{"gene":"UBAP2","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2016,"finding":"UBAP2 forms a complex with Annexin A2 and promotes ubiquitination-dependent proteasomal degradation of Annexin A2, thereby inhibiting invasion and proliferation of hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, knockdown and overexpression with invasion/proliferation readouts, in vivo xenograft","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal complex formation shown, functional ubiquitination assay, KD/OE with defined phenotype, single lab","pmids":["27121050"],"is_preprint":false},{"year":2022,"finding":"UBAP2 (and its paralogue UBAP2L) are the human orthologues of yeast Def1 and are required for UV-induced ubiquitylation and degradation of the largest RNA polymerase II subunit RPB1, acting through recruitment of the Elongin-Cul5 ubiquitin ligase complex.","method":"UV irradiation experiments, RNAPII ubiquitylation and degradation assays, knockdown of UBAP2/UBAP2L, Elongin-Cul5 recruitment assays","journal":"DNA repair","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional ubiquitylation assay with defined ligase recruitment, loss-of-function with specific molecular phenotype, identification of human orthology to yeast Def1 using multiple methods","pmids":["35633597"],"is_preprint":false},{"year":2023,"finding":"Polyubiquitinated PAICS (K6-linked, catalyzed by Cul5/ASB11 ubiquitin ligase) recruits UBAP2 via its ubiquitin-binding domain; UBAP2's intrinsically disordered regions then drive phase separation to trigger purinosome assembly and enhance de novo purine synthesis flux.","method":"Co-immunoprecipitation, phase separation assays, ubiquitination assays, UBAP2 knockdown/overexpression, purine synthesis flux measurements, xenograft model","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstitution of phase separation, defined ubiquitin-binding mechanism, multiple orthogonal assays (Co-IP, ubiquitination, flux, in vivo), single rigorous study","pmids":["37848033"],"is_preprint":false},{"year":2024,"finding":"UBAP2 promotes radioresistance in hepatocellular carcinoma by ubiquitinating and degrading SLC27A5 via the ubiquitin-proteasome system, which in turn decreases RAD51 (homologous recombination) but not CTIP (NHEJ), thereby enhancing homologous recombination-mediated DNA repair.","method":"UBAP2 knockdown and ectopic SLC27A5 expression rescue, in vitro and in vivo radiation resistance assays, ubiquitin-proteasome pathway inhibition, RAD51/CTIP protein level analysis","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue experiment, defined ubiquitination substrate, specific molecular pathway readout, single lab","pmids":["39186963"],"is_preprint":false},{"year":2023,"finding":"Pancreatic-specific knockout of Ubap2 in mice reduces NF-κB activation during cerulein-induced pancreatitis, leading to decreased inflammatory cytokines, reduced amylase/lipase, and lessened neutrophil infiltration; in vitro promoter binding studies confirmed reduced NF-κB binding to target promoters.","method":"Pancreas-specific Cre KO mice, cerulein pancreatitis model, NF-κB activation assays, promoter binding studies, cytokine/enzyme measurements","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with defined molecular phenotype (NF-κB), supported by promoter binding studies, single lab","pmids":["37865160"],"is_preprint":false},{"year":2023,"finding":"Knockdown of Ubap2 in mouse cells decreases osteoblastogenesis and increases osteoclastogenesis; Ubap2 expression is associated with E-cadherin (Cdh1) and Fra1 (Fosl1) expression in osteoclastogenesis-induced monocytes, indicating a role in bone remodeling.","method":"Ubap2 knockdown in mouse cells, osteoblastogenesis/osteoclastogenesis assays, zebrafish ubap2 knockdown with bone formation readout, expression correlation with Cdh1/Fosl1","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular differentiation phenotype in two model systems, molecular association with known bone regulators, single lab","pmids":["37339951"],"is_preprint":false},{"year":2020,"finding":"A circRNA derived from the UBAP2 locus (hsa_circ_0003141) acts as a ceRNA sponging miR-1827, thereby upregulating UBAP2 protein expression in hepatocellular carcinoma cells; knockdown of hsa_circ_0003141 suppresses UBAP2 expression, induces apoptosis, and inhibits proliferation and invasion.","method":"Bioinformatics, miRNA binding assay, UBAP2 protein measurement after circRNA knockdown, xenograft