{"gene":"SNRPG","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2020,"finding":"SNRPG knockdown via shRNA in glioblastoma cells caused cell cycle arrest and reduced Myc protein levels; the effect of SNRPG loss on p53 levels and cell cycle progression was Myc-dependent, placing SNRPG upstream of Myc in a p53-dependent signaling pathway. SNRPG was also elevated in TMZ-resistant GBM cells, and its downregulation sensitized resistant cells to temozolomide via the p53 signaling pathway.","method":"shRNA knockdown, gene expression profiling, Western blot, xenograft tumor model","journal":"Cancer biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype, Western blot pathway validation, and in vivo xenograft; single lab, multiple orthogonal methods","pmids":["32296580"],"is_preprint":false},{"year":2022,"finding":"SNRPG binds directly to the RING finger domain of RBBP6 with a strong binding affinity (KD ~3.16 nM), as measured by microscale thermophoresis (MST), confirming a physical protein-protein interaction between these two spliceosome-associated oncoproteins.","method":"Microscale thermophoresis (MST)-based binding assay with purified proteins","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vitro binding assay with quantified KD; single lab, single method","pmids":["34956492"],"is_preprint":false},{"year":2022,"finding":"SNRPG binds directly to HSP70.14 (heat shock protein 70.14) with a binding affinity of KD ~247 nM, as measured by microscale thermophoresis, revealing a physical interaction between SNRPG and a protein quality control chaperone in cancer cell networks.","method":"Microscale thermophoresis (MST)-based binding assay","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single in vitro binding assay, single lab, no functional validation of interaction consequence","pmids":["36247303"],"is_preprint":false},{"year":2025,"finding":"5-HT inhibits SNRPG expression in NSCLC cells; SNRPG in turn directly binds to WT1 protein and negatively regulates its protein levels, preventing WT1 from binding the CDK14 promoter. Loss of SNRPG leads to WT1 accumulation, CDK14 transcriptional activation, and promotion of EMT and metastasis. This defines a 5-HT/SNRPG/WT1/CDK14 signaling axis.","method":"RNA-seq, functional migration/invasion assays, RNA-seq for downstream target identification, direct binding assay (SNRPG–WT1 interaction), promoter binding assay","journal":"Molecular biomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RNA-seq, functional assays, direct binding, promoter assay) in a single study; single lab","pmids":["41016985"],"is_preprint":false},{"year":2026,"finding":"Co-immunoprecipitation followed by mass spectrometry (IP-MS) and co-IP in germ cells showed that SNRPG physically interacts with PCID2, hnRNPH1, and SF3B1 to modulate alternative splicing during spermatogenesis, placing SNRPG in a PCID2-containing splicing complex essential for spermatogonial differentiation.","method":"Co-immunoprecipitation (Co-IP), IP-MS, RNA sequencing, PCR validation of splicing targets","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with MS confirmation and functional splicing readout; single lab, multiple orthogonal methods","pmids":["41526677"],"is_preprint":false},{"year":1997,"finding":"Antisense RNA-mediated suppression of CaSm (an Sm-like protein with ~60% similarity to Sm-G/SNRPG) reduced the ability of pancreatic cancer cells to form colonies in soft agar, establishing that CaSm expression is required for maintenance of the transformed state. Note: CaSm is a distinct Sm-like protein, not SNRPG itself, but this paper identifies SNRPG as the closest human paralog for context.","method":"Antisense RNA transfection, soft-agar colony formation assay","journal":"Cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — this describes CaSm (a related but distinct Sm-like protein, not canonical SNRPG); single method, indirect relevance to SNRPG function","pmids":["9230209"],"is_preprint":false}],"current_model":"SNRPG (SmG) is an Sm-domain protein that is an obligate component of spliceosomal U snRNP particles and physically interacts with partners including the RING finger domain of RBBP6 (KD ~3 nM), HSP70.14, and—within a PCID2-containing complex—hnRNPH1 and SF3B1 to regulate alternative splicing; in glioblastoma cells SNRPG acts upstream of Myc in a p53-dependent pathway controlling cell cycle progression and chemoresistance, while in NSCLC cells it directly binds and destabilizes the transcription factor WT1, thereby suppressing CDK14 transcription and restraining epithelial-mesenchymal transition and metastasis downstream of 5-HT signaling."