{"gene":"UBL5","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2003,"finding":"UBL5 has a ubiquitin-like beta-grasp fold determined by NMR; unlike ubiquitin, its C-terminal di-tyrosine motif is embedded within the final beta-sheet rather than extending beyond it, consistent with the lack of canonical conjugation activity. UBL5 was confirmed to specifically interact with the cyclin-like kinase CLK4, and not with other CLK family members.","method":"NMR structure determination; specific binding confirmed by interaction assay with CLK family members","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional validation of CLK4 specificity, single lab but orthogonal structural and binding methods","pmids":["12824502"],"is_preprint":false},{"year":2001,"finding":"Recombinant UBL5 protein localizes to the cytoplasm in COS-7 cells as shown by intracellular localization experiments, and migrates at ~9 kDa on Western blot.","method":"Intracellular localization experiments in COS-7 cells; Western blot","journal":"Genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (overexpressed recombinant protein localization without functional consequence)","pmids":["11161819"],"is_preprint":false},{"year":2006,"finding":"Under hypo-osmotic conditions, UBL5 is exported from the nucleus and subsequently degraded in a proteasome-dependent, transcription-independent manner, establishing a regulated subcellular redistribution and stability change linked to osmotic stress.","method":"Time-course immunocytochemistry of exogenous UBL5 in NIH-3T3 cells; proteasome inhibitor treatment; brain slice experiments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (proteasomal degradation after nuclear export), two orthogonal methods (immunocytochemistry + proteasome inhibition), single lab","pmids":["17026961"],"is_preprint":false},{"year":2013,"finding":"Human UBL5 localizes to the nucleus and partially associates with Cajal bodies. UBL5 physically interacts with coilin (the Cajal body scaffold protein) as shown by GST pull-down using both in vitro-translated and cell-extracted coilin; this interaction is not influenced by coilin phosphorylation.","method":"Immunofluorescence localization; co-expression in HeLa cells; GST pull-down with in vitro-translated and HEK293T-extracted coilin","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pull-down with two sources of coilin plus co-localization, single lab, two orthogonal methods","pmids":["23726919"],"is_preprint":false},{"year":2014,"finding":"UBL5 is required for pre-mRNA splicing efficiency in human cells; its depletion causes globally enhanced intron retention. UBL5 primarily associates with spliceosomal proteins. Defective splicing leads to selective downregulation of the cohesion protection factor Sororin, which in turn causes defective sister chromatid cohesion.","method":"siRNA knockdown; RNA-seq (intron retention analysis); co-immunoprecipitation with spliceosomal proteins; sister chromatid cohesion assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with spliceosomal proteins, genome-wide splicing analysis, defined cellular phenotype (cohesion), epistasis through Sororin, replicated across multiple orthogonal methods","pmids":["25092792"],"is_preprint":false},{"year":2015,"finding":"UBL5 physically interacts with the Fanconi anemia pathway component FANCI via a specific non-covalent interaction. UBL5 loss causes spliceosome-independent reduction of FANCI protein stability. Separation-of-function mutants that selectively abolish UBL5-FANCI binding compromise FANCI-FANCD2 heterodimerization, FANCD2 and FANCI monoubiquitylation, and chromosome stability after DNA interstrand crosslink (ICL) damage.","method":"Co-immunoprecipitation; domain-mapping mutagenesis; separation-of-function mutants; FANCI stability assay; monoubiquitylation assay; ICL sensitivity assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, mutagenesis, functional assays for ubiquitylation and chromosomal stability), clear mechanistic dissection with separation-of-function mutants","pmids":["25862789"],"is_preprint":false}],"current_model":"UBL5 is an atypical ubiquitin-like protein that lacks covalent conjugation activity (due to its C-terminal di-tyrosine rather than di-glycine motif) and instead functions through non-covalent interactions: it associates with spliceosomal proteins and Cajal body component coilin to promote pre-mRNA splicing fidelity (loss causes global intron retention and consequent Sororin downregulation/cohesion defects), and it stabilizes the Fanconi anemia factor FANCI to support ICL-induced FANCI-FANCD2 heterodimerization and monoubiquitylation; additionally, UBL5 undergoes osmotic-stress-induced nuclear export followed by proteasomal degradation, and specifically binds the kinase CLK4."