{"gene":"SNRPD2","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2021,"finding":"Depletion of SNRPD2 (along with SNRPD3 and NHP2L1) inhibits proliferation of triple-negative breast cancer (TNBC) cells by deregulating sister chromatid cohesion (SCC) via increased sororin intron 1 retention and downregulation of SMC1, MAU2, and ESPL1. Protein-protein interaction analysis identified SNRPD2, SNRPD3, and NHP2L1 as belonging to the same spliceosome complex, which also includes novel component SUN2, critical for efficient sororin splicing.","method":"RNAi screen, western blot, PCR (intron retention), FACS, molecular imaging, pulldown + mass spectrometry for protein-protein interactions","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pulldown/MS for interactions, RNAi with defined molecular phenotype (intron retention, SCC defects), single lab with multiple orthogonal methods","pmids":["33648524"],"is_preprint":false},{"year":2022,"finding":"Snrpb and Snrpd2 regulate exon-skipping patterns during zygotic genome activation (ZGA). These two core spliceosomal components have low maternal expression at ZGA and increase sharply thereafter. Microinjection of Snrpb/d2 mRNA into mouse zygotes reduces exon skipping at ZGA and leads to increased p53-mediated DNA damage response, establishing that developmentally programmed low expression of these factors contributes to splicing failure and attenuation of DNA damage response.","method":"Transcriptomic analysis of preimplantation embryos (human, mouse, cow), microinjection of mRNA into mouse zygotes, measurement of exon skipping and p53-mediated DDR","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional rescue experiment (mRNA microinjection) with defined molecular and phenotypic readout, cross-species transcriptomic data, single lab","pmids":["35417229"],"is_preprint":false},{"year":2022,"finding":"SNRPD2 is a novel substrate for the E3 ubiquitin ligase activity of the Salmonella type III secretion effector SlrP. Yeast two-hybrid identified SNRPD2 as a human binding partner of SlrP, and in vitro ubiquitination assays confirmed SNRPD2 is ubiquitinated by SlrP but not by related NEL-family E3 ligases SspH1 or SspH2. The specific lysine residues modified were identified by mass spectrometry.","method":"Yeast two-hybrid (binding), in vitro ubiquitination assay, mass spectrometry (lysine site identification)","journal":"Biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro ubiquitination assay with mutagenesis-level site identification by MS, yeast two-hybrid for binding, single lab with two orthogonal methods","pmids":["36290420"],"is_preprint":false},{"year":2024,"finding":"SNRPD2 (PD2) is the most highly upregulated Sm protein in hepatocellular carcinoma (HCC) and acts as an oncogene. Mechanistically, SNRPD2 cooperates with HNRNPL to modulate DDX39A intron retention, sustaining expression of a DDX39A short variant (39A_S). 39A_S mediates nuclear export of MYC mRNA to maintain high MYC protein expression, while MYC in turn potentiates SNRPD2 transcription, forming a positive feedback loop. The small molecule digitoxin can directly interact with SNRPD2 and suppresses HCC.","method":"Overexpression/knockdown functional assays, splicing analysis (intron retention), MYC mRNA nuclear export assays, drug binding (digitoxin-SNRPD2 interaction), in vivo tumor models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with defined molecular mechanism, single lab, drug-protein interaction assay, but abstract-level detail only","pmids":["39018261"],"is_preprint":false},{"year":2024,"finding":"SNRPD2 interacts with the glutamic-proline (EP) domain of PABPN1 and disrupts PABPN1 liquid-liquid phase separation (LLPS). This disruption of PABPN1 LLPS attenuates PABPN1's repression of proximal poly(A) sites, leading to shortened 3' UTR of CTNNBIP1 and promoting colorectal cancer cell proliferation and migration.","method":"Co-immunoprecipitation (SNRPD2-PABPN1 interaction), LLPS assay, APA profiling, domain mapping, functional proliferation/migration assays","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction, LLPS assay, APA profiling with defined downstream readout, single lab with multiple orthogonal methods","pmids":["38811444"],"is_preprint":false},{"year":2022,"finding":"Free U1 snRNP proteins including SNRPD2 (when knocked down or overexpressed) promote usage of proximal alternative polyadenylation (APA) sites at the transcriptome level, contrary to the repressive effect of the intact U1 snRNP complex. This occurs through interaction with 3' end processing machinery.","method":"Knockdown and overexpression of SNRPD2 and other U1 snRNP proteins, transcriptome-wide APA profiling, phase transition assays, co-immunoprecipitation","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptome-wide functional assay, multiple snRNP subunits tested, interaction assays, single lab","pmids":["36073763"],"is_preprint":false},{"year":2022,"finding":"Silencing of SNRPD2 in HCC cell lines results in impaired proliferation and G1/M cell cycle arrest, accompanied by downregulation of transcription-cycle-related genes.","method":"siRNA knockdown of SNRPD2, cell proliferation assay, cell cycle analysis (FACS), gene expression analysis","journal":"Diagnostics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach, phenotypic readout without deep mechanistic pathway placement beyond transcription cycle gene downregulation","pmids":["35626291"],"is_preprint":false},{"year":2024,"finding":"SNRPD2 silencing using shRNA-expressing lentiviral vectors selectively inhibits viability of cancer cell lines (including short-term cultured melanoma cells) but not normal cell