},"narrative":{"mechanistic_narrative":"SNRPG (SmG) is an Sm-domain spliceosome-associated protein that participates in alternative splicing regulation and has been repeatedly implicated as a driver of cancer cell proliferation and metastasis [PMID:32296580, PMID:41526677]. In germ cells, SNRPG physically associates with PCID2, hnRNPH1, and SF3B1 within a PCID2-containing splicing complex that modulates alternative splicing during spermatogonial differentiation [PMID:41526677]. Beyond its splicing-complex role, SNRPG operates in oncogenic signaling through two distinct routes: in glioblastoma it acts upstream of Myc in a p53-dependent pathway, where its loss arrests the cell cycle, lowers Myc protein, and sensitizes temozolomide-resistant cells to chemotherapy [PMID:32296580]; in NSCLC it directly binds the transcription factor WT1 and destabilizes it, preventing WT1 from activating CDK14 transcription and thereby restraining epithelial-mesenchymal transition and metastasis downstream of 5-HT signaling [PMID:41016985]. SNRPG also engages in direct, high-affinity physical interaction with the RING finger domain of RBBP6 (KD ~3 nM) [PMID:34956492]. A unifying biochemical mechanism connecting its splicing function to its transcription-factor-destabilizing activity has not been characterized in the available corpus.","teleology":[{"year":2020,"claim":"Established that SNRPG is not merely a constitutive splicing factor but a node controlling proliferation and chemoresistance, placing it upstream of Myc in a p53-dependent pathway.","evidence":"shRNA knockdown with expression profiling, Western blot pathway validation, and xenograft in glioblastoma cells","pmids":["32296580"],"confidence":"Medium","gaps":["Mechanism by which SNRPG controls Myc/p53 levels is not defined","Whether the effect requires SNRPG's splicing function is untested","Single lab, single tumor type"]},{"year":2022,"claim":"Quantified a direct, high-affinity physical interaction between SNRPG and the RBBP6 RING finger domain, linking SNRPG to a specific binding partner in vitro.","evidence":"Microscale thermophoresis with purified proteins","pmids":["34956492"],"confidence":"Medium","gaps":["Functional consequence of the SNRPG-RBBP6 interaction not established","Interaction shown in vitro only, not validated in cells","No structural detail of the interface"]},{"year":2022,"claim":"Detected a direct binding of SNRPG to the HSP70.14 chaperone, hinting at a protein quality-control connection within cancer cell networks.","evidence":"Microscale thermophoresis binding assay","pmids":["36247303"],"confidence":"Low","gaps":["Single in vitro binding assay with no functional validation","Cellular relevance of the interaction unknown","Not independently confirmed"]},{"year":2025,"claim":"Defined a 5-HT/SNRPG/WT1/CDK14 axis, revealing that SNRPG acts as a metastasis suppressor in NSCLC by directly binding and destabilizing the WT1 transcription factor.","evidence":"RNA-seq, migration/invasion assays, direct SNRPG-WT1 binding assay, and CDK14 promoter binding assay in NSCLC cells","pmids":["41016985"],"confidence":"Medium","gaps":["Molecular basis of WT1 destabilization (e.g. degradation route) not defined","Reconciliation with the proliferation-promoting role in glioblastoma unresolved","Single lab"]},{"year":2026,"claim":"Placed SNRPG in a defined PCID2-containing splicing complex required for spermatogonial differentiation, connecting its canonical Sm/splicing identity to a tissue-specific developmental function.","evidence":"Reciprocal Co-IP, IP-MS, RNA-seq, and PCR validation of splicing targets in germ cells","pmids":["41526677"],"confidence":"Medium","gaps":["Direct vs indirect nature of each interaction within the complex not dissected","Specific splicing events driving differentiation only partially mapped","Single lab"]},{"year":null,"claim":"It remains unknown how SNRPG's role as a core splicing-complex component mechanistically relates to its context-dependent regulation of transcription factors (Myc, WT1) and its opposing pro- versus anti-tumor effects across cancer types.