model","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single circRNA-based regulatory mechanism for UBAP2 protein level, no direct enzymatic or structural characterization of UBAP2 itself","pmids":["32464601"],"is_preprint":false}],"current_model":"UBAP2 is a ubiquitin-binding protein that functions as the human orthologue of yeast Def1, mediating UV-induced ubiquitylation and degradation of RNA polymerase II (RPB1) via Elongin-Cul5 recruitment; it also promotes ubiquitin-proteasome-dependent degradation of specific substrates (Annexin A2, SLC27A5), and its ubiquitin-binding activity enables recruitment to polyubiquitinated PAICS where its intrinsically disordered regions drive phase separation to assemble purinosomes, thereby enhancing de novo purine synthesis; additionally, UBAP2 regulates NF-κB-dependent inflammation in the pancreas and plays a role in bone remodeling by influencing osteoblastogenesis and osteoclastogenesis."},"narrative":{"mechanistic_narrative":"UBAP2 is a ubiquitin-binding protein that couples recognition of polyubiquitinated proteins to substrate degradation and to higher-order assembly of metabolic condensates [PMID:37848033, PMID:35633597]. As the human orthologue of yeast Def1 (together with its paralogue UBAP2L), it is required for UV-induced ubiquitylation and degradation of the largest RNA polymerase II subunit RPB1, acting through recruitment of the Elongin-Cul5 ubiquitin ligase [PMID:35633597]. Beyond promoting degradation, its ubiquitin-binding domain reads K6-linked polyubiquitin on PAICS deposited by the Cul5/ASB11 ligase, and its intrinsically disordered regions then drive phase separation to nucleate purinosome assembly and increase de novo purine synthesis flux [PMID:37848033]. UBAP2 also promotes ubiquitin-proteasome-dependent turnover of specific substrates—Annexin A2, where its degradation restrains hepatocellular carcinoma invasion and proliferation [PMID:27121050], and SLC27A5, whose loss lowers RAD51 to bias DNA repair toward homologous recombination and confer radioresistance [PMID:39186963]. At the organismal level, UBAP2 supports NF-κB activation during pancreatitis [PMID:37865160] and influences bone remodeling by promoting osteoblastogenesis while restraining osteoclastogenesis [PMID:37339951].","teleology":[{"year":2016,"claim":"Established the first direct substrate relationship for UBAP2, showing it drives ubiquitination-dependent proteasomal degradation of a binding partner with a defined cellular consequence.","evidence":"Co-IP, ubiquitination assays, and knockdown/overexpression with invasion/proliferation readouts plus xenograft in hepatocellular carcinoma cells","pmids":["27121050"],"confidence":"Medium","gaps":["Does not identify the cognate E3 ligase for Annexin A2","Single lab; ubiquitin-binding domain dependence not dissected"]},{"year":2020,"claim":"Addressed how UBAP2 protein levels are upregulated in cancer, identifying an upstream circRNA-miRNA regulatory axis controlling UBAP2 expression.","evidence":"Bioinformatics, miRNA binding assay, and UBAP2 protein measurement after circRNA knockdown with xenograft in hepatocellular carcinoma cells","pmids":["32464601"],"confidence":"Low","gaps":["Indirect; describes regulation of UBAP2 abundance, not UBAP2 molecular function","No enzymatic or structural characterization of UBAP2 itself","Single lab, single circRNA mechanism"]},{"year":2022,"claim":"Defined UBAP2 as the human Def1 orthologue and placed it in a specific ubiquitin-ligase pathway, answering how transcription-blocking damage triggers RNA polymerase II degradation.","evidence":"UV irradiation, RPB1 ubiquitylation/degradation assays, UBAP2/UBAP2L knockdown, and Elongin-Cul5 recruitment assays","pmids":["35633597"],"confidence":"High","gaps":["Functional redundancy versus distinct roles of UBAP2 and UBAP2L not resolved","Structural basis of Elongin-Cul5 recruitment not defined"]},{"year":2023,"claim":"Revealed a non-degradative function: UBAP2 reads a specific ubiquitin signal and uses its disordered regions to nucleate a metabolic condensate, linking ubiquitin recognition to phase separation.","evidence":"Co-IP, ubiquitination assays, in vitro phase separation, purine flux measurements, and knockdown/overexpression with xenograft","pmids":["37848033"],"confidence":"High","gaps":["Determinants of K6-linkage specificity by the ubiquitin-binding domain not mapped","Stoichiometry and regulation of purinosome dissolution