{"gene":"U2SURP","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2018,"finding":"U2SURP physically interacts with RBM17 and CHERP as part of a spliceosomal complex; the three proteins reciprocally regulate each other's stability in both mouse and human cells. Individual knockdown of each protein induces overlapping changes in splicing and gene expression of transcripts enriched for RNA-processing factors.","method":"Co-immunoprecipitation, knockdown experiments, RNA-seq in mouse and human cells","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with functional follow-up (splicing and expression changes), replicated across mouse and human cells in a focused mechanistic study","pmids":["30332651"],"is_preprint":false},{"year":2021,"finding":"U2SURP (SR140), SPF45, and CHERP form a tight physical complex that regulates alternative splicing by repressing short exons flanked by suboptimal 3′ splice sites. Target alternative exons are embedded in cell-cycle genes including FOXM1 (G2/M regulator) and SPDL1 (spindle regulator). Knockdown of any of the three factors causes G2/M arrest and enhanced apoptosis in HeLa cells; promoting the FOXM1 or SPDL1 splicing changes induced by knockdown partially recapitulates effects on cell growth.","method":"Co-immunoprecipitation, siRNA knockdown, RNA-seq, minigene splicing assays, cell-cycle analysis, epistasis via splicing-mimicking constructs","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing the complex, multiple orthogonal methods (splicing assays, cell-cycle analysis, epistasis), functional rescue experiments","pmids":["34544891"],"is_preprint":false},{"year":2019,"finding":"U2SURP (SR140) and CHERP form a protein complex that stabilizes each other; both are upregulated in colorectal cancer. The complex regulates alternative splicing of UPF3A (binding specifically to its regulated exon 4), and UPF3A knockdown recapitulates proliferation defects caused by CHERP/SR140 depletion both in vitro and in mice.","method":"Co-immunoprecipitation, siRNA knockdown, alternative splicing analysis, RNA immunoprecipitation, xenograft mouse model, rescue experiments","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo xenograft, epistasis via rescue experiments, multiple orthogonal methods in one study","pmids":["30977118"],"is_preprint":false},{"year":2023,"finding":"MYC enhances U2SURP translation through an eIF3D (eukaryotic translation initiation factor 3 subunit D)-dependent mechanism. U2SURP promotes alternative splicing of SAT1 pre-mRNA by removal of intron 3, increasing SAT1 mRNA stability and protein expression. Re-expression of SAT1 in U2SURP-depleted TNBC cells partially rescues impaired malignant phenotypes both in vitro and in vivo, placing U2SURP downstream of MYC and upstream of SAT1 in a defined signaling axis.","method":"Knockdown/overexpression assays, splicing analysis (RT-PCR), mRNA stability assays, xenograft mouse model, rescue experiments, ribosome-related translation assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with defined molecular mechanism and in vivo rescue, single lab, multiple orthogonal methods but no structural or reconstitution validation","pmids":["36907504"],"is_preprint":false},{"year":2025,"finding":"HNF1A-AS1 lncRNA recruits U2SURP through its RRM-dependent domain via the 1001–1500 nt region (BR3) to form a functional SNAI2-HNF1A-AS1-U2SURP complex in the nucleus of pancreatic cancer cells. This complex specifically promotes alternative splicing of CD44 pre-mRNA, converting it from the standard isoform to CD44v(3-10), thereby promoting invasion and metastasis.","method":"RNA pull-down assay, Co-IP, FISH, mRNA sequencing, rescue assays, domain deletion experiments","journal":"Journal of gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown identifying direct interaction domain, supported by rescue and splicing assays, single lab study","pmids":["40518456"],"is_preprint":false},{"year":2026,"finding":"U2SURP increases CREB3L2 mRNA stability, leading to transcriptional activation of RIOK1 and reduced sensitivity to lenvatinib in hepatocellular carcinoma cells. Knockdown of CREB3L2 attenuates the U2SURP-mediated drug resistance phenotype in vitro and in xenograft models.","method":"mRNA stability assays, overexpression/knockdown, rescue experiments, xenograft mouse model","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional epistasis via rescue, mRNA stability assay, in vivo xenograft; single lab study","pmids":["41997041"],"is_preprint":false},{"year":2025,"finding":"U2SURP knockdown suppresses the expression of p-ERK, implicating U2SURP in the Ras/MAPK signaling pathway in CML cells. This effect was identified in the context of the circ_0058493/miR-548b-3p/U2SURP regulatory axis.","method":"siRNA knockdown, Western blotting for p-ERK","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single downstream readout (p-ERK Western blot) after knockdown, single lab, no direct mechanistic linkage established between U2SURP and ERK","pmids":["41274252"],"is_preprint":false},{"year":2024,"finding":"U2SURP was identified as a novel effector of the DNA damage response using proximity ligation (TurboID) tethered via a γH2AX-binding BRCT domain probe; functional characterization confirmed U2SURP as a previously uncharacterized DNA damage response factor.","method":"Proximity ligation/TurboID proteomics, engineered γH2AX-binding BRCT probes in living cells, functional characterization of hits","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proximity proteomics with functional follow-up, preprint, single lab, limited mechanistic detail in abstract","pmids":["bio_10.1101_2024.10.23.619792"],"is_preprint":true}],"current_model":"U2SURP is a spliceosomal serine/arginine-rich protein that forms a stable complex with SPF45 and CHERP (and also interacts with RBM17) to regulate alternative splicing of specific pre-mRNA targets—including cell-cycle regulators FOXM1 and SPDL1, the RNA surveillance factor UPF3A, and oncogenic targets SAT1 and CD44—by repressing short exons flanked by suboptimal 3′ splice sites; its complex partners reciprocally stabilize each other's protein levels, its translation is enhanced by MYC via eIF3D, and it also stabilizes CREB3L2 mRNA and has been implicated in the DNA damage response."},"narrative":{"mechanistic_narrative":"U2SURP is a serine/arginine-rich spliceosomal protein that regulates alternative splicing of specific pre-mRNA targets as part of a stable multiprotein complex [PMID:34544891]. It forms a tight physical complex with SPF45 and CHERP, and interacts with RBM17/SR-related factors; within this assembly the partners reciprocally stabilize each other's protein levels, and the complex represses inclusion of short exons flanked by suboptimal 3′ splice sites [PMID:30332651, PMID:34544891]. Through this activity U2SURP controls splicing of cell-cycle regulators including FOXM1 and SPDL1, such that depletion of any complex member produces G2/M arrest and apoptosis [PMID:34544891], and it regulates an alternative exon in the RNA surveillance factor UPF3A to support proliferation [PMID:30977118]. Beyond canonical splicing, U2SURP modulates transcript abundance: it promotes intron-3 removal in SAT1 to stabilize SAT1 mRNA in a MYC–eIF3D-enhanced translational axis [PMID:36907504], is recruited by the lncRNA HNF1A-AS1 via its RRM-dependent domain to drive a CD44 isoform switch promoting invasion [PMID:40518456], and stabilizes CREB3L2 mRNA to activate RIOK1 and confer drug resistance [PMID:41997041]. Across these settings U2SURP behaves as a pro-proliferative, pro-metastatic factor upregulated in multiple cancers [PMID:30977118, PMID:36907504, PMID:40518456].","teleology":[{"year":2018,"claim":"Established that U2SURP is not an isolated factor but part of a co-regulated spliceosomal module, answering whether it has stable physical partners.","evidence":"Co-IP plus knockdown and RNA-seq in mouse and human cells","pmids":["30332651"],"confidence":"High","gaps":["Did not define the splice-site features targeted","Functional consequences described only at the transcriptome level, not phenotype"]},{"year":2019,"claim":"Showed the U2SURP–CHERP complex regulates a defined target (UPF3A exon 4) with proliferative consequences, linking the complex to cancer cell growth.","evidence":"Co-IP, RNA immunoprecipitation, splicing analysis, and xenograft rescue experiments","pmids":["30977118"],"confidence":"High","gaps":["Mechanism of exon selection not resolved","Restricted to colorectal cancer context"]},{"year":2021,"claim":"Defined the biochemical logic of the complex—repression of short exons with weak 3′ splice sites—and tied it causally to G2/M control via FOXM1 and SPDL1.","evidence":"Co-IP, minigene