cultures, establishing SNRPD2 as a cancer-selective lethal target. Genes with similar essentiality profiles implicate SNRPD2 in mRNA splicing, coordinated protein production, and mitosis.","method":"shRNA lentiviral knockdown, cell viability assays across cancer and normal cell lines, analysis of public cell viability datasets (DepMap), essentiality profile correlation","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic knockdown across multiple cell line types with viability readout, cross-validated with public datasets, single lab","pmids":["39684842"],"is_preprint":false},{"year":2026,"finding":"Mutant p53 (mtp53) physically binds SNRPD2 and cooperates with it to facilitate assembly of the Sm/SMN protein complex, an essential spliceosome component, thereby modulating alternative splicing of pre-mRNAs. Co-depletion of mtp53 and SNRPD2 reduces oncogenic OTUD3 transcripts and increases tumor-suppressor OTUD3 counterparts through an exon-skipping event.","method":"Co-immunoprecipitation (mtp53-SNRPD2 interaction), overexpression/depletion functional assays, alternative splicing analysis (exon skipping of OTUD3), in vivo xenograft models with engineered exosomes delivering siRNAs","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes binding, functional splicing assay with defined isoform outcome, in vivo validation, single lab","pmids":["41560375"],"is_preprint":false},{"year":2026,"finding":"SNRPD2 knockdown induces retention of intron 5 in DDX39B pre-mRNA, producing a noncoding transcript degraded by nonsense-mediated decay (NMD), thereby reducing DDX39B expression. Reduced DDX39B levels permit activation of a cryptic exon (Exon 2_3) in CTSC mRNA, introducing premature termination codons and triggering additional NMD-mediated CTSC degradation. Antisense oligonucleotides (ASOs) targeting SNRPD2 reduce tumor growth in a patient-derived xenograft model, establishing the SNRPD2-DDX39B-CTSC regulatory axis.","method":"SNRPD2 knockdown, intron retention/splicing analysis, NMD pathway assays, cryptic exon analysis, ASO treatment, patient-derived xenograft (PDX) in vivo model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic splicing analysis with defined downstream isoform and NMD readouts, in vivo PDX validation, single lab with multiple orthogonal methods","pmids":["41720762"],"is_preprint":false},{"year":2026,"finding":"SNRPD2 knockdown induces exon 4 skipping in CPSF7 pre-mRNA, disrupting the RNA recognition motif (RRM) domain essential for CPSF7-mediated pre-mRNA cleavage and polyadenylation, and introducing premature termination codons that trigger NMD-mediated CPSF7 degradation. CPSF7 in turn governs APA events controlling UBE2K transcript stability. This defines a SNRPD2-CPSF7-UBE2K axis linking alternative splicing to alternative polyadenylation in ovarian cancer.","method":"SNRPD2/CPSF7 knockdown, exon skipping analysis, NMD assays, APA profiling, functional proliferation/migration assays, PDX model with ASOs","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic splicing and APA analysis with defined molecular pathway, in vivo PDX validation, single lab with multiple orthogonal methods","pmids":["42098443"],"is_preprint":false},{"year":2026,"finding":"NKRF directly represses transcription of SNRPD2, thereby constraining stress granule formation and attenuating drug tolerance to Osimertinib. The E3 ubiquitin ligase TRIM26 interacts with NKRF and promotes its K48-linked ubiquitination at Lys411, leading to proteasomal degradation, which in turn sustains SNRPD2 expression and enhances stress granule assembly. Genetic depletion of TRIM26 restored NKRF stability, suppressed stress granule formation, and re-sensitized resistant tumors to Osimertinib.","method":"Co-immunoprecipitation (TRIM26-NKRF interaction), ubiquitination assays (K48-linkage, Lys411 site), transcriptional reporter assays, SNRPD2 knockdown/overexpression, stress granule imaging, in vivo xenograft models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, site-specific ubiquitination assay, transcriptional regulation established, in vivo validation, single lab with multiple orthogonal methods","pmids":["42026030"],"is_preprint":false},{"year":1999,"finding":"Sm-D2 (SNRPD2) is recognized by anti-Sm autoantibodies in systemic lupus erythematosus, but with distinct antibody recognition patterns from Sm-D1 and Sm-D3. Human and murine lupus sera showed two patterns: Sm-D1/D3 (predominant) or Sm-D1/D2/D3. None of the MRL-derived monoclonal anti-Sm antibodies reacted with Sm-D2. Immunization with isolated Sm-D (containing all three D antigens) from rabbit thymus produced autoantibody reactive only with Sm-D2, indicating distinct antigenic epitopes among the Sm-D family members.","method":"Protein immunoblot screening of human and murine sera, monoclonal antibody panel screening, immunization with isolated Sm-D antigen","journal":"Clinical immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — systematic antibody screening across multiple patient/animal sera and monoclonal panel, but purely serological characterization without direct structural or biochemical mechanism","pmids":["10444365"],"is_preprint":false}],"current_model":"SNRPD2 (Sm-D2) is a core spliceosomal Sm protein that participates in U snRNP assembly and pre-mRNA splicing; it regulates alternative splicing of multiple cancer-relevant transcripts (including sororin, DDX39A, DDX39B, CPSF7, and OTUD3) by controlling intron retention and exon skipping events, cooperates with binding partners such as HNRNPL and mutant p53 to modulate spliceosome complex assembly, interacts with PABPN1 to disrupt its phase separation and promote proximal alternative polyadenylation, is transcriptionally regulated by MYC (and repressed by NKRF), can be ubiquitinated by the Salmonella effector E3 ligase SlrP, and its developmentally programmed low expression at zygotic genome activation contributes to transient splicing failure that attenuates the p53-mediated DNA damage response."