{"gene":"UBP1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2005,"finding":"LBP-1a (UBP1) is exclusively localized to the cytosol when expressed alone, but undergoes nuclear translocation upon co-expression with LBP-1b. Heterodimerization with LBP-1b, which contains a nuclear localization signal (NLS) encoded by exon 6, is required for nuclear localization of LBP-1a. Once in the nucleus, LBP-1a accumulates in PML bodies, with the N-terminal region of LBP-1a being sufficient for PML body accumulation.","method":"YFP-fusion subcellular localization imaging in COS-7 cells, co-expression experiments, NLS mapping by domain deletion","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live-cell imaging with functional co-expression rescue, domain mapping, single lab with two orthogonal methods (imaging + deletion analysis)","pmids":["16115195"],"is_preprint":false},{"year":2004,"finding":"LBP-1a (UBP1) knockout mice develop intrauterine growth retardation and die by embryonic day 11.5 due to a defect in extraembryonic angiogenesis. In LBP-1a−/− placentas, allantoic blood vessels fail to branch into the labyrinthine layer, and yolk sac capillary tubes fail to connect into a vascular network. Tetraploid complementation studies excluded a primary trophoblast defect, placing the angiogenic role of LBP-1a in endothelial cells.","method":"Germline knockout mouse, histological analysis of placenta and yolk sac vasculature, tetraploid complementation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous in vivo loss-of-function with defined vascular phenotype, complementation experiment to localize defect, single lab with multiple orthogonal approaches","pmids":["15282311"],"is_preprint":false},{"year":2004,"finding":"NF2d9 (LBP-1a/UBP1) binds directly to the positive regulatory element (PREX) upstream of the XRE in the CYP2A8 gene, as demonstrated by gel mobility shift assay. Overexpression of NF2d9 enhanced both PREX- and XRE-driven CYP2A8 transcriptional induction in luciferase reporter assays, indicating that LBP-1a/UBP1 functions as a transcriptional activator at this locus by interacting with PREX and indirectly with XRE.","method":"Gel mobility shift assay (EMSA), luciferase reporter gene assay with overexpression","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct DNA-binding assay plus reporter assay, single lab, single study","pmids":["15716014"],"is_preprint":false},{"year":2009,"finding":"LBP-1a (UBP1) is the predominant LSF/LBP-1 family member in B lymphocytes and binds genomic switch (S) regions Smu and Salpha (but not Sgamma1) in an isotype-specific manner in vivo, as shown by ChIP. LPS stimulation dramatically decreases LBP-1a occupancy at S regions. Inhibition of LSF/LBP-1 activity in bone marrow chimeric mice increases CSR efficiency specifically to IgA but not IgG1, establishing LBP-1a as an isotype-specific repressor of class switch recombination acting through direct S-region binding.","method":"Chromatin immunoprecipitation (ChIP) in primary splenic B cells, bone marrow chimeric mice with in vitro stimulation, isotype-specific CSR measurement","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal evidence from ChIP (direct binding) and in vivo loss-of-function (chimeric mice) with specific phenotypic readout, multiple orthogonal methods","pmids":["19384868"],"is_preprint":false},{"year":2009,"finding":"The UBP1 locus was identified as a blood pressure determinant. UBP1 (LBP-1a) plays a role in cholesterol and steroid metabolism via transcriptional activation of CYP11A, the rate-limiting enzyme in pregnenolone and aldosterone biosynthesis, linking UBP1 transcriptional activity to blood pressure regulation.","method":"QTL mapping in BXD recombinant inbred mouse strains, human association study, functional annotation of UBP1 as CYP11A transcriptional activator","journal":"PLoS genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic association plus stated functional role as CYP11A activator, but the direct transcriptional activation experiment for CYP11A is not described in detail in the abstract; single study","pmids":["19662162"],"is_preprint":false},{"year":2025,"finding":"MED16, a