splicing assays, cell-cycle analysis, and splicing-mimicking epistasis in HeLa cells","pmids":["34544891"],"confidence":"High","gaps":["No structural model of the SPF45/CHERP/U2SURP complex","Rescue was only partial, implying additional targets"]},{"year":2023,"claim":"Placed U2SURP in a signaling axis by showing MYC drives its translation via eIF3D and that it acts upstream of SAT1 through intron retention/removal affecting mRNA stability.","evidence":"Translation and mRNA-stability assays, RT-PCR splicing analysis, and xenograft rescue in TNBC cells","pmids":["36907504"],"confidence":"Medium","gaps":["No reconstitution of the splicing event","Direct binding to SAT1 pre-mRNA not demonstrated"]},{"year":2025,"claim":"Demonstrated lncRNA-directed recruitment of U2SURP, showing HNF1A-AS1 engages its RRM domain to redirect CD44 splicing toward a pro-metastatic isoform.","evidence":"RNA pull-down, Co-IP, FISH, domain-deletion, and rescue assays in pancreatic cancer cells","pmids":["40518456"],"confidence":"Medium","gaps":["Single-lab study","Generality of lncRNA-guided targeting to other transcripts unknown"]},{"year":2026,"claim":"Extended U2SURP function to mRNA stabilization of CREB3L2 with downstream RIOK1 activation and drug-resistance phenotypes.","evidence":"mRNA stability assays, knockdown/overexpression rescue, and xenograft models in HCC cells","pmids":["41997041"],"confidence":"Medium","gaps":["Mechanism of mRNA stabilization undefined","Direct U2SURP–CREB3L2 interaction not shown"]},{"year":2025,"claim":"Associated U2SURP with Ras/MAPK output via reduced p-ERK after knockdown.","evidence":"siRNA knockdown and p-ERK Western blot in CML cells","pmids":["41274252"],"confidence":"Low","gaps":["Single downstream readout with no direct mechanistic link to ERK","Not confirmed independently"]},{"year":2024,"claim":"Nominated U2SURP as a DNA damage response factor through proximity to γH2AX-marked chromatin.","evidence":"TurboID proximity proteomics with γH2AX-binding BRCT probes (preprint)","pmids":["bio_10.1101_2024.10.23.619792"],"confidence":"Low","gaps":["Preprint, not peer-reviewed","Mechanistic role in DNA repair undefined"]},{"year":null,"claim":"How U2SURP selects its specific exon and mRNA targets across diverse contexts—and whether its splicing activity and reported mRNA-stabilization/DDR roles are mechanistically distinct functions—remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the complex or RNA recognition","Unclear how splicing repression relates to mRNA stabilization","DDR role uncharacterized at the mechanistic level"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2,4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2]}],"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":[0,1,2]}],"complexes":["SPF45-CHERP-U2SURP splicing complex","SNAI2-HNF1A-AS1-U2SURP complex"],"partners":["SPF45","CHERP","RBM17"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15042","full_name":"U2 snRNP-associated SURP motif-containing protein","aliases":["140 kDa Ser/Arg-rich domain protein","U2-associated protein SR140"],"length_aa":1029,"mass_kda":118.3,"function":"","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O15042/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/U2SURP","classification":"Common Essential","n_dependent_lines":1201,"n_total_lines":1208,"dependency_fraction":0.9942052980132451},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000163714","cell_line_id":"CID001770","localizations":[{"compartment":"chromatin","grade":3},{"compartment":"nuclear_punctae","grade":1}],"interactors":[{"gene":"COMMD2","stoichiometry":10.0},{"gene":"COMMD6","stoichiometry":10.0},{"gene":"DKC1","stoichiometry":10.0},{"gene":"GNL3","stoichiometry":10.0},{"gene":"RANBP2","stoichiometry":10.0},{"gene":"RBM17","stoichiometry":10.0},{"gene":"RSL1D1","stoichiometry":10.0},{"gene":"SF3A1","stoichiometry":10.0},{"gene":"SNRPA1","stoichiometry":10.0},{"gene":"CHERP","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001770","total_profiled":1310},"omim":[{"mim_id":"618539","title":"CALCIUM HOMEOSTASIS ENDOPLASMIC RETICULUM PROTEIN; CHERP","url":"https://www.omim.org/entry/618539"},{"mim_id":"617849","title":"U2 SMALL NUCLEAR RIBONUCLEOPROTEIN-ASSOCIATED SURP DOMAIN-CONTAINING