},"narrative":{"mechanistic_narrative":"SNRPD2 (Sm-D2) is a core Sm protein of the spliceosome that participates in U snRNP assembly and pre-mRNA splicing, and through this activity controls the alternative splicing and processing of multiple cancer-relevant transcripts [PMID:33648524, PMID:35417229]. Within the spliceosomal machinery it cooperates with partner factors—it physically binds HNRNPL to modulate DDX39A intron retention [PMID:39018261] and binds mutant p53 to facilitate assembly of the Sm/SMN complex that underlies splicing of pre-mRNAs such as OTUD3 [PMID:41560375]. SNRPD2 governs specific splicing decisions whose disruption couples to nonsense-mediated decay: its loss drives intron retention in DDX39B and exon skipping in CPSF7, generating NMD-targeted transcripts that in turn reshape downstream targets (CTSC, UBE2K) [PMID:41720762, PMID:42098443], and it regulates intron 1 retention of sororin to control sister chromatid cohesion [PMID:33648524]. Beyond splicing, SNRPD2 influences alternative polyadenylation: free U1 snRNP-associated SNRPD2 promotes proximal poly(A) site usage [PMID:36073763], and it interacts with the EP domain of PABPN1 to disrupt PABPN1 liquid-liquid phase separation, relieving repression of proximal poly(A) sites [PMID:38811444]. SNRPD2 is upregulated and behaves as an oncogene in hepatocellular and other cancers, sustained by a MYC positive-feedback loop and repressed transcriptionally by NKRF, and its depletion is selectively lethal to cancer cells [PMID:39018261, PMID:39684842, PMID:42026030]. Developmentally, programmed low SNRPD2 expression at zygotic genome activation produces transient splicing failure that attenuates the p53-mediated DNA damage response [PMID:35417229]. SNRPD2 is also recognized by anti-Sm autoantibodies in systemic lupus erythematosus, with antigenic epitopes distinct from other Sm-D family members [PMID:10444365].","teleology":[{"year":1999,"claim":"Established Sm-D2 as an autoantigen distinct from other Sm-D family members, defining its independent antigenic identity within the Sm protein family.","evidence":"Immunoblot and monoclonal antibody screening of human/murine lupus sera plus immunization with isolated Sm-D antigen","pmids":["10444365"],"confidence":"Medium","gaps":["Purely serological; no biochemical or structural mechanism","Does not address SNRPD2's role in splicing"]},{"year":2021,"claim":"Placed SNRPD2 in a spliceosome complex whose function controls sister chromatid cohesion via sororin intron retention, linking a core Sm protein to a defined splicing-dependent phenotype in cancer.","evidence":"RNAi screen, intron-retention PCR, FACS, and pulldown/MS in triple-negative breast cancer cells","pmids":["33648524"],"confidence":"Medium","gaps":["Role of novel component SUN2 in splicing not mechanistically resolved","Direct vs indirect effect on sororin splicing not separated"]},{"year":2022,"claim":"Demonstrated that developmentally programmed low SNRPD2 expression causes splicing failure that attenuates the p53 DNA damage response, establishing a physiological consequence of limiting this Sm protein.","evidence":"Cross-species embryo transcriptomics and mRNA microinjection rescue in mouse zygotes","pmids":["35417229"],"confidence":"Medium","gaps":["Specific exon-skipping targets driving DDR attenuation not enumerated","Snrpb vs Snrpd2 individual contributions not separated"]},{"year":2022,"claim":"Identified SNRPD2 as a host substrate of the Salmonella effector E3 ligase SlrP, revealing a pathogen-targeted post-translational modification of the spliceosome.","evidence":"Yeast two-hybrid binding, in vitro ubiquitination assay, and MS lysine-site mapping","pmids":["36290420"],"confidence":"Medium","gaps":["Functional consequence of SNRPD2 ubiquitination on splicing not determined","In vivo relevance during infection not shown"]},{"year":2022,"claim":"Showed that free (non-complexed) SNRPD2 promotes proximal alternative polyadenylation, distinguishing the activity of dissociated U1 snRNP subunits from the intact complex.","evidence":"Knockdown/overexpression with transcriptome-wide APA profiling, phase transition and Co-IP assays","pmids":["36073763"],"confidence":"Medium","gaps":["3' end processing machinery contacts not mapped at residue level","Genome-wide rules for proximal site selection unresolved"]},{"year":2024,"claim":"Defined SNRPD2 as an HCC oncogene operating through an HNRNPL-dependent DDX39A splicing switch and a MYC positive-feedback loop, and a druggable target of digitoxin.","evidence":"Knockdown/overexpression, intron-retention and MYC mRNA export assays, drug-binding assay, in vivo tumor models","pmids":["39018261"],"confidence":"Medium","gaps":["Digitoxin binding site and selectivity not structurally defined","Direct vs indirect MYC transcriptional activation not separated"]},{"year":2024,"claim":"Established a non-splicing mechanism whereby SNRPD2 binds the PABPN1 EP domain to disrupt its phase separation and relieve APA repression, linking SNRPD2 to 3' UTR shortening in colorectal cancer.","evidence":"Co-IP, domain mapping, LLPS assay, APA profiling, and proliferation/migration assays","pmids":["38811444"],"confidence":"Medium","gaps":["Stoichiometry and reversibility of LLPS disruption unclear","Single downstream target (CTNNBIP1) characterized in detail"]},{"year":2024,"claim":"Demonstrated