},"narrative":{"mechanistic_narrative":"UBL5 is an atypical ubiquitin-like protein that adopts the ubiquitin beta-grasp fold yet lacks canonical conjugation activity, because its C-terminal di-tyrosine motif is embedded within the final beta-sheet rather than extending outward as in ubiquitin; it instead acts through non-covalent protein interactions, and binds specifically to the cyclin-like kinase CLK4 among the CLK family [PMID:12824502]. In the nucleus it partially associates with Cajal bodies through a phosphorylation-independent physical interaction with the scaffold protein coilin [PMID:23726919], and it associates predominantly with spliceosomal proteins to support pre-mRNA splicing efficiency: its depletion causes global intron retention, which selectively downregulates the cohesion protection factor Sororin and thereby produces defective sister chromatid cohesion [PMID:25092792]. Independently of its splicing role, UBL5 binds the Fanconi anemia factor FANCI and stabilizes the FANCI protein; separation-of-function mutants that selectively disrupt UBL5-FANCI binding compromise FANCI-FANCD2 heterodimerization, FANCD2/FANCI monoubiquitylation, and chromosome stability after DNA interstrand crosslink damage [PMID:25862789]. UBL5 abundance and localization are also regulated by stress, undergoing nuclear export followed by proteasome-dependent, transcription-independent degradation under hypo-osmotic conditions [PMID:17026961].","teleology":[{"year":2003,"claim":"Establishing why UBL5 behaves unlike ubiquitin: its fold and motif positioning explain the absence of conjugation activity, while defining CLK4 as a specific binding partner reframed UBL5 as a non-covalent interactor.","evidence":"NMR structure determination with interaction assays across CLK family members","pmids":["12824502"],"confidence":"High","gaps":["Functional consequence of UBL5-CLK4 binding not determined","No structure of a UBL5-partner complex","CLK4 specificity not connected to splicing or other downstream pathways"]},{"year":2006,"claim":"Showed that UBL5 levels and localization are dynamically regulated, linking osmotic stress to its nuclear export and proteasomal turnover rather than being a static structural protein.","evidence":"Time-course immunocytochemistry of exogenous UBL5 in NIH-3T3 cells, proteasome inhibition, and brain slice experiments","pmids":["17026961"],"confidence":"Medium","gaps":["Export and degradation machinery not identified","Used exogenous protein rather than endogenous UBL5","Physiological purpose of stress-induced turnover unresolved"]},{"year":2013,"claim":"Connected UBL5 to a defined nuclear compartment by demonstrating direct binding to the Cajal body scaffold coilin, providing a structural basis for its nuclear association.","evidence":"Immunofluorescence co-localization and GST pull-down with in vitro-translated and cell-extracted coilin in HeLa/HEK293T cells","pmids":["23726919"],"confidence":"Medium","gaps":["Functional consequence of UBL5-coilin binding not established","Binding interface not mapped","Relationship between Cajal body association and splicing role unclear"]},{"year":2014,"claim":"Defined UBL5's principal cellular function as supporting splicing fidelity, and traced an epistatic chain from intron retention to Sororin loss and cohesion defects.","evidence":"siRNA knockdown with RNA-seq intron-retention analysis, co-IP with spliceosomal proteins, and sister chromatid cohesion assays in human cells","pmids":["25092792"],"confidence":"High","gaps":["Which spliceosomal step UBL5 acts at is undefined","Direct molecular mechanism within the spliceosome unknown","Whether CLK4 or coilin binding contributes to the splicing role untested"]},{"year":2015,"claim":"Revealed a splicing-independent role in genome stability by showing UBL5 stabilizes FANCI and is required for FANCI-FANCD2 activation after crosslink damage.","evidence":"Co-IP, domain mapping, separation-of-function mutants, FANCI stability, monoubiquitylation, and ICL sensitivity assays","pmids":["25862789"],"confidence":"High","gaps":["Mechanism by which UBL5 binding stabilizes FANCI not resolved","Whether this role requires nuclear/Cajal body localization untested","No structure of the UBL5-FANCI complex"]},{"year":null,"claim":"How UBL5's distinct activities — CLK4 binding, coilin/Cajal body association, spliceosomal support, FANCI stabilization, and stress-regulated turnover — are mechanistically unified through a single non-covalent interaction surface remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of UBL5's interaction surface across partners","Functional significance of CLK4 and coilin binding unestablished","Whether splicing and FA roles share a common binding mode unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4]}],"complexes":["spliceosome","Cajal body"],"partners":["CLK4","COILIN","FANCI","FANCD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BZL1","full_name":"Ubiquitin-like protein 5","aliases":[],"length_aa":73,"mass_kda":8.5,"function":"Ubiquitin-like protein that plays a role in cell proliferation and sister chromatid cohesion by associating with spliceosomal proteins (PubMed:25092792). Participates thereby in pre-mRNA splicing by maintaining spliceosome integrity. Promotes the functional integrity of the Fanconi anemia DNA repair pathway