unaddressed"]},{"year":2023,"claim":"Extended UBAP2 function to inflammatory signaling in vivo, showing it is required for full NF-κB activation in the pancreas.","evidence":"Pancreas-specific Cre knockout mice in cerulein pancreatitis, NF-κB activation and promoter binding studies, cytokine/enzyme measurements","pmids":["37865160"],"confidence":"Medium","gaps":["Molecular link between UBAP2 ubiquitin-binding activity and NF-κB not defined","Single lab"]},{"year":2023,"claim":"Implicated UBAP2 in skeletal homeostasis by showing opposing effects on osteoblast and osteoclast differentiation.","evidence":"Ubap2 knockdown in mouse cells and zebrafish, osteoblastogenesis/osteoclastogenesis assays, expression correlation with Cdh1/Fosl1","pmids":["37339951"],"confidence":"Medium","gaps":["Mechanistic connection to UBAP2's ubiquitin-binding/degradation activity unknown","Direct molecular targets in bone cells not identified"]},{"year":2024,"claim":"Identified a second degradation substrate that links UBAP2 to DNA repair pathway choice and therapy resistance.","evidence":"UBAP2 knockdown with SLC27A5 rescue, proteasome inhibition, RAD51/CTIP analysis, and in vitro/in vivo radiation assays in hepatocellular carcinoma","pmids":["39186963"],"confidence":"Medium","gaps":["E3 ligase mediating SLC27A5 ubiquitination not identified","Mechanism connecting SLC27A5 to RAD51 levels not resolved","Single lab"]},{"year":null,"claim":"How UBAP2's ubiquitin-binding activity is mechanistically partitioned between substrate degradation, condensate nucleation, and inflammatory/skeletal signaling, and how it differs functionally from UBAP2L, remains unresolved.","evidence":"No single study reconciles the degradative, phase-separation, and signaling roles into one regulatory framework","pmids":[],"confidence":"Low","gaps":["No structure of the ubiquitin-binding domain or IDRs","Linkage specificity rules across contexts unknown","Division of labor between UBAP2 and UBAP2L undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,3]}],"complexes":["purinosome","Elongin-Cul5 ubiquitin ligase (recruited)"],"partners":["ANXA2","PAICS","UBAP2L","SLC27A5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5T6F2","full_name":"Ubiquitin-associated protein 2","aliases":["RNA polymerase II degradation factor UBAP2"],"length_aa":1119,"mass_kda":117.1,"function":"Recruits the ubiquitination machinery to RNA polymerase II for polyubiquitination, removal and degradation, when the transcription-coupled nucleotide excision repair (TC-NER) machinery fails to resolve DNA damage (PubMed:35633597). May promote the degradation of ANXA2 (PubMed:27121050)","subcellular_location":"Nucleus; Chromosome; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q5T6F2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBAP2","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UBAP2","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UBAP2"},"hgnc":{"alias_symbol":["KIAA1491","bA176F3.5","FLJ22435"],"prev_symbol":[]},"alphafold":{"accession":"Q5T6F2","domains":[{"cath_id":"1.10.8.10","chopping":"53-90","consensus_level":"medium","plddt":93.66,"start":53,"end":90}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T6F2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T6F2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T6F2-F1-predicted_aligned_error_v6.png","plddt_mean":43.16},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBAP2","jax_strain_url":"https://www.jax.org/strain/search?query=UBAP2"},"sequence":{"accession":"Q5T6F2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5T6F2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5T6F2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T6F2"}},"corpus_meta":[{"pmid":"28977896","id":"PMC_28977896","title":"Increased circular RNA UBAP2 acts as a sponge of miR-143 to promote osteosarcoma progression.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28977896","citation_count":131,"is_preprint":false},{"pmid":"32690086","id":"PMC_32690086","title":"circRNA-UBAP2 promotes the proliferation and inhibits apoptosis of ovarian cancer though miR-382-5p/PRPF8 axis.","date":"2020","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/32690086","citation_count":57,"is_preprint":false},{"pmid":"31539115","id":"PMC_31539115","title":"CircRNA UBAP2 promotes the progression of ovarian cancer by sponging microRNA-144.","date":"2019","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31539115","citation_count":37,"is_preprint":false},{"pmid":"35263216","id":"PMC_35263216","title":"Circular RNA UBAP2 facilitates the cisplatin resistance of triple-negative breast cancer via microRNA-300/anti-silencing function 1B histone chaperone/PI3K/AKT/mTOR axis.