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying biochemical mechanism linking splicing function to transcription-factor destabilization","No structural model of SNRPG within its reported complexes","Tissue-specific opposing roles not reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4]}],"complexes":["PCID2-containing splicing complex"],"partners":["RBBP6","HSPA14","WT1","PCID2","HNRNPH1","SF3B1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P62308","full_name":"Small nuclear ribonucleoprotein G","aliases":["Sm protein G","Sm-G","SmG"],"length_aa":76,"mass_kda":8.5,"function":"Plays a role in pre-mRNA splicing as a core component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome (PubMed:11991638, PubMed:18984161, PubMed:19325628, PubMed:23333303, PubMed:25555158, PubMed:26912367, PubMed:28076346, PubMed:28502770, PubMed:28781166, PubMed:32494006). Component of both the pre-catalytic spliceosome B complex and activated spliceosome C complexes (PubMed:11991638, PubMed:28076346, PubMed:28502770, PubMed:28781166). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (PubMed:15146077). As part of the U7 snRNP it is involved in histone 3'-end processing (PubMed:12975319)","subcellular_location":"Cytoplasm, cytosol; Nucleus","url":"https://www.uniprot.org/uniprotkb/P62308/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SNRPG","classification":"Common Essential","n_dependent_lines":1090,"n_total_lines":1090,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SNRPG","total_profiled":1310},"omim":[{"mim_id":"607795","title":"PRE-mRNA-PROCESSING FACTOR 4; PRPF4","url":"https://www.omim.org/entry/607795"},{"mim_id":"603542","title":"SMALL NUCLEAR RIBONUCLEOPROTEIN POLYPEPTIDE G; SNRPG","url":"https://www.omim.org/entry/603542"},{"mim_id":"603541","title":"SMALL NUCLEAR RIBONUCLEOPROTEIN POLYPEPTIDE F; SNRPF","url":"https://www.omim.org/entry/603541"},{"mim_id":"180740","title":"SMALL NUCLEAR RIBONUCLEOPROTEIN, U1 SUBUNIT, 70-KD; SNRNP70","url":"https://www.omim.org/entry/180740"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNRPG"},"hgnc":{"alias_symbol":["Sm-G"],"prev_symbol":[]},"alphafold":{"accession":"P62308","domains":[{"cath_id":"2.30.30.100","chopping":"9-71","consensus_level":"high","plddt":96.4975,"start":9,"end":71}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62308","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62308-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62308-F1-predicted_aligned_error_v6.png","plddt_mean":93.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNRPG","jax_strain_url":"https://www.jax.org/strain/search?query=SNRPG"},"sequence":{"accession":"P62308","fasta_url":"https://rest.uniprot.org/uniprotkb/P62308.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62308/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62308"}},"corpus_meta":[{"pmid":"32308643","id":"PMC_32308643","title":"The Predicted Key Molecules, Functions, and Pathways That Bridge Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD).","date":"2020","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/32308643","citation_count":66,"is_preprint":false},{"pmid":"36405716","id":"PMC_36405716","title":"Identification of diagnostic genes for both Alzheimer's disease and Metabolic syndrome by the machine learning algorithm.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36405716","citation_count":62,"is_preprint":false},{"pmid":"34422815","id":"PMC_34422815","title":"m6A Modification Mediates Mucosal Immune Microenvironment and Therapeutic Response in Inflammatory Bowel Disease.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34422815","citation_count":38,"is_preprint":false},{"pmid":"32296580","id":"PMC_32296580","title":"Downregulation of SNRPG induces cell cycle arrest and sensitizes human glioblastoma cells to temozolomide by targeting Myc through a p53-dependent signaling pathway.","date":"2020","source":"Cancer biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32296580","citation_count":37,"is_preprint":false},{"pmid":"9230209","id":"PMC_9230209","title":"CaSm: an Sm-like protein that contributes to the transformed state in cancer cells.","date":"1997","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/9230209","citation_count":37,"is_preprint":false},{"pmid":"34461609","id":"PMC_34461609","title":"N6-methyladenosine (m6A) modification and its clinical relevance in cognitive dysfunctions.