by interacting with FANCI component and subsequently mediating the formation of FANCI homodimers (PubMed:25862789). Also plays a protective role against ER stress-induced apoptosis (PubMed:37315790)","subcellular_location":"Cytoplasm; Nucleus; Nucleus, Cajal body","url":"https://www.uniprot.org/uniprotkb/Q9BZL1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/UBL5","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ATL3","stoichiometry":0.2},{"gene":"DDX39B","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"U2AF2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/UBL5","total_profiled":1310},"omim":[{"mim_id":"620743","title":"SDE2 TELOMERE MAINTENANCE HOMOLOG; SDE2","url":"https://www.omim.org/entry/620743"},{"mim_id":"606849","title":"UBIQUITIN-LIKE 5; UBL5","url":"https://www.omim.org/entry/606849"},{"mim_id":"604749","title":"ZINC FINGER PROTEIN 235; ZNF235","url":"https://www.omim.org/entry/604749"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UBL5"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9BZL1","domains":[{"cath_id":"3.10.20.90","chopping":"1-71","consensus_level":"high","plddt":91.4676,"start":1,"end":71}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BZL1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BZL1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BZL1-F1-predicted_aligned_error_v6.png","plddt_mean":91.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBL5","jax_strain_url":"https://www.jax.org/strain/search?query=UBL5"},"sequence":{"accession":"Q9BZL1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BZL1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BZL1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BZL1"}},"corpus_meta":[{"pmid":"25092792","id":"PMC_25092792","title":"UBL5 is essential for pre-mRNA splicing and sister chromatid cohesion in human cells.","date":"2014","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/25092792","citation_count":41,"is_preprint":false},{"pmid":"12824502","id":"PMC_12824502","title":"Structural analysis of UBL5, a novel ubiquitin-like modifier.","date":"2003","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/12824502","citation_count":38,"is_preprint":false},{"pmid":"11161819","id":"PMC_11161819","title":"Isolation of a ubiquitin-like (UBL5) gene from a screen identifying highly expressed and conserved iris genes.","date":"2001","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11161819","citation_count":36,"is_preprint":false},{"pmid":"25862789","id":"PMC_25862789","title":"Ubiquitin-like protein UBL5 promotes the functional integrity of the Fanconi anemia pathway.","date":"2015","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/25862789","citation_count":20,"is_preprint":false},{"pmid":"17026961","id":"PMC_17026961","title":"Hypo-osmotic shock induces nuclear export and proteasome-dependent decrease of UBL5.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17026961","citation_count":18,"is_preprint":false},{"pmid":"34502293","id":"PMC_34502293","title":"UBL5/Hub1: An Atypical Ubiquitin-Like Protein with a Typical Role as a Stress-Responsive Regulator.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34502293","citation_count":15,"is_preprint":false},{"pmid":"17036923","id":"PMC_17036923","title":"Association of genetic variation within UBL5 with phenotypes of metabolic syndrome.","date":"2006","source":"Human biology","url":"https://pubmed.ncbi.nlm.nih.gov/17036923","citation_count":15,"is_preprint":false},{"pmid":"23726919","id":"PMC_23726919","title":"Human UBL5 protein interacts with coilin and meets the Cajal bodies.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23726919","citation_count":10,"is_preprint":false},{"pmid":"19189687","id":"PMC_19189687","title":"Identification of sequence variants in the UBL5 (ubiquitin-like 5 or BEACON) gene in obese children by PCR-SSCP: no evidence for association with obesity.","date":"2008","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/19189687","citation_count":4,"is_preprint":false},{"pmid":"24458823","id":"PMC_24458823","title":"Porcine ubiquitin-like 5 (UBL5) gene: genomic organization, polymorphisms, mRNA cloning, splicing variants and association study.","date":"2014","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/24458823","citation_count":1,"is_preprint":false},{"pmid":"39772229","id":"PMC_39772229","title":"UBL5 and Its Role in Viral Infections.","date":"2024","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/39772229","citation_count":0,"is_preprint":false},{"pmid":"41485651","id":"PMC_41485651","title":"Ubiquitin-like protein UBL5 and spliceosome associated factor SART1 jointly maintain the virulence in Toxoplasma gondii.","date":"2026","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41485651","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7459,"output_tokens":1622,"usd":0.023353,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8362,"output_tokens":2283,"usd":0.049443,"stage2_stop_reason":"end_turn"},"total_usd":0.072796,"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\": 2003,\n      \"finding\": \"UBL5 has a ubiquitin-like beta-grasp fold determined by NMR; unlike ubiquitin, its C-terminal di-tyrosine motif is embedded within the final beta-sheet rather than extending beyond it, consistent with the lack of canonical conjugation activity. UBL5 was confirmed to specifically interact with the cyclin-like kinase CLK4, and not with other CLK family members.