dissociable subunit of the Mediator complex, forms a subcomplex with transcription factors UBP1 and TFCP2. This interaction was identified by protein purification coupled with mass spectrometry. The MED16-UBP1 complex modulates transcriptional activation or repression in a promoter-position-dependent manner: transcription is activated when the UBP1-TFCP2 binding motif is proximal to the TSS, but repressed when the motif overlaps the TSS. MED16 and UBP1 cooperatively bind the HIV-1 transcriptional start site to inhibit preinitiation complex assembly, reinforcing viral latency.","method":"Protein purification with mass spectrometry, gene expression analysis, genomic-scale binding analysis, HIV-1 transcription reporter assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein purification/MS for complex identification plus functional reporter assays and genomic analysis; preprint, single lab, not yet peer-reviewed","pmids":["bio_10.1101_2025.08.12.669905"],"is_preprint":true},{"year":2024,"finding":"In Xenopus laevis embryonic development, Ubp1 cooperates with Foxi1 and Dmrt2 in a multi-step process of ionocyte specification and differentiation. Foxi1 at high levels induces ISC specification in cooperation with Ubp1, placing Ubp1 as a co-factor in the transcriptional program governing ionocyte fate.","method":"Xenopus gain- and loss-of-function experiments, transcriptional analysis during embryonic epidermis development","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional cooperation inferred from Xenopus developmental assays, preprint, no direct biochemical characterization of Ubp1 mechanism, single study","pmids":["bio_10.1101_2024.10.27.620464"],"is_preprint":true}],"current_model":"UBP1 (LBP-1a) is a member of the TFCP2/Grainyhead subfamily of transcription factors that resides in the cytoplasm unless heterodimerized with its splicing variant LBP-1b, which supplies a nuclear localization signal; once nuclear, UBP1 accumulates at PML bodies and functions as a context-dependent transcriptional regulator—directly binding DNA elements (including immunoglobulin switch regions and the CYP2A8 PREX element) to repress class switch recombination in an isotype-specific manner and activate steroidogenic gene expression (CYP11A), and forming a subcomplex with Mediator subunit MED16 and TFCP2 to activate or repress transcription depending on the position of the UBP1-TFCP2 binding motif relative to the transcription start site; in vivo, LBP-1a is essential for extraembryonic angiogenesis, with its loss causing placental labyrinthine and yolk sac vascular defects leading to embryonic lethality."},"narrative":{"mechanistic_narrative":"UBP1 (LBP-1a) is a sequence-specific DNA-binding transcription factor of the LSF/LBP-1 family that acts as a context-dependent activator or repressor and is required for extraembryonic vascular development [PMID:15282311, PMID:15716014, PMID:19384868]. Its nuclear access is conditional: expressed alone it is confined to the cytosol, and only heterodimerization with the splice variant LBP-1b, which provides a nuclear localization signal, drives nuclear translocation, after which UBP1 accumulates at PML bodies via its N-terminal region [PMID:16115195]. In the nucleus UBP1 directs distinct gene programs through direct DNA binding—occupying the PREX element upstream of the CYP2A8 gene to enhance its transcription [PMID:15716014] and binding immunoglobulin switch regions Smu and Salpha in an isotype-specific manner to repress class switch recombination, with loss of LSF/LBP-1 activity selectively increasing IgA switching [PMID:19384868]. The direction of its regulatory output depends on promoter geometry: in a subcomplex with the Mediator subunit MED16 and TFCP2, UBP1 activates transcription when its binding motif lies proximal to the transcription start site but represses when the motif overlaps the start site, a mechanism that enforces HIV-1 latency by blocking preinitiation complex assembly [PMID:bio_10.1101_2025.08.12.669905]. Genetically, LBP-1a knockout mice die by embryonic day 11.5 from failed extraembryonic angiogenesis—placental labyrinthine and yolk sac vascular networks fail to form—a defect