PROTEIN; U2SURP","url":"https://www.omim.org/entry/617849"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/U2SURP"},"hgnc":{"alias_symbol":["fSAPa","SR140"],"prev_symbol":[]},"alphafold":{"accession":"O15042","domains":[{"cath_id":"3.30.70.330","chopping":"274-351","consensus_level":"high","plddt":90.9388,"start":274,"end":351},{"cath_id":"1.10.10.790","chopping":"372-395_409-522","consensus_level":"high","plddt":83.4284,"start":372,"end":522},{"cath_id":"1.25.40.90","chopping":"535-675","consensus_level":"high","plddt":95.3661,"start":535,"end":675},{"cath_id":"-","chopping":"840-899","consensus_level":"high","plddt":88.1807,"start":840,"end":899}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15042","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15042-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15042-F1-predicted_aligned_error_v6.png","plddt_mean":64.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=U2SURP","jax_strain_url":"https://www.jax.org/strain/search?query=U2SURP"},"sequence":{"accession":"O15042","fasta_url":"https://rest.uniprot.org/uniprotkb/O15042.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15042/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15042"}},"corpus_meta":[{"pmid":"11159701","id":"PMC_11159701","title":"Neural 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Individual knockdown of each protein induces overlapping changes in splicing and gene expression of transcripts enriched for RNA-processing factors.\",\n      \"method\": \"Co-immunoprecipitation, knockdown experiments, RNA-seq in mouse and human cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with functional follow-up (splicing and expression changes), replicated across mouse and human cells in a focused mechanistic study\",\n      \"pmids\": [\"30332651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"U2SURP (SR140), SPF45, and CHERP form a tight physical complex that regulates alternative splicing by repressing short exons flanked by suboptimal 3′ splice sites. Target alternative exons are embedded in cell-cycle genes including FOXM1 (G2/M regulator) and SPDL1 (spindle regulator). Knockdown of any of the three factors causes G2/M arrest and enhanced apoptosis in HeLa cells; promoting the FOXM1 or SPDL1 splicing changes induced by knockdown partially recapitulates effects on cell growth.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, RNA-seq, minigene splicing assays, cell-cycle analysis, epistasis via splicing-mimicking constructs\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing the complex, multiple orthogonal methods (splicing assays, cell-cycle analysis, epistasis), functional rescue experiments\",\n      \"pmids\": [\"34544891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"U2SURP (SR140) and CHERP form a protein complex that stabilizes each other; both are upregulated in colorectal cancer. The complex regulates alternative splicing of UPF3A (binding specifically to its regulated exon 4), and UPF3A knockdown recapitulates proliferation defects caused by CHERP/SR140 depletion both in vitro and in mice.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, alternative splicing analysis, RNA immunoprecipitation, xenograft mouse model, rescue experiments\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo xenograft, epistasis via rescue experiments, multiple orthogonal methods in one study\",\n      \"pmids\": [\"30977118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYC enhances U2SURP translation through an eIF3D (eukaryotic translation initiation factor 3 subunit D)-dependent mechanism. U2SURP promotes alternative splicing of SAT1 pre-mRNA by removal of intron 3, increasing SAT1 mRNA stability and protein expression. Re-expression of SAT1 in U2SURP-depleted TNBC cells partially rescues impaired malignant phenotypes both in vitro and in vivo, placing U2SURP downstream of MYC and upstream of SAT1 in a defined signaling axis.\",\n      \"method\": \"Knockdown/overexpression assays, splicing analysis (RT-PCR), mRNA stability assays, xenograft mouse model, rescue experiments, ribosome-related translation assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with defined molecular mechanism and in vivo rescue, single lab, multiple orthogonal methods but no structural or reconstitution validation\",\n      \"pmids\": [\"36907504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HNF1A-AS1 lncRNA recruits U2SURP through its RRM-dependent domain via the 1001–1500 nt region (BR3) to form a functional SNAI2-HNF1A-AS1-U2SURP complex in the nucleus of pancreatic cancer cells. This complex specifically promotes alternative splicing of CD44 pre-mRNA, converting it from the standard isoform to CD44v(3-10), thereby promoting invasion and metastasis.