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/34461609","citation_count":36,"is_preprint":false},{"pmid":"38545822","id":"PMC_38545822","title":"Identification and validation of extracellular vesicle reference genes for the normalization of RT-qPCR data.","date":"2024","source":"Journal of extracellular vesicles","url":"https://pubmed.ncbi.nlm.nih.gov/38545822","citation_count":32,"is_preprint":false},{"pmid":"34225819","id":"PMC_34225819","title":"Identification of potential biomarkers for pathogenesis of Alzheimer's disease.","date":"2021","source":"Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/34225819","citation_count":25,"is_preprint":false},{"pmid":"31814883","id":"PMC_31814883","title":"The oncogenic potential of small nuclear ribonucleoprotein polypeptide G: a comprehensive and perspective view.","date":"2019","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/31814883","citation_count":20,"is_preprint":false},{"pmid":"35016150","id":"PMC_35016150","title":"Identification of potential blood biomarkers for early diagnosis of schizophrenia through RNA sequencing analysis.","date":"2022","source":"Journal of psychiatric research","url":"https://pubmed.ncbi.nlm.nih.gov/35016150","citation_count":13,"is_preprint":false},{"pmid":"39994525","id":"PMC_39994525","title":"Single-cell RNA transcriptome uncovers distinct developmental trajectories in the embryonic skeletal muscle of Daheng broiler and Tibetan chicken.","date":"2025","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/39994525","citation_count":13,"is_preprint":false},{"pmid":"32983981","id":"PMC_32983981","title":"Clinical Significance, Cellular Function, and Potential Molecular Pathways of CCT7 in Endometrial Cancer.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32983981","citation_count":11,"is_preprint":false},{"pmid":"33970702","id":"PMC_33970702","title":"Identification of COL6A1 as the Key Gene Associated with Antivascular Endothelial Growth Factor Therapy in Glioblastoma Multiforme.","date":"2021","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/33970702","citation_count":11,"is_preprint":false},{"pmid":"38094862","id":"PMC_38094862","title":"Dye Degradation, Antimicrobial Activity, and Molecular Docking Analysis of Samarium-Grafted Carbon Nitride Doped-Bismuth Oxobromide Quantum Dots.","date":"2023","source":"Global challenges (Hoboken, NJ)","url":"https://pubmed.ncbi.nlm.nih.gov/38094862","citation_count":7,"is_preprint":false},{"pmid":"37752077","id":"PMC_37752077","title":"A MACHINE LEARNING MODEL DERIVED FROM ANALYSIS OF TIME-COURSE GENE-EXPRESSION DATASETS REVEALS TEMPORALLY STABLE GENE MARKERS PREDICTIVE OF SEPSIS MORTALITY.","date":"2023","source":"Shock (Augusta, Ga.)","url":"https://pubmed.ncbi.nlm.nih.gov/37752077","citation_count":7,"is_preprint":false},{"pmid":"35711689","id":"PMC_35711689","title":"The Underlying Molecular Basis and Mechanisms of Venous Thrombosis in Patients with Osteomyelitis: A Data-Driven Analysis.","date":"2022","source":"Genetics research","url":"https://pubmed.ncbi.nlm.nih.gov/35711689","citation_count":6,"is_preprint":false},{"pmid":"35925494","id":"PMC_35925494","title":"An NADPH-auxotrophic Corynebacterium glutamicum recombinant strain and used it to construct L-leucine high-yielding strain.","date":"2022","source":"International microbiology : the official journal of the Spanish Society for Microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/35925494","citation_count":6,"is_preprint":false},{"pmid":"33721662","id":"PMC_33721662","title":"Fluctuation analysis to select for Samarium bio-uptaking microalgae clones the repurposing of a classical evolution experiment.","date":"2021","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/33721662","citation_count":3,"is_preprint":false},{"pmid":"36247303","id":"PMC_36247303","title":"Molecular interaction between small nuclear ribonucleoprotein polypeptide G and heat shock protein 70.14: a microscale thermophoresis exposition towards developing anti-cancer drugs.","date":"2022","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/36247303","citation_count":2,"is_preprint":false},{"pmid":"40884870","id":"PMC_40884870","title":"Construction and differential analysis of testicular atlas between 10-week-old and 23-week-old ducks using single-cell RNA sequencing.","date":"2025","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/40884870","citation_count":2,"is_preprint":false},{"pmid":"34956492","id":"PMC_34956492","title":"Microscale thermophoresis analysis of the molecular interaction between small nuclear ribonucleoprotein polypeptide G and the RING finger domain of RBBP6 towards anti-cancer drug discovery.","date":"2021","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/34956492","citation_count":2,"is_preprint":false},{"pmid":"39375436","id":"PMC_39375436","title":"In-silico identification of therapeutic targets in pancreatic ductal adenocarcinoma using WGCNA and Trader.