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35263216","citation_count":34,"is_preprint":false},{"pmid":"32767322","id":"PMC_32767322","title":"CircRNA UBAP2 facilitates the progression of colorectal cancer by regulating miR-199a/VEGFA pathway.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32767322","citation_count":33,"is_preprint":false},{"pmid":"37848033","id":"PMC_37848033","title":"PAICS ubiquitination recruits UBAP2 to trigger phase separation for purinosome assembly.","date":"2023","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/37848033","citation_count":28,"is_preprint":false},{"pmid":"32760224","id":"PMC_32760224","title":"Circular RNA UBAP2 contributes to tumor growth and metastasis of cervical cancer via modulating miR-361-3p/SOX4 axis.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/32760224","citation_count":28,"is_preprint":false},{"pmid":"33543830","id":"PMC_33543830","title":"Circ-UBAP2 functions as sponges of miR-1205 and miR-382 to promote glioma progression by modulating STC1 expression.","date":"2021","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33543830","citation_count":27,"is_preprint":false},{"pmid":"27121050","id":"PMC_27121050","title":"UBAP2 negatively regulates the invasion of hepatocellular carcinoma cell by ubiquitinating and degradating Annexin A2.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27121050","citation_count":25,"is_preprint":false},{"pmid":"29277177","id":"PMC_29277177","title":"[Effect of Circular RNA UBAP2 Silencing on Proliferation and Invasion of Human Lung Cancer A549 Cells and Its Mechanism].","date":"2017","source":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29277177","citation_count":25,"is_preprint":false},{"pmid":"34608841","id":"PMC_34608841","title":"Downregulation of circ-UBAP2 ameliorates oxidative stress and dysfunctions of human retinal microvascular endothelial cells (hRMECs) via miR-589-5p/EGR1 axis.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34608841","citation_count":24,"is_preprint":false},{"pmid":"32012318","id":"PMC_32012318","title":"Knockdown of circular RNA UBAP2 inhibits the malignant behaviours of esophageal squamous cell carcinoma by microRNA-422a/Rab10 axis.","date":"2020","source":"Clinical and experimental pharmacology & physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32012318","citation_count":24,"is_preprint":false},{"pmid":"34314478","id":"PMC_34314478","title":"CircRNA UBAP2 serves as a sponge of miR-1294 to increase tumorigenesis in hepatocellular carcinoma through regulating c-Myc expression.","date":"2021","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/34314478","citation_count":24,"is_preprint":false},{"pmid":"32464601","id":"PMC_32464601","title":"Circular RNA hsa_circ_0003141 promotes tumorigenesis of hepatocellular carcinoma via a miR-1827/UBAP2 axis.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32464601","citation_count":22,"is_preprint":false},{"pmid":"33968202","id":"PMC_33968202","title":"Circular RNA UBAP2 promotes the proliferation of prostate cancer cells via the miR-1244/MAP3K2 axis.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/33968202","citation_count":19,"is_preprint":false},{"pmid":"35633597","id":"PMC_35633597","title":"UBAP2/UBAP2L regulate UV-induced ubiquitylation of RNA polymerase II and are the human orthologues of yeast Def1.","date":"2022","source":"DNA repair","url":"https://pubmed.ncbi.nlm.nih.gov/35633597","citation_count":18,"is_preprint":false},{"pmid":"35114890","id":"PMC_35114890","title":"Circular RNA circ_UBAP2 facilitates the progression of osteosarcoma by regulating microRNA miR-637/high-mobility group box (HMGB) 2 axis.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35114890","citation_count":17,"is_preprint":false},{"pmid":"37339951","id":"PMC_37339951","title":"UBAP2 plays a role in bone homeostasis through the regulation of osteoblastogenesis and osteoclastogenesis.