residue in U1A (Leu-44) accounts for much of the intrinsic RNA-binding specificity difference between U1A and U2B''; U2A' binds U2B'' with ~500-fold greater affinity than U1A.\",\n      \"method\": \"In vitro RNA-binding assays with purified recombinant proteins, site-directed mutagenesis\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, quantitative binding assays, single lab with multiple orthogonal experiments\",\n      \"pmids\": [\"9814759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"In yeast, the U2B'' counterpart Yib9p (Msl1p) requires the U2A' counterpart Lea1p for association with U2 snRNA in vivo, even though Yib9p can bind U2 snRNA stem-loop IV in vitro alone; deletion of LEA1 and/or YIB9 impairs pre-mRNA splicing and blocks spliceosome assembly prior to U2 snRNP addition.\",\n      \"method\": \"Yeast genetics (deletion strains), in vitro splicing/spliceosome assembly assays, recombinant protein rescue\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis combined with in vitro spliceosome assembly rescue, yeast ortholog study\",\n      \"pmids\": [\"9799242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"U2A' binds U2B'' with nanomolar affinity but binds U1A with only micromolar affinity; RNA-dependent cooperativity (thermodynamic linkage) between protein-protein and protein-RNA interactions ensures partitioning of the U2A'/U2B'' complex exclusively to the U2 snRNP.\",\n      \"method\": \"Fluorescence binding assays and isothermal titration calorimetry (ITC) with purified recombinant proteins\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative in vitro reconstitution with two orthogonal biophysical methods (fluorescence + ITC), single lab\",\n      \"pmids\": [\"24866816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human U2B'' binds not only U2 snRNA stem-loop IV but also U1 snRNA stem-loop II and Drosophila U2 snRNA SLIV in vitro with similar thermodynamics, indicating a relaxed RNA-binding specificity compared to U1A.\",\n      \"method\": \"In vitro RNA-protein binding assays and thermodynamic measurements\",\n      \"journal\": \"Biophysical chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — quantitative in vitro binding, single lab, single method type\",\n      \"pmids\": [\"21684671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In C. elegans, RNP-3 (U2B'') is U2 snRNP-associated and binds U2 snRNA even in the absence of U2A'; knockout of both rnp-2 (U1A) and rnp-3 (U2B'') is required for lethality, demonstrating functional redundancy; U1A can associate with U2 RNA when U2B'' is deleted.\",\n      \"method\": \"Co-immunoprecipitation, genetic knockouts, RNA co-precipitation in C. elegans\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and double knockout genetics in C. elegans with defined phenotypic readout\",\n      \"pmids\": [\"17535930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNRPB2 knockdown in TNBC cells causes skipping of exon 6 in MDM4 pre-mRNA generating the MDM4-S transcript, reducing MDM4 protein levels, which decreases Rb1 protein expression and inactivates E2F1 signaling, suppressing cell proliferation and invasion.\",\n      \"method\": \"siRNA knockdown, transcriptome/alternative splicing analysis, Western blot, cell proliferation and invasion assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined molecular pathway (splicing → MDM4 → Rb1 → E2F1) validated by multiple assays, single lab\",\n      \"pmids\": [\"39329452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNRPB2 stabilizes E2F4 protein by preventing its proteasomal degradation; SNRPB2 knockdown in esophageal squamous cell carcinoma cells reduces E2F4 levels and suppresses proliferation, migration, and invasion, which is rescued by E2F4 overexpression.\",\n      \"method\": \"siRNA knockdown, cycloheximide chase assay, rescue overexpression, in vitro and in vivo functional assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CHX chase assay demonstrating protein stability mechanism with rescue experiment, single lab\",\n      \"pmids\": [\"40612943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SNRPB2 knockdown in breast cancer cells induces G2/M cell cycle arrest and alters alternative splicing events including HMGA2 splicing; proposed mechanism is that SNRPB2 regulates cell cycle progression partly through HMGA2 splicing modulation.