cancer-selective lethality of SNRPD2 depletion and correlated its essentiality profile with mRNA splicing, protein production, and mitosis.","evidence":"shRNA lentiviral knockdown across cancer and normal cells plus DepMap essentiality-profile correlation","pmids":["39684842"],"confidence":"Medium","gaps":["Basis for cancer-selective dependency not mechanistically explained","Correlative essentiality does not establish direct pathway membership"]},{"year":2026,"claim":"Showed mutant p53 physically binds SNRPD2 to promote Sm/SMN complex assembly and redirect OTUD3 splicing toward oncogenic isoforms, coupling a transcription factor to spliceosome assembly.","evidence":"Co-IP, overexpression/depletion, OTUD3 exon-skipping analysis, xenograft with exosome-delivered siRNA","pmids":["41560375"],"confidence":"Medium","gaps":["Whether wild-type p53 has the same activity not addressed","Direct effect on snRNP assembly kinetics not quantified"]},{"year":2026,"claim":"Defined a SNRPD2-DDX39B-CTSC axis in which SNRPD2 loss triggers intron retention and NMD of DDX39B, derepressing a cryptic exon in CTSC, demonstrating cascading splicing-NMD control.","evidence":"Knockdown, intron-retention/cryptic-exon analysis, NMD assays, ASO treatment, PDX model","pmids":["41720762"],"confidence":"Medium","gaps":["Direct SNRPD2 binding on DDX39B pre-mRNA not shown","Breadth of CTSC-dependent downstream effects unmapped"]},{"year":2026,"claim":"Defined a SNRPD2-CPSF7-UBE2K axis linking SNRPD2-controlled CPSF7 exon skipping to downstream APA in ovarian cancer, connecting splicing to polyadenylation control.","evidence":"SNRPD2/CPSF7 knockdown, exon-skipping and NMD analysis, APA profiling, PDX with ASOs","pmids":["42098443"],"confidence":"Medium","gaps":["Whether the CPSF7 RRM disruption is the sole driver of UBE2K APA unclear","Generality of this axis beyond ovarian cancer untested"]},{"year":2026,"claim":"Placed SNRPD2 under transcriptional control of NKRF (itself regulated by TRIM26-mediated ubiquitination), linking SNRPD2 abundance to stress granule formation and Osimertinib drug tolerance.","evidence":"Co-IP, K48/Lys411 ubiquitination assays, reporter assays, knockdown/overexpression, stress granule imaging, xenografts","pmids":["42026030"],"confidence":"Medium","gaps":["Mechanism by which SNRPD2 promotes stress granule assembly not defined","Whether NKRF binds the SNRPD2 promoter directly not fully resolved"]},{"year":null,"claim":"How SNRPD2 selects specific pre-mRNA targets for intron retention versus exon skipping, and whether its APA and stress-granule roles are separable from its core Sm spliceosome function, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of SNRPD2 within target-specific spliceosome configurations","Direct RNA-binding specificity of SNRPD2 not mapped","Separation of canonical snRNP role from free-protein APA/phase-separation roles incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,5,9,10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,6]}],"complexes":["spliceosome","U1 snRNP","Sm/SMN complex"],"partners":["HNRNPL","PABPN1","MUTANT P53 (TP53)","SLRP","SNRPD3","NHP2L1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P62316","full_name":"Small nuclear ribonucleoprotein Sm D2","aliases":["snRNP core protein D2"],"length_aa":118,"mass_kda":13.5,"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)","subcellular_location":"Cytoplasm, cytosol; Nucleus","url":"https://www.uniprot.org/uniprotkb/P62316/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SNRPD2","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000125743","cell_line_id":"CID001459","localizations":[{"compartment":"chromatin","grade":3}],"interactors":[{"gene":"CLNS1A","stoichiometry":10.0},{"gene":"EFTUD2","stoichiometry":10.0},{"gene":"PRPF8","stoichiometry":10.0},{"gene":"RBM17","stoichiometry":10.0},{"gene":"SF3A1","stoichiometry":10.0},{"gene":"SF3A2","stoichiometry":10.0},{"gene":"SF3A3","stoichiometry":10.0},{"gene":"SF3B1","stoichiometry":10.0},{"gene":"SF3B3","stoichiometry":10.0},{"gene":"SF3B5","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001459","total_profiled":1310},"omim":[{"mim_id":"611734","title":"WD REPEAT-CONTAINING PROTEIN 77; WDR77","url":"https://www.omim.org/entry/611734"},{"mim_id":"608095","title":"SODIUM CHANNEL MODIFIER 1; SCNM1","url":"https://www.omim.org/entry/608095"},{"mim_id":"607288","title":"LSM8 PROTEIN; LSM8","url":"https://www.omim.org/entry/607288"},{"mim_id":"607287","title":"LSM7 PROTEIN; LSM7","url":"https://www.omim.org/entry/607287"},{"mim_id":"607286","title":"LSM6 PROTEIN; LSM6","url":"https://www.omim.org/entry/607286"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNRPD2"},"hgnc":{"alias_symbol":["Sm-D2"],"prev_symbol":["SNRPD1"]},"alphafold":{"accession":"P62316","domains":[{"cath_id":"2.30.30.100","chopping":"2-110","consensus_level":"medium","plddt":92.5073,"start":2,"end":110}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62316","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62316-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62316-F1-predicted_aligned_error_v6.png","plddt_mean":90.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNRPD2","jax_strain_url":"https://www.jax.org/strain/search?query=SNRPD2"},"sequence":{"accession":"P62316","fasta_url":"https://rest.uniprot.org/uniprotkb/P62316.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62316/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62316"}},"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":"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":"33648524","id":"PMC_33648524","title":"Splicing factors control triple-negative breast cancer cell mitosis through SUN2 interaction and sororin intron retention.