\",\n      \"method\": \"RNA pull-down assay, Co-IP, FISH, mRNA sequencing, rescue assays, domain deletion experiments\",\n      \"journal\": \"Journal of gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown identifying direct interaction domain, supported by rescue and splicing assays, single lab study\",\n      \"pmids\": [\"40518456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"U2SURP increases CREB3L2 mRNA stability, leading to transcriptional activation of RIOK1 and reduced sensitivity to lenvatinib in hepatocellular carcinoma cells. Knockdown of CREB3L2 attenuates the U2SURP-mediated drug resistance phenotype in vitro and in xenograft models.\",\n      \"method\": \"mRNA stability assays, overexpression/knockdown, rescue experiments, xenograft mouse model\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional epistasis via rescue, mRNA stability assay, in vivo xenograft; single lab study\",\n      \"pmids\": [\"41997041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"U2SURP knockdown suppresses the expression of p-ERK, implicating U2SURP in the Ras/MAPK signaling pathway in CML cells. This effect was identified in the context of the circ_0058493/miR-548b-3p/U2SURP regulatory axis.\",\n      \"method\": \"siRNA knockdown, Western blotting for p-ERK\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single downstream readout (p-ERK Western blot) after knockdown, single lab, no direct mechanistic linkage established between U2SURP and ERK\",\n      \"pmids\": [\"41274252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"U2SURP was identified as a novel effector of the DNA damage response using proximity ligation (TurboID) tethered via a γH2AX-binding BRCT domain probe; functional characterization confirmed U2SURP as a previously uncharacterized DNA damage response factor.\",\n      \"method\": \"Proximity ligation/TurboID proteomics, engineered γH2AX-binding BRCT probes in living cells, functional characterization of hits\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proximity proteomics with functional follow-up, preprint, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"bio_10.1101_2024.10.23.619792\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"U2SURP is a spliceosomal serine/arginine-rich protein that forms a stable complex with SPF45 and CHERP (and also interacts with RBM17) to regulate alternative splicing of specific pre-mRNA targets—including cell-cycle regulators FOXM1 and SPDL1, the RNA surveillance factor UPF3A, and oncogenic targets SAT1 and CD44—by repressing short exons flanked by suboptimal 3′ splice sites; its complex partners reciprocally stabilize each other's protein levels, its translation is enhanced by MYC via eIF3D, and it also stabilizes CREB3L2 mRNA and has been implicated in the DNA damage response.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"U2SURP is a serine/arginine-rich spliceosomal protein that regulates alternative splicing of specific pre-mRNA targets as part of a stable multiprotein complex [#1]. It forms a tight physical complex with SPF45 and CHERP, and interacts with RBM17/SR-related factors; within this assembly the partners reciprocally stabilize each other's protein levels, and the complex represses inclusion of short exons flanked by suboptimal 3′ splice sites [#0, #1]. Through this activity U2SURP controls splicing of cell-cycle regulators including FOXM1 and SPDL1, such that depletion of any complex member produces G2/M arrest and apoptosis [#1], and it regulates an alternative exon in the RNA surveillance factor UPF3A to support proliferation [#2]. Beyond canonical splicing, U2SURP modulates transcript abundance: it promotes intron-3 removal in SAT1 to stabilize SAT1 mRNA in a MYC–eIF3D-enhanced translational axis [#3], is recruited by the lncRNA HNF1A-AS1 via its RRM-dependent domain to drive a CD44 isoform switch promoting invasion [#4], and stabilizes CREB3L2 mRNA to activate RIOK1 and confer drug resistance [#5]. Across these settings U2SURP behaves as a pro-proliferative, pro-metastatic factor upregulated in multiple cancers [#2, #3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that U2SURP is not an isolated factor but part of a co-regulated spliceosomal module, answering whether it has stable physical partners.