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37339951","citation_count":11,"is_preprint":false},{"pmid":"35759302","id":"PMC_35759302","title":"Circular RNA UBAP2 (hsa_circ_0007367) Correlates with Microcirculatory Perfusion and Predicts Outcomes of Cardiogenic Shock Patients Undergoing Extracorporeal Membrane Oxygenation Support.","date":"2022","source":"Shock (Augusta, Ga.)","url":"https://pubmed.ncbi.nlm.nih.gov/35759302","citation_count":10,"is_preprint":false},{"pmid":"39186963","id":"PMC_39186963","title":"UBAP2 contributes to radioresistance by enhancing homologous recombination through SLC27A5 ubiquitination in hepatocellular carcinoma.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/39186963","citation_count":8,"is_preprint":false},{"pmid":"37865160","id":"PMC_37865160","title":"Pancreatic Ubap2 deletion regulates glucose tolerance, inflammation, and protection from cerulein-induced pancreatitis.","date":"2023","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/37865160","citation_count":6,"is_preprint":false},{"pmid":"37676907","id":"PMC_37676907","title":"Circ_UBAP2 exacerbates proliferation and metastasis of OS via targeting miR-665/miR-370-3p/HMGA1 axis.","date":"2023","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/37676907","citation_count":2,"is_preprint":false},{"pmid":"41201975","id":"PMC_41201975","title":"Functional Divergence between the Z and W Alleles of the <italic>UBAP2</italic> Gene Revealed by Differences in Their Expression Patterns in Japanese Quail.","date":"2025","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/41201975","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.08.652797","title":"Locus-specific Convergent Evolution and Interchromosomal Rearrangements Contribute Type I Interferon Diversification in Amniotes","date":"2025-05-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.08.652797","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14637,"output_tokens":1901,"usd":0.036213,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8826,"output_tokens":2805,"usd":0.057127,"stage2_stop_reason":"end_turn"},"total_usd":0.09334,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"UBAP2 forms a complex with Annexin A2 and promotes ubiquitination-dependent proteasomal degradation of Annexin A2, thereby inhibiting invasion and proliferation of hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, knockdown and overexpression with invasion/proliferation readouts, in vivo xenograft\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal complex formation shown, functional ubiquitination assay, KD/OE with defined phenotype, single lab\",\n      \"pmids\": [\"27121050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UBAP2 (and its paralogue UBAP2L) are the human orthologues of yeast Def1 and are required for UV-induced ubiquitylation and degradation of the largest RNA polymerase II subunit RPB1, acting through recruitment of the Elongin-Cul5 ubiquitin ligase complex.\",\n      \"method\": \"UV irradiation experiments, RNAPII ubiquitylation and degradation assays, knockdown of UBAP2/UBAP2L, Elongin-Cul5 recruitment assays\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional ubiquitylation assay with defined ligase recruitment, loss-of-function with specific molecular phenotype, identification of human orthology to yeast Def1 using multiple methods\",\n      \"pmids\": [\"35633597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Polyubiquitinated PAICS (K6-linked, catalyzed by Cul5/ASB11 ubiquitin ligase) recruits UBAP2 via its ubiquitin-binding domain; UBAP2's intrinsically disordered regions then drive phase separation to trigger purinosome assembly and enhance de novo purine synthesis flux.\",\n      \"method\": \"Co-immunoprecipitation, phase separation assays, ubiquitination assays, UBAP2 knockdown/overexpression, purine synthesis flux measurements, xenograft model\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstitution of phase separation, defined ubiquitin-binding mechanism, multiple orthogonal assays (Co-IP, ubiquitination, flux, in vivo), single rigorous study\",\n      \"pmids\": [\"37848033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBAP2 promotes radioresistance in hepatocellular carcinoma by ubiquitinating and degrading SLC27A5 via the ubiquitin-proteasome system, which in turn decreases RAD51 (homologous recombination) but not CTIP (NHEJ), thereby enhancing homologous recombination-mediated DNA repair.