\",\n      \"method\": \"NMR structure determination; specific binding confirmed by interaction assay with CLK family members\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional validation of CLK4 specificity, single lab but orthogonal structural and binding methods\",\n      \"pmids\": [\"12824502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Recombinant UBL5 protein localizes to the cytoplasm in COS-7 cells as shown by intracellular localization experiments, and migrates at ~9 kDa on Western blot.\",\n      \"method\": \"Intracellular localization experiments in COS-7 cells; Western blot\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (overexpressed recombinant protein localization without functional consequence)\",\n      \"pmids\": [\"11161819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Under hypo-osmotic conditions, UBL5 is exported from the nucleus and subsequently degraded in a proteasome-dependent, transcription-independent manner, establishing a regulated subcellular redistribution and stability change linked to osmotic stress.\",\n      \"method\": \"Time-course immunocytochemistry of exogenous UBL5 in NIH-3T3 cells; proteasome inhibitor treatment; brain slice experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (proteasomal degradation after nuclear export), two orthogonal methods (immunocytochemistry + proteasome inhibition), single lab\",\n      \"pmids\": [\"17026961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Human UBL5 localizes to the nucleus and partially associates with Cajal bodies. UBL5 physically interacts with coilin (the Cajal body scaffold protein) as shown by GST pull-down using both in vitro-translated and cell-extracted coilin; this interaction is not influenced by coilin phosphorylation.\",\n      \"method\": \"Immunofluorescence localization; co-expression in HeLa cells; GST pull-down with in vitro-translated and HEK293T-extracted coilin\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pull-down with two sources of coilin plus co-localization, single lab, two orthogonal methods\",\n      \"pmids\": [\"23726919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"UBL5 is required for pre-mRNA splicing efficiency in human cells; its depletion causes globally enhanced intron retention. UBL5 primarily associates with spliceosomal proteins. Defective splicing leads to selective downregulation of the cohesion protection factor Sororin, which in turn causes defective sister chromatid cohesion.\",\n      \"method\": \"siRNA knockdown; RNA-seq (intron retention analysis); co-immunoprecipitation with spliceosomal proteins; sister chromatid cohesion assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with spliceosomal proteins, genome-wide splicing analysis, defined cellular phenotype (cohesion), epistasis through Sororin, replicated across multiple orthogonal methods\",\n      \"pmids\": [\"25092792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"UBL5 physically interacts with the Fanconi anemia pathway component FANCI via a specific non-covalent interaction. UBL5 loss causes spliceosome-independent reduction of FANCI protein stability. Separation-of-function mutants that selectively abolish UBL5-FANCI binding compromise FANCI-FANCD2 heterodimerization, FANCD2 and FANCI monoubiquitylation, and chromosome stability after DNA interstrand crosslink (ICL) damage.\",\n      \"method\": \"Co-immunoprecipitation; domain-mapping mutagenesis; separation-of-function mutants; FANCI stability assay; monoubiquitylation assay; ICL sensitivity assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, mutagenesis, functional assays for ubiquitylation and chromosomal stability), clear mechanistic dissection with separation-of-function mutants\",\n      \"pmids\": [\"25862789\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBL5 is an atypical ubiquitin-like protein that lacks covalent conjugation activity (due to its C-terminal di-tyrosine rather than di-glycine motif) and instead functions through non-covalent interactions: it associates with spliceosomal proteins and Cajal body component coilin to promote pre-mRNA splicing fidelity (loss causes global intron retention and consequent Sororin downregulation/cohesion defects), and it stabilizes the Fanconi anemia factor FANCI to support ICL-induced FANCI-FANCD2 heterodimerization and monoubiquitylation; additionally, UBL5 undergoes osmotic-stress-induced nuclear export followed by proteasomal degradation, and specifically binds the kinase CLK4.