\",\n      \"evidence\": \"Co-IP plus knockdown and RNA-seq in mouse and human cells\",\n      \"pmids\": [\"30332651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the splice-site features targeted\", \"Functional consequences described only at the transcriptome level, not phenotype\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed the U2SURP–CHERP complex regulates a defined target (UPF3A exon 4) with proliferative consequences, linking the complex to cancer cell growth.\",\n      \"evidence\": \"Co-IP, RNA immunoprecipitation, splicing analysis, and xenograft rescue experiments\",\n      \"pmids\": [\"30977118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of exon selection not resolved\", \"Restricted to colorectal cancer context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the biochemical logic of the complex—repression of short exons with weak 3′ splice sites—and tied it causally to G2/M control via FOXM1 and SPDL1.\",\n      \"evidence\": \"Co-IP, minigene splicing assays, cell-cycle analysis, and splicing-mimicking epistasis in HeLa cells\",\n      \"pmids\": [\"34544891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the SPF45/CHERP/U2SURP complex\", \"Rescue was only partial, implying additional targets\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed U2SURP in a signaling axis by showing MYC drives its translation via eIF3D and that it acts upstream of SAT1 through intron retention/removal affecting mRNA stability.\",\n      \"evidence\": \"Translation and mRNA-stability assays, RT-PCR splicing analysis, and xenograft rescue in TNBC cells\",\n      \"pmids\": [\"36907504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstitution of the splicing event\", \"Direct binding to SAT1 pre-mRNA not demonstrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated lncRNA-directed recruitment of U2SURP, showing HNF1A-AS1 engages its RRM domain to redirect CD44 splicing toward a pro-metastatic isoform.\",\n      \"evidence\": \"RNA pull-down, Co-IP, FISH, domain-deletion, and rescue assays in pancreatic cancer cells\",\n      \"pmids\": [\"40518456\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Generality of lncRNA-guided targeting to other transcripts unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended U2SURP function to mRNA stabilization of CREB3L2 with downstream RIOK1 activation and drug-resistance phenotypes.\",\n      \"evidence\": \"mRNA stability assays, knockdown/overexpression rescue, and xenograft models in HCC cells\",\n      \"pmids\": [\"41997041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of mRNA stabilization undefined\", \"Direct U2SURP–CREB3L2 interaction not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Associated U2SURP with Ras/MAPK output via reduced p-ERK after knockdown.\",\n      \"evidence\": \"siRNA knockdown and p-ERK Western blot in CML cells\",\n      \"pmids\": [\"41274252\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single downstream readout with no direct mechanistic link to ERK\", \"Not confirmed independently\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Nominated U2SURP as a DNA damage response factor through proximity to γH2AX-marked chromatin.\",\n      \"evidence\": \"TurboID proximity proteomics with γH2AX-binding BRCT probes (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.10.23.619792\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Mechanistic role in DNA repair undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How U2SURP selects its specific exon and mRNA targets across diverse contexts—and whether its splicing activity and reported mRNA-stabilization/DDR roles are mechanistically distinct functions—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the complex or RNA recognition\", \"Unclear how splicing repression relates to mRNA stabilization\", \"DDR role uncharacterized at the mechanistic level\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\"SPF45-CHERP-U2SURP splicing complex\", \"SNAI2-HNF1A-AS1-U2SURP complex\"],\n    \"partners\": [\"SPF45\", \"CHERP\", \"RBM17\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}