\",\n      \"method\": \"UBAP2 knockdown and ectopic SLC27A5 expression rescue, in vitro and in vivo radiation resistance assays, ubiquitin-proteasome pathway inhibition, RAD51/CTIP protein level analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue experiment, defined ubiquitination substrate, specific molecular pathway readout, single lab\",\n      \"pmids\": [\"39186963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Pancreatic-specific knockout of Ubap2 in mice reduces NF-κB activation during cerulein-induced pancreatitis, leading to decreased inflammatory cytokines, reduced amylase/lipase, and lessened neutrophil infiltration; in vitro promoter binding studies confirmed reduced NF-κB binding to target promoters.\",\n      \"method\": \"Pancreas-specific Cre KO mice, cerulein pancreatitis model, NF-κB activation assays, promoter binding studies, cytokine/enzyme measurements\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with defined molecular phenotype (NF-κB), supported by promoter binding studies, single lab\",\n      \"pmids\": [\"37865160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Knockdown of Ubap2 in mouse cells decreases osteoblastogenesis and increases osteoclastogenesis; Ubap2 expression is associated with E-cadherin (Cdh1) and Fra1 (Fosl1) expression in osteoclastogenesis-induced monocytes, indicating a role in bone remodeling.\",\n      \"method\": \"Ubap2 knockdown in mouse cells, osteoblastogenesis/osteoclastogenesis assays, zebrafish ubap2 knockdown with bone formation readout, expression correlation with Cdh1/Fosl1\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular differentiation phenotype in two model systems, molecular association with known bone regulators, single lab\",\n      \"pmids\": [\"37339951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A circRNA derived from the UBAP2 locus (hsa_circ_0003141) acts as a ceRNA sponging miR-1827, thereby upregulating UBAP2 protein expression in hepatocellular carcinoma cells; knockdown of hsa_circ_0003141 suppresses UBAP2 expression, induces apoptosis, and inhibits proliferation and invasion.\",\n      \"method\": \"Bioinformatics, miRNA binding assay, UBAP2 protein measurement after circRNA knockdown, xenograft model\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single circRNA-based regulatory mechanism for UBAP2 protein level, no direct enzymatic or structural characterization of UBAP2 itself\",\n      \"pmids\": [\"32464601\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBAP2 is a ubiquitin-binding protein that functions as the human orthologue of yeast Def1, mediating UV-induced ubiquitylation and degradation of RNA polymerase II (RPB1) via Elongin-Cul5 recruitment; it also promotes ubiquitin-proteasome-dependent degradation of specific substrates (Annexin A2, SLC27A5), and its ubiquitin-binding activity enables recruitment to polyubiquitinated PAICS where its intrinsically disordered regions drive phase separation to assemble purinosomes, thereby enhancing de novo purine synthesis; additionally, UBAP2 regulates NF-κB-dependent inflammation in the pancreas and plays a role in bone remodeling by influencing osteoblastogenesis and osteoclastogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBAP2 is a ubiquitin-binding protein that couples recognition of polyubiquitinated proteins to substrate degradation and to higher-order assembly of metabolic condensates [#2, #1]. As the human orthologue of yeast Def1 (together with its paralogue UBAP2L), it is required for UV-induced ubiquitylation and degradation of the largest RNA polymerase II subunit RPB1, acting through recruitment of the Elongin-Cul5 ubiquitin ligase [#1]. Beyond promoting degradation, its ubiquitin-binding domain reads K6-linked polyubiquitin on PAICS deposited by the Cul5/ASB11 ligase, and its intrinsically disordered regions then drive phase separation to nucleate purinosome assembly and increase de novo purine synthesis flux [#2]. UBAP2 also promotes ubiquitin-proteasome-dependent turnover of specific substrates—Annexin A2, where its degradation restrains hepatocellular carcinoma invasion and proliferation [#0], and SLC27A5, whose loss lowers RAD51 to bias DNA repair toward homologous recombination and confer radioresistance [#3]. At the organismal level, UBAP2 supports NF-\\u03baB activation during pancreatitis [#4] and influences bone remodeling by promoting osteoblastogenesis while restraining osteoclastogenesis [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established the first direct substrate relationship for UBAP2, showing it drives ubiquitination-dependent proteasomal degradation of a binding partner with a defined cellular consequence.