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBL5 is an atypical ubiquitin-like protein that adopts the ubiquitin beta-grasp fold yet lacks canonical conjugation activity, because its C-terminal di-tyrosine motif is embedded within the final beta-sheet rather than extending outward as in ubiquitin; it instead acts through non-covalent protein interactions, and binds specifically to the cyclin-like kinase CLK4 among the CLK family [#0]. In the nucleus it partially associates with Cajal bodies through a phosphorylation-independent physical interaction with the scaffold protein coilin [#3], and it associates predominantly with spliceosomal proteins to support pre-mRNA splicing efficiency: its depletion causes global intron retention, which selectively downregulates the cohesion protection factor Sororin and thereby produces defective sister chromatid cohesion [#4]. Independently of its splicing role, UBL5 binds the Fanconi anemia factor FANCI and stabilizes the FANCI protein; separation-of-function mutants that selectively disrupt UBL5-FANCI binding compromise FANCI-FANCD2 heterodimerization, FANCD2/FANCI monoubiquitylation, and chromosome stability after DNA interstrand crosslink damage [#5]. UBL5 abundance and localization are also regulated by stress, undergoing nuclear export followed by proteasome-dependent, transcription-independent degradation under hypo-osmotic conditions [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing why UBL5 behaves unlike ubiquitin: its fold and motif positioning explain the absence of conjugation activity, while defining CLK4 as a specific binding partner reframed UBL5 as a non-covalent interactor.\",\n      \"evidence\": \"NMR structure determination with interaction assays across CLK family members\",\n      \"pmids\": [\"12824502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of UBL5-CLK4 binding not determined\", \"No structure of a UBL5-partner complex\", \"CLK4 specificity not connected to splicing or other downstream pathways\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed that UBL5 levels and localization are dynamically regulated, linking osmotic stress to its nuclear export and proteasomal turnover rather than being a static structural protein.\",\n      \"evidence\": \"Time-course immunocytochemistry of exogenous UBL5 in NIH-3T3 cells, proteasome inhibition, and brain slice experiments\",\n      \"pmids\": [\"17026961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Export and degradation machinery not identified\", \"Used exogenous protein rather than endogenous UBL5\", \"Physiological purpose of stress-induced turnover unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected UBL5 to a defined nuclear compartment by demonstrating direct binding to the Cajal body scaffold coilin, providing a structural basis for its nuclear association.\",\n      \"evidence\": \"Immunofluorescence co-localization and GST pull-down with in vitro-translated and cell-extracted coilin in HeLa/HEK293T cells\",\n      \"pmids\": [\"23726919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of UBL5-coilin binding not established\", \"Binding interface not mapped\", \"Relationship between Cajal body association and splicing role unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined UBL5's principal cellular function as supporting splicing fidelity, and traced an epistatic chain from intron retention to Sororin loss and cohesion defects.\",\n      \"evidence\": \"siRNA knockdown with RNA-seq intron-retention analysis, co-IP with spliceosomal proteins, and sister chromatid cohesion assays in human cells\",\n      \"pmids\": [\"25092792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which spliceosomal step UBL5 acts at is undefined\", \"Direct molecular mechanism within the spliceosome unknown\", \"Whether CLK4 or coilin binding contributes to the splicing role untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a splicing-independent role in genome stability by showing UBL5 stabilizes FANCI and is required for FANCI-FANCD2 activation after crosslink damage.\",\n      \"evidence\": \"Co-IP, domain mapping, separation-of-function mutants, FANCI stability, monoubiquitylation, and ICL sensitivity assays\",\n      \"pmids\": [\"25862789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which UBL5 binding stabilizes FANCI not resolved\", \"Whether this role requires nuclear/Cajal body localization untested\", \"No structure of the UBL5-FANCI complex\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UBL5's distinct activities — CLK4 binding, coilin/Cajal body association, spliceosomal support, FANCI stabilization, and stress-regulated turnover — are mechanistically unified through a single non-covalent interaction surface remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of UBL5's interaction surface across partners\", \"Functional significance of CLK4 and coilin binding unestablished\", \"Whether splicing and FA roles share a common binding mode unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"spliceosome\", \"Cajal body\"],\n    \"partners\": [\"CLK4\", \"coilin\", \"FANCI\", \"FANCD2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}