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39375436","citation_count":2,"is_preprint":false},{"pmid":"27816419","id":"PMC_27816419","title":"Ectopic Gastric and Intestinal Phenotypes, Neuroendocrine Cell Differentiation, and SOX2 Expression Correlated With Early Tumor Progression in Colorectal Laterally Spreading Tumors.","date":"2016","source":"Clinical colorectal cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27816419","citation_count":2,"is_preprint":false},{"pmid":"41016985","id":"PMC_41016985","title":"5-Hydroxytryptamine promotes non-small cell lung cancer metastasis via the SNRPG/WT1/CDK14 Axis.","date":"2025","source":"Molecular biomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/41016985","citation_count":1,"is_preprint":false},{"pmid":"39452046","id":"PMC_39452046","title":"From Diabetes to Dementia: Identifying Key Genes in the Progression of Cognitive Impairment.","date":"2024","source":"Brain sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39452046","citation_count":1,"is_preprint":false},{"pmid":"38708342","id":"PMC_38708342","title":"Phosphoproteomics analysis of serum from dogs affected with pulmonary hypertension secondary to degenerative mitral valve disease.","date":"2024","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/38708342","citation_count":1,"is_preprint":false},{"pmid":"40867231","id":"PMC_40867231","title":"A Validated Proteomic Signature of Basal-like Triple-Negative Breast Cancer Subtypes Obtained from Publicly Available Data.","date":"2025","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/40867231","citation_count":1,"is_preprint":false},{"pmid":"37779977","id":"PMC_37779977","title":"Efficient Samarium-Grafted-C3N4-Doped α-MoO3 Used as a Dye Degrader and Antibacterial Agent: In Silico Molecular Docking Study.","date":"2023","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/37779977","citation_count":1,"is_preprint":false},{"pmid":"40895471","id":"PMC_40895471","title":"Enhancement of direct interspecies electron transfer and methane production by co-culture of dual Methanosarcina species and Geobacter metallireducens.","date":"2025","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/40895471","citation_count":1,"is_preprint":false},{"pmid":"32017444","id":"PMC_32017444","title":"Variation in mouse pelvic morphology maps to locations enriched in Sox9 Class II and Pitx1 regulatory features.","date":"2020","source":"Journal of experimental zoology. Part B, Molecular and developmental evolution","url":"https://pubmed.ncbi.nlm.nih.gov/32017444","citation_count":1,"is_preprint":false},{"pmid":"41526677","id":"PMC_41526677","title":"PCID2 is essential for spermatogonial differentiation by regulating alternative splicing.","date":"2026","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/41526677","citation_count":0,"is_preprint":false},{"pmid":"39636551","id":"PMC_39636551","title":"Single-cell RNA-seq reveals diverse molecular signatures associated with Methotrexate resistance in primary central nervous system lymphoma cells.","date":"2024","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39636551","citation_count":0,"is_preprint":false},{"pmid":"42190478","id":"PMC_42190478","title":"Comparison of Sertoli cells in duck testes pre- and post-sexual maturation.","date":"2026","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/42190478","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19665,"output_tokens":1625,"usd":0.041685,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8353,"output_tokens":2033,"usd":0.046295,"stage2_stop_reason":"end_turn"},"total_usd":0.08798,"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\": 2020,\n      \"finding\": \"SNRPG knockdown via shRNA in glioblastoma cells caused cell cycle arrest and reduced Myc protein levels; the effect of SNRPG loss on p53 levels and cell cycle progression was Myc-dependent, placing SNRPG upstream of Myc in a p53-dependent signaling pathway. SNRPG was also elevated in TMZ-resistant GBM cells, and its downregulation sensitized resistant cells to temozolomide via the p53 signaling pathway.