mapped to endothelial cells by tetraploid complementation [PMID:15282311].","teleology":[{"year":2004,"claim":"Establishing whether UBP1 has an essential physiological role, in vivo loss-of-function defined it as a non-redundant regulator of extraembryonic blood vessel formation.","evidence":"germline knockout mouse with placental/yolk sac histology and tetraploid complementation","pmids":["15282311"],"confidence":"High","gaps":["The direct transcriptional targets driving the endothelial angiogenic program are not identified","Whether the vascular role depends on LBP-1b heterodimerization is untested"]},{"year":2004,"claim":"To determine a molecular activity, UBP1 was shown to bind a defined promoter element and activate transcription, establishing it as a direct DNA-binding transcriptional activator at a metabolic gene.","evidence":"EMSA and luciferase reporter assays with overexpression at the CYP2A8 PREX/XRE locus","pmids":["15716014"],"confidence":"Medium","gaps":["Single locus and single study","Cofactors mediating activation not defined"]},{"year":2005,"claim":"Addressing how a cytosolic factor reaches its DNA targets, imaging revealed that UBP1 nuclear entry is gated by heterodimerization with the NLS-bearing splice variant LBP-1b, followed by PML body accumulation.","evidence":"YFP-fusion live-cell localization in COS-7 cells with co-expression rescue and NLS/domain deletion mapping","pmids":["16115195"],"confidence":"Medium","gaps":["Functional consequence of PML body accumulation unknown","Whether endogenous LBP-1b stoichiometry controls UBP1 nuclear access in vivo not shown"]},{"year":2009,"claim":"To define UBP1 function in the immune system, ChIP and in vivo perturbation showed it binds switch regions in an isotype-specific manner and represses class switch recombination to IgA.","evidence":"ChIP in primary B cells and bone marrow chimeric mice with isotype-specific CSR readout","pmids":["19384868"],"confidence":"High","gaps":["Molecular mechanism of repression at S regions not resolved","Why occupancy is lost upon LPS stimulation is unexplained"]},{"year":2009,"claim":"Linking UBP1 to physiology, genetic mapping associated the locus with blood pressure and attributed a role in steroidogenesis via CYP11A activation.","evidence":"QTL mapping in BXD mice plus human association and functional annotation as a CYP11A activator","pmids":["19662162"],"confidence":"Low","gaps":["Direct CYP11A transcriptional activation experiment not detailed","Causal link between UBP1 genotype and blood pressure not mechanistically established"]},{"year":2024,"claim":"Extending UBP1 to developmental gene regulation, Xenopus assays placed it as a cofactor with Foxi1 and Dmrt2 in ionocyte specification.","evidence":"gain- and loss-of-function in Xenopus embryonic epidermis (preprint)","pmids":["bio_10.1101_2024.10.27.620464"],"confidence":"Low","gaps":["No direct biochemical characterization of Ubp1 in this program","Direct target genes and binding sites not defined"]},{"year":2025,"claim":"Resolving how UBP1's activator-versus-repressor output is determined, purification and reporter assays defined a MED16-UBP1-TFCP2 subcomplex whose effect depends on motif position relative to the TSS, with TSS-overlapping binding repressing HIV-1 to enforce latency.","evidence":"protein purification/mass spectrometry, genomic binding analysis, and HIV-1 transcription reporter assays (preprint)","pmids":["bio_10.1101_2025.08.12.669905"],"confidence":"Medium","gaps":["Preprint, single lab, not peer-reviewed","Structural basis for position-dependent switching not determined","Generality of the rule beyond HIV-1 and tested loci unproven"]},{"year":null,"claim":"It remains unknown how UBP1's distinct context-dependent roles—angiogenesis, CSR repression, steroidogenesis, and latency control—are coordinated by its dimerization state, cofactor availability, and promoter geometry across cell types.