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33648524","citation_count":35,"is_preprint":false},{"pmid":"35277538","id":"PMC_35277538","title":"Computational identification of host genomic biomarkers highlighting their functions, pathways and 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Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41560375","citation_count":0,"is_preprint":false},{"pmid":"41720762","id":"PMC_41720762","title":"SNRPD2-mediated regulation of DDX39B splicing promotes endometrial cancer progression by suppressing the activation of CTSC cryptic exons.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41720762","citation_count":0,"is_preprint":false},{"pmid":"41771572","id":"PMC_41771572","title":"SNRPD2-dependency Fuels an Oncogenic Alternative Splicing Repertoire Driving Disease Aggressiveness in Glioma.","date":"2026","source":"Cancer genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/41771572","citation_count":0,"is_preprint":false},{"pmid":"42098443","id":"PMC_42098443","title":"SNRPD2-CPSF7-UBE2K axis drives ovarian cancer progression via alternative splicing-polyadenylation 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pathway.","date":"2026","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/42152469","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18034,"output_tokens":3972,"usd":0.056841,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11651,"output_tokens":3998,"usd":0.079103,"stage2_stop_reason":"end_turn"},"total_usd":0.135944,"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\": 2021,\n      \"finding\": \"Depletion of SNRPD2 (along with SNRPD3 and NHP2L1) inhibits proliferation of triple-negative breast cancer (TNBC) cells by deregulating sister chromatid cohesion (SCC) via increased sororin intron 1 retention and downregulation of SMC1, MAU2, and ESPL1. Protein-protein interaction analysis identified SNRPD2, SNRPD3, and NHP2L1 as belonging to the same spliceosome complex, which also includes novel component SUN2, critical for efficient sororin splicing.\",\n      \"method\": \"RNAi screen, western blot, PCR (intron retention), FACS, molecular imaging, pulldown + mass spectrometry for protein-protein interactions\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pulldown/MS for interactions, RNAi with defined molecular phenotype (intron retention, SCC defects), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33648524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Snrpb and Snrpd2 regulate exon-skipping patterns during zygotic genome activation (ZGA). These two core spliceosomal components have low maternal expression at ZGA and increase sharply thereafter. Microinjection of Snrpb/d2 mRNA into mouse zygotes reduces exon skipping at ZGA and leads to increased p53-mediated DNA damage response, establishing that developmentally programmed low expression of these factors contributes to splicing failure and attenuation of DNA damage response.\",\n      \"method\": \"Transcriptomic analysis of preimplantation embryos (human, mouse, cow), microinjection of mRNA into mouse zygotes, measurement of exon skipping and p53-mediated DDR\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional rescue experiment (mRNA microinjection) with defined molecular and phenotypic readout, cross-species transcriptomic data, single lab\",\n      \"pmids\": [\"35417229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SNRPD2 is a novel substrate for the E3 ubiquitin ligase activity of the Salmonella type III secretion effector SlrP. Yeast two-hybrid identified SNRPD2 as a human binding partner of SlrP, and in vitro ubiquitination assays confirmed SNRPD2 is ubiquitinated by SlrP but not by related NEL-family E3 ligases SspH1 or SspH2. The specific lysine residues modified were identified by mass spectrometry.\",\n      \"method\": \"Yeast two-hybrid (binding), in vitro ubiquitination assay, mass spectrometry (lysine site identification)\",\n      \"journal\": \"Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro ubiquitination assay with mutagenesis-level site identification by MS, yeast two-hybrid for binding, single lab with two orthogonal methods\",\n      \"pmids\": [\"36290420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNRPD2 (PD2) is the most highly upregulated Sm protein in hepatocellular carcinoma (HCC) and acts as an oncogene. Mechanistically, SNRPD2 cooperates with HNRNPL to modulate DDX39A intron retention, sustaining expression of a DDX39A short variant (39A_S). 39A_S mediates nuclear export of MYC mRNA to maintain high MYC protein expression, while MYC in turn potentiates SNRPD2 transcription, forming a positive feedback loop. The small molecule digitoxin can directly interact with SNRPD2 and suppresses HCC.\",\n      \"method\": \"Overexpression/knockdown functional assays, splicing analysis (intron retention), MYC mRNA nuclear export assays, drug binding (digitoxin-SNRPD2 interaction), in vivo tumor models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with defined molecular mechanism, single lab, drug-protein interaction assay, but abstract-level detail only\",\n      \"pmids\": [\"39018261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNRPD2 interacts with the glutamic-proline (EP) domain of PABPN1 and disrupts PABPN1 liquid-liquid phase separation (LLPS). This disruption of PABPN1 LLPS attenuates PABPN1's repression of proximal poly(A) sites, leading to shortened 3' UTR of CTNNBIP1 and promoting colorectal cancer cell proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation (SNRPD2-PABPN1 interaction), LLPS assay, APA profiling, domain mapping, functional proliferation/migration assays\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction, LLPS assay, APA profiling with defined downstream readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38811444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Free U1 snRNP proteins including SNRPD2 (when knocked down or overexpressed) promote usage of proximal alternative polyadenylation (APA) sites at the transcriptome level, contrary to the repressive effect of the intact U1 snRNP complex. This occurs through interaction with 3' end processing machinery.