\",\n      \"method\": \"siRNA knockdown, RNA-seq, RT-qPCR, cell cycle analysis\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD phenotype with splicing readout but HMGA2 mechanism not directly validated\",\n      \"pmids\": [\"42068395\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNRPB2 (U2B'') is an RRM-domain protein that associates with stem-loop IV of U2 snRNA as part of the U2 snRNP; its specific RNA binding requires cooperative interaction with U2A', whose leucine-rich repeat domain contacts the opposite face of U2B'''s RRM while U2A'''s basic C-terminus contacts the RNA stem—a mechanism revealed by X-ray crystallography—and nanomolar U2A'/U2B'' affinity combined with RNA-dependent cooperativity ensures exclusive partitioning to the U2 snRNP; in mammalian cancer cells SNRPB2 additionally regulates alternative splicing of pre-mRNAs (e.g., MDM4) to control cell cycle progression and can stabilize cell cycle transcription factors (E2F4) against proteasomal degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNRPB2 (U2B'') is an RRM-domain protein that functions as a sequence-specific RNA-binding component of the U2 snRNP, where its association with U2 snRNA stem-loop IV is the molecular basis for incorporating this protein into the spliceosomal U2 particle [#0, #1]. On its own U2B'' binds RNA only weakly and non-specifically; specific recognition of U2 snRNA requires the accessory protein U2A', whose leucine-rich repeats contact the face of the U2B'' RRM opposite the RNA-binding surface while its basic C-terminus contacts the RNA stem, an arrangement resolved by crystallography that explains why protein-protein interaction is a prerequisite for specific RNA binding [#0, #2, #3]. U2A' binds U2B'' with nanomolar affinity, far tighter than its interaction with the paralogous U1A protein, and RNA-dependent cooperativity (thermodynamic linkage between the protein-protein and protein-RNA contacts) ensures the U2A'/U2B'' complex partitions exclusively to the U2 snRNP rather than to U1 [#5, #7]. The functional importance of this interaction is conserved: in yeast the U2B''/U2A' counterparts Yib9p/Lea1p are required for U2 snRNP association with snRNA in vivo, and their loss blocks spliceosome assembly prior to U2 addition and impairs pre-mRNA splicing [#6]. In mammalian cancer cells SNRPB2 additionally shapes alternative splicing of specific pre-mRNAs to control proliferation: its depletion drives skipping of MDM4 exon 6 to generate MDM4-S, lowering MDM4 and Rb1 and inactivating E2F1 signaling [#10], and it stabilizes the transcription factor E2F4 against proteasomal degradation, with E2F4 re-expression rescuing the proliferative defect [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established the central rule of U2B'' biology: that it cannot recognize U2 snRNA on its own but requires the accessory protein U2A', and pinpointed the RNA and protein determinants of binding specificity.\",\n      \"evidence\": \"in vitro RNA binding assays with recombinant proteins and reciprocal nucleotide/amino-acid swaps between the U1 and U2 systems\",\n      \"pmids\": [\"2140872\", \"2145152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic geometry of the U2B''/U2A'/RNA contacts not yet resolved\", \"In vivo requirement in a cellular splicing context not addressed\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Showed the ternary complex is stabilized by a direct, if weak, U2A'-RNA contact at the hairpin IV stem, refining the model from a purely protein-bridged one to a tripartite assembly.\",\n      \"evidence\": \"RNA-protein binding assays with wild-type and mutant U2A' and mutant U2 RNA\",\n      \"pmids\": [\"1826350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative affinities of each pairwise contact not measured\", \"Structural basis still inferred rather than observed\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Addressed how U2B'' reaches its site of action, showing it can enter the nucleus via its own internal NLS or by piggy-backing on U2A'.\",\n      \"evidence\": \"nuclear import assays in Xenopus oocytes and mammalian cells using deletion mutants and microinjection\",\n      \"pmids\": [\"7983149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each import route in normal cells unknown\", \"Import receptors mediating either pathway not identified\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Resolved the ternary complex at atomic resolution and dissected the chemical origin of U2 versus U1 specificity, converting the genetic/biochemical model into a structural mechanism.