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model connecting LBP-1b dimerization to target selection","Endothelial angiogenic targets unidentified","No structural model of the UBP1-TFCP2-MED16 complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3,5]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,3,5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,3,5]}],"complexes":["MED16-UBP1-TFCP2 subcomplex"],"partners":["LBP-1B","MED16","TFCP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NZI7","full_name":"Upstream-binding protein 1","aliases":["Transcription factor LBP-1"],"length_aa":540,"mass_kda":60.5,"function":"Functions as a transcriptional activator in a promoter context-dependent manner. Modulates the placental expression of CYP11A1. Involved in regulation of the alpha-globin gene in erythroid cells. Activation of the alpha-globin promoter in erythroid cells is via synergistic interaction with TFCP2 (By similarity). Involved in regulation of the alpha-globin gene in erythroid cells. Binds strongly to sequences around the HIV-1 initiation site and weakly over the TATA-box. Represses HIV-1 transcription by inhibiting the binding of TFIID to the TATA-box","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NZI7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBP1","classification":"Not Classified","n_dependent_lines":14,"n_total_lines":1208,"dependency_fraction":0.011589403973509934},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PARP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/UBP1","total_profiled":1310},"omim":[{"mim_id":"609785","title":"TRANSCRIPTION FACTOR CP2-LIKE 1; TFCP2L1","url":"https://www.omim.org/entry/609785"},{"mim_id":"609784","title":"UPSTREAM BINDING PROTEIN 1; UBP1","url":"https://www.omim.org/entry/609784"},{"mim_id":"608985","title":"RING FINGER PROTEIN 2; RNF2","url":"https://www.omim.org/entry/608985"},{"mim_id":"606673","title":"BETA-UREIDOPROPIONASE; UPB1","url":"https://www.omim.org/entry/606673"},{"mim_id":"189889","title":"TRANSCRIPTION FACTOR CP2; TFCP2","url":"https://www.omim.org/entry/189889"}],"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/UBP1"},"hgnc":{"alias_symbol":["LBP-1a"],"prev_symbol":[]},"alphafold":{"accession":"Q9NZI7","domains":[{"cath_id":"2.60.40","chopping":"65-274","consensus_level":"high","plddt":92.4339,"start":65,"end":274},{"cath_id":"3.10.20,3.10.20","chopping":"431-439_464-540","consensus_level":"high","plddt":91.095,"start":431,"end":540},{"cath_id":"1.10.150","chopping":"371-423","consensus_level":"high","plddt":91.2489,"start":371,"end":423}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZI7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZI7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZI7-F1-predicted_aligned_error_v6.png","plddt_mean":74.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBP1","jax_strain_url":"https://www.jax.org/strain/search?query=UBP1"},"sequence":{"accession":"Q9NZI7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZI7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZI7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZI7"}},"corpus_meta":[{"pmid":"3138113","id":"PMC_3138113","title":"Purification of the human immunodeficiency virus type 1 enhancer and TAR binding proteins EBP-1 and UBP-1.","date":"1988","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/3138113","citation_count":195,"is_preprint":false},{"pmid":"2050695","id":"PMC_2050695","title":"Cloning and functional analysis of the ubiquitin-specific protease gene UBP1 of Saccharomyces cerevisiae.","date":"1991","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2050695","citation_count":143,"is_preprint":false},{"pmid":"10747031","id":"PMC_10747031","title":"UBP1, a novel hnRNP-like protein that functions at multiple steps of higher plant nuclear pre-mRNA maturation.","date":"2000","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10747031","citation_count":92,"is_preprint":false},{"pmid":"29410248","id":"PMC_29410248","title":"TFCP2/TFCP2L1/UBP1 transcription factors in cancer.