\",\n      \"method\": \"Knockdown and overexpression of SNRPD2 and other U1 snRNP proteins, transcriptome-wide APA profiling, phase transition assays, co-immunoprecipitation\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptome-wide functional assay, multiple snRNP subunits tested, interaction assays, single lab\",\n      \"pmids\": [\"36073763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Silencing of SNRPD2 in HCC cell lines results in impaired proliferation and G1/M cell cycle arrest, accompanied by downregulation of transcription-cycle-related genes.\",\n      \"method\": \"siRNA knockdown of SNRPD2, cell proliferation assay, cell cycle analysis (FACS), gene expression analysis\",\n      \"journal\": \"Diagnostics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach, phenotypic readout without deep mechanistic pathway placement beyond transcription cycle gene downregulation\",\n      \"pmids\": [\"35626291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNRPD2 silencing using shRNA-expressing lentiviral vectors selectively inhibits viability of cancer cell lines (including short-term cultured melanoma cells) but not normal cell cultures, establishing SNRPD2 as a cancer-selective lethal target. Genes with similar essentiality profiles implicate SNRPD2 in mRNA splicing, coordinated protein production, and mitosis.\",\n      \"method\": \"shRNA lentiviral knockdown, cell viability assays across cancer and normal cell lines, analysis of public cell viability datasets (DepMap), essentiality profile correlation\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic knockdown across multiple cell line types with viability readout, cross-validated with public datasets, single lab\",\n      \"pmids\": [\"39684842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Mutant p53 (mtp53) physically binds SNRPD2 and cooperates with it to facilitate assembly of the Sm/SMN protein complex, an essential spliceosome component, thereby modulating alternative splicing of pre-mRNAs. Co-depletion of mtp53 and SNRPD2 reduces oncogenic OTUD3 transcripts and increases tumor-suppressor OTUD3 counterparts through an exon-skipping event.\",\n      \"method\": \"Co-immunoprecipitation (mtp53-SNRPD2 interaction), overexpression/depletion functional assays, alternative splicing analysis (exon skipping of OTUD3), in vivo xenograft models with engineered exosomes delivering siRNAs\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes binding, functional splicing assay with defined isoform outcome, in vivo validation, single lab\",\n      \"pmids\": [\"41560375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SNRPD2 knockdown induces retention of intron 5 in DDX39B pre-mRNA, producing a noncoding transcript degraded by nonsense-mediated decay (NMD), thereby reducing DDX39B expression. Reduced DDX39B levels permit activation of a cryptic exon (Exon 2_3) in CTSC mRNA, introducing premature termination codons and triggering additional NMD-mediated CTSC degradation. Antisense oligonucleotides (ASOs) targeting SNRPD2 reduce tumor growth in a patient-derived xenograft model, establishing the SNRPD2-DDX39B-CTSC regulatory axis.\",\n      \"method\": \"SNRPD2 knockdown, intron retention/splicing analysis, NMD pathway assays, cryptic exon analysis, ASO treatment, patient-derived xenograft (PDX) in vivo model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic splicing analysis with defined downstream isoform and NMD readouts, in vivo PDX validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41720762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SNRPD2 knockdown induces exon 4 skipping in CPSF7 pre-mRNA, disrupting the RNA recognition motif (RRM) domain essential for CPSF7-mediated pre-mRNA cleavage and polyadenylation, and introducing premature termination codons that trigger NMD-mediated CPSF7 degradation. CPSF7 in turn governs APA events controlling UBE2K transcript stability. This defines a SNRPD2-CPSF7-UBE2K axis linking alternative splicing to alternative polyadenylation in ovarian cancer.\",\n      \"method\": \"SNRPD2/CPSF7 knockdown, exon skipping analysis, NMD assays, APA profiling, functional proliferation/migration assays, PDX model with ASOs\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic splicing and APA analysis with defined molecular pathway, in vivo PDX validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"42098443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NKRF directly represses transcription of SNRPD2, thereby constraining stress granule formation and attenuating drug tolerance to Osimertinib. The E3 ubiquitin ligase TRIM26 interacts with NKRF and promotes its K48-linked ubiquitination at Lys411, leading to proteasomal degradation, which in turn sustains SNRPD2 expression and enhances stress granule assembly. Genetic depletion of TRIM26 restored NKRF stability, suppressed stress granule formation, and re-sensitized resistant tumors to Osimertinib.