\",\n      \"method\": \"shRNA knockdown, gene expression profiling, Western blot, xenograft tumor model\",\n      \"journal\": \"Cancer biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype, Western blot pathway validation, and in vivo xenograft; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32296580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SNRPG binds directly to the RING finger domain of RBBP6 with a strong binding affinity (KD ~3.16 nM), as measured by microscale thermophoresis (MST), confirming a physical protein-protein interaction between these two spliceosome-associated oncoproteins.\",\n      \"method\": \"Microscale thermophoresis (MST)-based binding assay with purified proteins\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vitro binding assay with quantified KD; single lab, single method\",\n      \"pmids\": [\"34956492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SNRPG binds directly to HSP70.14 (heat shock protein 70.14) with a binding affinity of KD ~247 nM, as measured by microscale thermophoresis, revealing a physical interaction between SNRPG and a protein quality control chaperone in cancer cell networks.\",\n      \"method\": \"Microscale thermophoresis (MST)-based binding assay\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vitro binding assay, single lab, no functional validation of interaction consequence\",\n      \"pmids\": [\"36247303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"5-HT inhibits SNRPG expression in NSCLC cells; SNRPG in turn directly binds to WT1 protein and negatively regulates its protein levels, preventing WT1 from binding the CDK14 promoter. Loss of SNRPG leads to WT1 accumulation, CDK14 transcriptional activation, and promotion of EMT and metastasis. This defines a 5-HT/SNRPG/WT1/CDK14 signaling axis.\",\n      \"method\": \"RNA-seq, functional migration/invasion assays, RNA-seq for downstream target identification, direct binding assay (SNRPG–WT1 interaction), promoter binding assay\",\n      \"journal\": \"Molecular biomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RNA-seq, functional assays, direct binding, promoter assay) in a single study; single lab\",\n      \"pmids\": [\"41016985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Co-immunoprecipitation followed by mass spectrometry (IP-MS) and co-IP in germ cells showed that SNRPG physically interacts with PCID2, hnRNPH1, and SF3B1 to modulate alternative splicing during spermatogenesis, placing SNRPG in a PCID2-containing splicing complex essential for spermatogonial differentiation.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), IP-MS, RNA sequencing, PCR validation of splicing targets\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with MS confirmation and functional splicing readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41526677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Antisense RNA-mediated suppression of CaSm (an Sm-like protein with ~60% similarity to Sm-G/SNRPG) reduced the ability of pancreatic cancer cells to form colonies in soft agar, establishing that CaSm expression is required for maintenance of the transformed state. Note: CaSm is a distinct Sm-like protein, not SNRPG itself, but this paper identifies SNRPG as the closest human paralog for context.\",\n      \"method\": \"Antisense RNA transfection, soft-agar colony formation assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — this describes CaSm (a related but distinct Sm-like protein, not canonical SNRPG); single method, indirect relevance to SNRPG function\",\n      \"pmids\": [\"9230209\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNRPG (SmG) is an Sm-domain protein that is an obligate component of spliceosomal U snRNP particles and physically interacts with partners including the RING finger domain of RBBP6 (KD ~3 nM), HSP70.14, and—within a PCID2-containing complex—hnRNPH1 and SF3B1 to regulate alternative splicing; in glioblastoma cells SNRPG acts upstream of Myc in a p53-dependent pathway controlling cell cycle progression and chemoresistance, while in NSCLC cells it directly binds and destabilizes the transcription factor WT1, thereby suppressing CDK14 transcription and restraining epithelial-mesenchymal transition and metastasis downstream of 5-HT signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNRPG (SmG) is an Sm-domain spliceosome-associated protein that participates in alternative splicing regulation and has been repeatedly implicated as a driver of cancer cell proliferation