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/29410248","citation_count":74,"is_preprint":false},{"pmid":"12024044","id":"PMC_12024044","title":"UBA1 and UBA2, two proteins that interact with UBP1, a multifunctional effector of pre-mRNA maturation in plants.","date":"2002","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12024044","citation_count":62,"is_preprint":false},{"pmid":"19662162","id":"PMC_19662162","title":"Identification of the UBP1 locus as a critical blood pressure determinant using a combination of mouse and human genetics.","date":"2009","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19662162","citation_count":51,"is_preprint":false},{"pmid":"15282311","id":"PMC_15282311","title":"Defective extraembryonic angiogenesis in mice lacking LBP-1a, a member of the grainyhead family of transcription factors.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15282311","citation_count":33,"is_preprint":false},{"pmid":"30241344","id":"PMC_30241344","title":"Neglected Functions of TFCP2/TFCP2L1/UBP1 Transcription Factors May Offer Valuable Insights into Their Mechanisms of Action.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30241344","citation_count":31,"is_preprint":false},{"pmid":"15635103","id":"PMC_15635103","title":"The deubiquitinating enzyme Ubp1 affects sorting of the ATP-binding cassette-transporter Ste6 in the endocytic pathway.","date":"2005","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15635103","citation_count":27,"is_preprint":false},{"pmid":"32340987","id":"PMC_32340987","title":"Experimentally Engineered Mutations in a Ubiquitin Hydrolase, UBP-1, Modulate In Vivo Susceptibility to Artemisinin and Chloroquine in Plasmodium berghei.","date":"2020","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/32340987","citation_count":25,"is_preprint":false},{"pmid":"38413566","id":"PMC_38413566","title":"Deaggregation of mutant Plasmodium yoelii de-ubiquitinase UBP1 alters MDR1 localization to confer multidrug resistance.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38413566","citation_count":11,"is_preprint":false},{"pmid":"15924623","id":"PMC_15924623","title":"Expression of yeast deubiquitination enzyme UBP1 analogues in E. coli.","date":"2005","source":"Microbial cell factories","url":"https://pubmed.ncbi.nlm.nih.gov/15924623","citation_count":9,"is_preprint":false},{"pmid":"16115195","id":"PMC_16115195","title":"Heterodimerization with LBP-1b is necessary for nuclear localization of LBP-1a and LBP-1c.","date":"2005","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/16115195","citation_count":9,"is_preprint":false},{"pmid":"25158991","id":"PMC_25158991","title":"Use of Ubp1 protease analog to produce recombinant human growth hormone in Escherichia coli.","date":"2014","source":"Microbial cell factories","url":"https://pubmed.ncbi.nlm.nih.gov/25158991","citation_count":8,"is_preprint":false},{"pmid":"34877752","id":"PMC_34877752","title":"Novel EWSR1::UBP1 fusion expands the spectrum of spindle cell rhabdomyosarcomas.","date":"2021","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34877752","citation_count":7,"is_preprint":false},{"pmid":"24994500","id":"PMC_24994500","title":"A lack of association between polymorphisms of three positional candidate genes (CLASP2 , UBP1, and FBXL2) and canine disorder of sexual development (78,XX; SRY -negative).","date":"2014","source":"Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/24994500","citation_count":7,"is_preprint":false},{"pmid":"26096620","id":"PMC_26096620","title":"Association of UBP1 to ribonucleoprotein complexes is regulated by interaction with the trypanosome ortholog of the human multifunctional P32 protein.","date":"2015","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/26096620","citation_count":7,"is_preprint":false},{"pmid":"19384868","id":"PMC_19384868","title":"Binding of LBP-1a to specific immunoglobulin switch regions in vivo correlates with specific repression of class switch recombination.","date":"2009","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19384868","citation_count":7,"is_preprint":false},{"pmid":"15716014","id":"PMC_15716014","title":"Transcription factor NF2d9 (LBP-1a) interacts with the positive regulatory element for the xenobiotic responsive element.","date":"2004","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/15716014","citation_count":3,"is_preprint":false},{"pmid":"38758959","id":"PMC_38758959","title":"Transcriptomic analysis of N-terminal mutated Trypanosoma cruzi UBP1 knockdown underlines the importance of this RNA-binding protein in parasite development.","date":"2024","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/38758959","citation_count":2,"is_preprint":false},{"pmid":"39909372","id":"PMC_39909372","title":"Drug resistance-associated mutations in Plasmodium UBP-1 disrupt its essential deubiquitinating activity.