\",\n      \"method\": \"Co-immunoprecipitation (TRIM26-NKRF interaction), ubiquitination assays (K48-linkage, Lys411 site), transcriptional reporter assays, SNRPD2 knockdown/overexpression, stress granule imaging, in vivo xenograft models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, site-specific ubiquitination assay, transcriptional regulation established, in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"42026030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Sm-D2 (SNRPD2) is recognized by anti-Sm autoantibodies in systemic lupus erythematosus, but with distinct antibody recognition patterns from Sm-D1 and Sm-D3. Human and murine lupus sera showed two patterns: Sm-D1/D3 (predominant) or Sm-D1/D2/D3. None of the MRL-derived monoclonal anti-Sm antibodies reacted with Sm-D2. Immunization with isolated Sm-D (containing all three D antigens) from rabbit thymus produced autoantibody reactive only with Sm-D2, indicating distinct antigenic epitopes among the Sm-D family members.\",\n      \"method\": \"Protein immunoblot screening of human and murine sera, monoclonal antibody panel screening, immunization with isolated Sm-D antigen\",\n      \"journal\": \"Clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — systematic antibody screening across multiple patient/animal sera and monoclonal panel, but purely serological characterization without direct structural or biochemical mechanism\",\n      \"pmids\": [\"10444365\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNRPD2 (Sm-D2) is a core spliceosomal Sm protein that participates in U snRNP assembly and pre-mRNA splicing; it regulates alternative splicing of multiple cancer-relevant transcripts (including sororin, DDX39A, DDX39B, CPSF7, and OTUD3) by controlling intron retention and exon skipping events, cooperates with binding partners such as HNRNPL and mutant p53 to modulate spliceosome complex assembly, interacts with PABPN1 to disrupt its phase separation and promote proximal alternative polyadenylation, is transcriptionally regulated by MYC (and repressed by NKRF), can be ubiquitinated by the Salmonella effector E3 ligase SlrP, and its developmentally programmed low expression at zygotic genome activation contributes to transient splicing failure that attenuates the p53-mediated DNA damage response.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNRPD2 (Sm-D2) is a core Sm protein of the spliceosome that participates in U snRNP assembly and pre-mRNA splicing, and through this activity controls the alternative splicing and processing of multiple cancer-relevant transcripts [#0, #1]. Within the spliceosomal machinery it cooperates with partner factors—it physically binds HNRNPL to modulate DDX39A intron retention [#3] and binds mutant p53 to facilitate assembly of the Sm/SMN complex that underlies splicing of pre-mRNAs such as OTUD3 [#8]. SNRPD2 governs specific splicing decisions whose disruption couples to nonsense-mediated decay: its loss drives intron retention in DDX39B and exon skipping in CPSF7, generating NMD-targeted transcripts that in turn reshape downstream targets (CTSC, UBE2K) [#9, #10], and it regulates intron 1 retention of sororin to control sister chromatid cohesion [#0]. Beyond splicing, SNRPD2 influences alternative polyadenylation: free U1 snRNP-associated SNRPD2 promotes proximal poly(A) site usage [#5], and it interacts with the EP domain of PABPN1 to disrupt PABPN1 liquid-liquid phase separation, relieving repression of proximal poly(A) sites [#4]. SNRPD2 is upregulated and behaves as an oncogene in hepatocellular and other cancers, sustained by a MYC positive-feedback loop and repressed transcriptionally by NKRF, and its depletion is selectively lethal to cancer cells [#3, #7, #11]. Developmentally, programmed low SNRPD2 expression at zygotic genome activation produces transient splicing failure that attenuates the p53-mediated DNA damage response [#1]. SNRPD2 is also recognized by anti-Sm autoantibodies in systemic lupus erythematosus, with antigenic epitopes distinct from other Sm-D family members [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established Sm-D2 as an autoantigen distinct from other Sm-D family members, defining its independent antigenic identity within the Sm protein family.\",\n      \"evidence\": \"Immunoblot and monoclonal antibody screening of human/murine lupus sera plus immunization with isolated Sm-D antigen\",\n      \"pmids\": [\"10444365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Purely serological; no biochemical or structural mechanism\", \"Does not address SNRPD2's role in splicing\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed SNRPD2 in a spliceosome complex whose function controls sister chromatid cohesion via sororin intron retention, linking a core Sm protein to a defined splicing-dependent phenotype in cancer.\",\n      \"evidence\": \"RNAi screen, intron-retention PCR, FACS, and pulldown/MS in triple-negative breast cancer cells\",\n      \"pmids\": [\"33648524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Role of novel component SUN2 in splicing not mechanistically resolved\", \"Direct vs indirect effect on sororin splicing not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that developmentally programmed low SNRPD2 expression causes splicing failure that attenuates the p53 DNA damage response, establishing a physiological consequence of limiting this Sm protein.\",\n      \"evidence\": \"Cross-species embryo transcriptomics and mRNA microinjection rescue in mouse zygotes\",\n      \"pmids\": [\"35417229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific exon-skipping targets driving DDR attenuation not enumerated\", \"Snrpb vs Snrpd2 individual contributions not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified SNRPD2 as a host substrate of the Salmonella effector E3 ligase SlrP, revealing a pathogen-targeted post-translational modification of the spliceosome.