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, and knockdown/overexpression with invasion/proliferation readouts plus xenograft in hepatocellular carcinoma cells\",\n      \"pmids\": [\"27121050\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the cognate E3 ligase for Annexin A2\", \"Single lab; ubiquitin-binding domain dependence not dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Addressed how UBAP2 protein levels are upregulated in cancer, identifying an upstream circRNA-miRNA regulatory axis controlling UBAP2 expression.\",\n      \"evidence\": \"Bioinformatics, miRNA binding assay, and UBAP2 protein measurement after circRNA knockdown with xenograft in hepatocellular carcinoma cells\",\n      \"pmids\": [\"32464601\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Indirect; describes regulation of UBAP2 abundance, not UBAP2 molecular function\", \"No enzymatic or structural characterization of UBAP2 itself\", \"Single lab, single circRNA mechanism\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined UBAP2 as the human Def1 orthologue and placed it in a specific ubiquitin-ligase pathway, answering how transcription-blocking damage triggers RNA polymerase II degradation.\",\n      \"evidence\": \"UV irradiation, RPB1 ubiquitylation/degradation assays, UBAP2/UBAP2L knockdown, and Elongin-Cul5 recruitment assays\",\n      \"pmids\": [\"35633597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional redundancy versus distinct roles of UBAP2 and UBAP2L not resolved\", \"Structural basis of Elongin-Cul5 recruitment not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a non-degradative function: UBAP2 reads a specific ubiquitin signal and uses its disordered regions to nucleate a metabolic condensate, linking ubiquitin recognition to phase separation.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, in vitro phase separation, purine flux measurements, and knockdown/overexpression with xenograft\",\n      \"pmids\": [\"37848033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of K6-linkage specificity by the ubiquitin-binding domain not mapped\", \"Stoichiometry and regulation of purinosome dissolution unaddressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended UBAP2 function to inflammatory signaling in vivo, showing it is required for full NF-\\u03baB activation in the pancreas.\",\n      \"evidence\": \"Pancreas-specific Cre knockout mice in cerulein pancreatitis, NF-\\u03baB activation and promoter binding studies, cytokine/enzyme measurements\",\n      \"pmids\": [\"37865160\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between UBAP2 ubiquitin-binding activity and NF-\\u03baB not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated UBAP2 in skeletal homeostasis by showing opposing effects on osteoblast and osteoclast differentiation.\",\n      \"evidence\": \"Ubap2 knockdown in mouse cells and zebrafish, osteoblastogenesis/osteoclastogenesis assays, expression correlation with Cdh1/Fosl1\",\n      \"pmids\": [\"37339951\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic connection to UBAP2's ubiquitin-binding/degradation activity unknown\", \"Direct molecular targets in bone cells not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a second degradation substrate that links UBAP2 to DNA repair pathway choice and therapy resistance.\",\n      \"evidence\": \"UBAP2 knockdown with SLC27A5 rescue, proteasome inhibition, RAD51/CTIP analysis, and in vitro/in vivo radiation assays in hepatocellular carcinoma\",\n      \"pmids\": [\"39186963\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating SLC27A5 ubiquitination not identified\", \"Mechanism connecting SLC27A5 to RAD51 levels not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UBAP2's ubiquitin-binding activity is mechanistically partitioned between substrate degradation, condensate nucleation, and inflammatory/skeletal signaling, and how it differs functionally from UBAP2L, remains unresolved.\",\n      \"evidence\": \"No single study reconciles the degradative, phase-separation, and signaling roles into one regulatory framework\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of the ubiquitin-binding domain or IDRs\", \"Linkage specificity rules across contexts unknown\", \"Division of labor between UBAP2 and UBAP2L undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [\"purinosome\", \"Elongin-Cul5 ubiquitin ligase (recruited)\"],\n    \"partners\": [\"ANXA2\", \"PAICS\", \"UBAP2L\", \"SLC27A5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}