\",\n      \"evidence\": \"2.4 Å X-ray crystal structure of the U2B''/U2A'/U2 hairpin IV complex plus in vitro binding with single-residue mutants\",\n      \"pmids\": [\"9716128\", \"9814759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics and kinetics of complex assembly not captured by a static structure\", \"Did not quantify the thermodynamic linkage driving snRNP partitioning\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated the in vivo functional consequence of the interaction in a whole organism, showing the accessory protein is needed for U2 snRNP assembly and splicing.\",\n      \"evidence\": \"yeast deletion genetics of LEA1/YIB9 with in vitro spliceosome assembly and recombinant rescue\",\n      \"pmids\": [\"9799242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Discrepancy between in vitro RNA binding by Yib9p alone and in vivo dependence on Lea1p not fully reconciled\", \"Direct extension to human cells not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed evolutionary flexibility in the partnership, showing functional redundancy between U1A and U2B'' orthologs and U2A'-independent U2 binding in nematodes.\",\n      \"evidence\": \"reciprocal co-IP, RNA co-precipitation and double knockouts in C. elegans\",\n      \"pmids\": [\"17535930\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the human protein shares this redundancy not established\", \"Molecular basis of U2A'-independent binding in worm not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided the thermodynamic explanation for exclusive U2 snRNP targeting, showing RNA-dependent cooperativity and nanomolar U2A'/U2B'' affinity bias the complex away from U1.\",\n      \"evidence\": \"fluorescence binding and isothermal titration calorimetry with purified recombinant proteins\",\n      \"pmids\": [\"24866816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cooperativity demonstrated in vitro; partitioning not measured in living cells\", \"Role of additional snRNP factors in vivo unaddressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Characterized the intrinsic RNA-binding promiscuity of human U2B'', which binds U1 and Drosophila U2 hairpins with similar thermodynamics, underscoring why U2A' is needed for fidelity.\",\n      \"evidence\": \"in vitro RNA-protein binding and thermodynamic measurements\",\n      \"pmids\": [\"21684671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method type, single lab\", \"Cellular relevance of relaxed specificity not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended SNRPB2 beyond core snRNP assembly to a regulator of specific alternative splicing events controlling proliferation, defining an MDM4-Rb1-E2F1 axis in cancer cells.\",\n      \"evidence\": \"siRNA knockdown, splicing/transcriptome analysis, Western blot and proliferation/invasion assays in TNBC cells\",\n      \"pmids\": [\"39329452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of SNRPB2 to MDM4 pre-mRNA not shown\", \"Specificity for MDM4 versus global U2 snRNP function not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a non-splicing role in which SNRPB2 stabilizes the transcription factor E2F4 against proteasomal turnover, broadening its proliferative function.\",\n      \"evidence\": \"siRNA knockdown, cycloheximide chase, E2F4 rescue and in vitro/in vivo functional assays in esophageal squamous cell carcinoma\",\n      \"pmids\": [\"40612943\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SNRPB2 acts directly on E2F4 or via an intermediate not resolved\", \"Connection to its RNA-binding/splicing activity unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked SNRPB2 depletion to G2/M arrest and altered HMGA2 splicing, proposing an additional splicing-dependent route to cell cycle control.\",\n      \"evidence\": \"siRNA knockdown, RNA-seq, RT-qPCR and cell cycle analysis in breast cancer cells\",\n      \"pmids\": [\"42068395\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"HMGA2 mechanism not directly validated\", \"Causality between HMGA2 splicing and G2/M arrest not established\", \"Single lab, descriptive readout\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SNRPB2's core U2 snRNP function mechanistically connects to its reported gene-specific splicing and protein-stabilization activities in cancer cells remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct in vivo CLIP/binding map of SNRPB2 target transcripts\", \"Mechanism linking a core snRNP subunit to E2F4 protein stability undefined\", \"Whether splicing changes are direct or secondary to perturbed U2 snRNP function unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 5, 7, 8]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [6, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"complexes\": [\"U2 snRNP\"],\n    \"partners\": [\"SNRPA1\", \"U2 snRNA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}