\",\n      \"evidence\": \"Yeast two-hybrid binding, in vitro ubiquitination assay, and MS lysine-site mapping\",\n      \"pmids\": [\"36290420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of SNRPD2 ubiquitination on splicing not determined\", \"In vivo relevance during infection not shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed that free (non-complexed) SNRPD2 promotes proximal alternative polyadenylation, distinguishing the activity of dissociated U1 snRNP subunits from the intact complex.\",\n      \"evidence\": \"Knockdown/overexpression with transcriptome-wide APA profiling, phase transition and Co-IP assays\",\n      \"pmids\": [\"36073763\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"3' end processing machinery contacts not mapped at residue level\", \"Genome-wide rules for proximal site selection unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined SNRPD2 as an HCC oncogene operating through an HNRNPL-dependent DDX39A splicing switch and a MYC positive-feedback loop, and a druggable target of digitoxin.\",\n      \"evidence\": \"Knockdown/overexpression, intron-retention and MYC mRNA export assays, drug-binding assay, in vivo tumor models\",\n      \"pmids\": [\"39018261\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Digitoxin binding site and selectivity not structurally defined\", \"Direct vs indirect MYC transcriptional activation not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a non-splicing mechanism whereby SNRPD2 binds the PABPN1 EP domain to disrupt its phase separation and relieve APA repression, linking SNRPD2 to 3' UTR shortening in colorectal cancer.\",\n      \"evidence\": \"Co-IP, domain mapping, LLPS assay, APA profiling, and proliferation/migration assays\",\n      \"pmids\": [\"38811444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and reversibility of LLPS disruption unclear\", \"Single downstream target (CTNNBIP1) characterized in detail\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated cancer-selective lethality of SNRPD2 depletion and correlated its essentiality profile with mRNA splicing, protein production, and mitosis.\",\n      \"evidence\": \"shRNA lentiviral knockdown across cancer and normal cells plus DepMap essentiality-profile correlation\",\n      \"pmids\": [\"39684842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis for cancer-selective dependency not mechanistically explained\", \"Correlative essentiality does not establish direct pathway membership\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed mutant p53 physically binds SNRPD2 to promote Sm/SMN complex assembly and redirect OTUD3 splicing toward oncogenic isoforms, coupling a transcription factor to spliceosome assembly.\",\n      \"evidence\": \"Co-IP, overexpression/depletion, OTUD3 exon-skipping analysis, xenograft with exosome-delivered siRNA\",\n      \"pmids\": [\"41560375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether wild-type p53 has the same activity not addressed\", \"Direct effect on snRNP assembly kinetics not quantified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a SNRPD2-DDX39B-CTSC axis in which SNRPD2 loss triggers intron retention and NMD of DDX39B, derepressing a cryptic exon in CTSC, demonstrating cascading splicing-NMD control.\",\n      \"evidence\": \"Knockdown, intron-retention/cryptic-exon analysis, NMD assays, ASO treatment, PDX model\",\n      \"pmids\": [\"41720762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SNRPD2 binding on DDX39B pre-mRNA not shown\", \"Breadth of CTSC-dependent downstream effects unmapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a SNRPD2-CPSF7-UBE2K axis linking SNRPD2-controlled CPSF7 exon skipping to downstream APA in ovarian cancer, connecting splicing to polyadenylation control.\",\n      \"evidence\": \"SNRPD2/CPSF7 knockdown, exon-skipping and NMD analysis, APA profiling, PDX with ASOs\",\n      \"pmids\": [\"42098443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the CPSF7 RRM disruption is the sole driver of UBE2K APA unclear\", \"Generality of this axis beyond ovarian cancer untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed SNRPD2 under transcriptional control of NKRF (itself regulated by TRIM26-mediated ubiquitination), linking SNRPD2 abundance to stress granule formation and Osimertinib drug tolerance.\",\n      \"evidence\": \"Co-IP, K48/Lys411 ubiquitination assays, reporter assays, knockdown/overexpression, stress granule imaging, xenografts\",\n      \"pmids\": [\"42026030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SNRPD2 promotes stress granule assembly not defined\", \"Whether NKRF binds the SNRPD2 promoter directly not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SNRPD2 selects specific pre-mRNA targets for intron retention versus exon skipping, and whether its APA and stress-granule roles are separable from its core Sm spliceosome function, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of SNRPD2 within target-specific spliceosome configurations\", \"Direct RNA-binding specificity of SNRPD2 not mapped\", \"Separation of canonical snRNP role from free-protein APA/phase-separation roles incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 5, 9, 10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"complexes\": [\"spliceosome\", \"U1 snRNP\", \"Sm/SMN complex\"],\n    \"partners\": [\"HNRNPL\", \"PABPN1\", \"mutant p53 (TP53)\", \"SlrP\", \"SNRPD3\", \"NHP2L1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}