and metastasis [#0, #4]. In germ cells, SNRPG physically associates with PCID2, hnRNPH1, and SF3B1 within a PCID2-containing splicing complex that modulates alternative splicing during spermatogonial differentiation [#4]. Beyond its splicing-complex role, SNRPG operates in oncogenic signaling through two distinct routes: in glioblastoma it acts upstream of Myc in a p53-dependent pathway, where its loss arrests the cell cycle, lowers Myc protein, and sensitizes temozolomide-resistant cells to chemotherapy [#0]; in NSCLC it directly binds the transcription factor WT1 and destabilizes it, preventing WT1 from activating CDK14 transcription and thereby restraining epithelial-mesenchymal transition and metastasis downstream of 5-HT signaling [#3]. SNRPG also engages in direct, high-affinity physical interaction with the RING finger domain of RBBP6 (KD ~3 nM) [#1]. A unifying biochemical mechanism connecting its splicing function to its transcription-factor-destabilizing activity has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that SNRPG is not merely a constitutive splicing factor but a node controlling proliferation and chemoresistance, placing it upstream of Myc in a p53-dependent pathway.\",\n      \"evidence\": \"shRNA knockdown with expression profiling, Western blot pathway validation, and xenograft in glioblastoma cells\",\n      \"pmids\": [\"32296580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SNRPG controls Myc/p53 levels is not defined\", \"Whether the effect requires SNRPG's splicing function is untested\", \"Single lab, single tumor type\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Quantified a direct, high-affinity physical interaction between SNRPG and the RBBP6 RING finger domain, linking SNRPG to a specific binding partner in vitro.\",\n      \"evidence\": \"Microscale thermophoresis with purified proteins\",\n      \"pmids\": [\"34956492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the SNRPG-RBBP6 interaction not established\", \"Interaction shown in vitro only, not validated in cells\", \"No structural detail of the interface\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Detected a direct binding of SNRPG to the HSP70.14 chaperone, hinting at a protein quality-control connection within cancer cell networks.\",\n      \"evidence\": \"Microscale thermophoresis binding assay\",\n      \"pmids\": [\"36247303\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single in vitro binding assay with no functional validation\", \"Cellular relevance of the interaction unknown\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a 5-HT/SNRPG/WT1/CDK14 axis, revealing that SNRPG acts as a metastasis suppressor in NSCLC by directly binding and destabilizing the WT1 transcription factor.\",\n      \"evidence\": \"RNA-seq, migration/invasion assays, direct SNRPG-WT1 binding assay, and CDK14 promoter binding assay in NSCLC cells\",\n      \"pmids\": [\"41016985\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of WT1 destabilization (e.g. degradation route) not defined\", \"Reconciliation with the proliferation-promoting role in glioblastoma unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed SNRPG in a defined PCID2-containing splicing complex required for spermatogonial differentiation, connecting its canonical Sm/splicing identity to a tissue-specific developmental function.\",\n      \"evidence\": \"Reciprocal Co-IP, IP-MS, RNA-seq, and PCR validation of splicing targets in germ cells\",\n      \"pmids\": [\"41526677\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect nature of each interaction within the complex not dissected\", \"Specific splicing events driving differentiation only partially mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how SNRPG's role as a core splicing-complex component mechanistically relates to its context-dependent regulation of transcription factors (Myc, WT1) and its opposing pro- versus anti-tumor effects across cancer types.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying biochemical mechanism linking splicing function to transcription-factor destabilization\", \"No structural model of SNRPG within its reported complexes\", \"Tissue-specific opposing roles not reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"PCID2-containing splicing complex\"],\n    \"partners\": [\"RBBP6\", \"HSPA14\", \"WT1\", \"PCID2\", \"HNRNPH1\", \"SF3B1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}