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39909372","citation_count":2,"is_preprint":false},{"pmid":"38348324","id":"PMC_38348324","title":"Proteomic data of the Trypanosoma cruzi insect-dwelling epimastigotes overexpressing the RNA-binding protein UBP1.","date":"2024","source":"Data in brief","url":"https://pubmed.ncbi.nlm.nih.gov/38348324","citation_count":1,"is_preprint":false},{"pmid":"8392872","id":"PMC_8392872","title":"Characterization of Ustilago maydis DNA binding protein one (UBP1).","date":"1993","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/8392872","citation_count":0,"is_preprint":false},{"pmid":"38389957","id":"PMC_38389957","title":"RNA-seq data exploration after trypanosome RNA-binding protein UBP1 expression is altered by CRISPR-Cas9 gene editing and overexpression.","date":"2024","source":"Data in brief","url":"https://pubmed.ncbi.nlm.nih.gov/38389957","citation_count":0,"is_preprint":false},{"pmid":"39964481","id":"PMC_39964481","title":"Ubiquitin protease Ubp1 cooperates with Ubp10 and Ubp12 to revert lysine-164 PCNA ubiquitylation at replication forks.","date":"2025","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/39964481","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.12.669905","title":"Mediator Subunit MED16 Collaborates with UBP1-TFCP2 to Control Transcriptional Activation or Repression via Promoter Positional Specificity","date":"2025-08-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.12.669905","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.27.620464","title":"Foxi1 regulates multipotent mucociliary progenitors and ionocyte specification through transcriptional and epigenetic mechanisms","date":"2024-10-27","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.27.620464","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14332,"output_tokens":3196,"usd":0.045468,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9215,"output_tokens":2634,"usd":0.055962,"stage2_stop_reason":"end_turn"},"total_usd":0.10143,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"I need to carefully classify each paper before extracting discoveries.\n\nThe query gene is human **UBP1** (alias: **LBP-1a**), which based on the corpus is a member of the TFCP2/Grainyhead family of transcription factors (LBP-1a/NF2d9).\n\n**Classification notes:**\n- Papers [1]: UBP-1 as a HIV TAR-binding protein - likely a different protein, not the grainyhead TF. However, looking at the corpus, the human UBP1/LBP-1a is the grainyhead family TF. Paper [1] describes a different \"UBP-1\" (TAR region binding protein). EXCLUDE as symbol collision.\n- Papers [2], [9], [12], [13 partial], [25]: Yeast Saccharomyces cerevisiae Ubp1 - a deubiquitinating enzyme. This is NOT an ortholog of human UBP1/LBP-1a (which is a transcription factor). EXCLUDE as symbol collision.\n- Paper [3]: Plant Nicotiana UBP1 - hnRNP-like protein. Symbol collision with plant gene. EXCLUDE.\n- Paper [4]: Review of TFCP2/TFCP2L1/UBP1 - this IS about human UBP1/LBP-1a. INCLUDE.\n- Paper [5]: Plant UBP1 interactors. EXCLUDE (plant ortholog collision).\n- Paper [6]: Human UBP1 locus and blood pressure. INCLUDE.\n- Paper [7]: LBP-1a (=UBP1) mouse knockout - angiogenesis. INCLUDE.\n- Paper [8]: Review including UBP1. INCLUDE selectively.\n- Paper [10]: Plasmodium UBP-1 - malaria parasite ubiquitin hydrolase. Symbol collision. EXCLUDE.\n- Paper [11]: Plasmodium yoelii UBP1 deubiquitinase. EXCLUDE.\n- Paper [13]: LBP-1a nuclear localization. This IS about human UBP1/LBP-1a. INCLUDE.\n- Paper [15]: EWSR1::UBP1 fusion in sarcoma - involves human UBP1. INCLUDE for fusion info but limited mechanism.\n- Paper [16]: Canine UBP1 polymorphisms - association study. EXCLUDE (no mechanism).\n- Paper [17]: Trypanosome UBP1 (TcUBP1) - RNA-binding protein. Symbol collision. EXCLUDE.\n- Paper [18]: LBP-1a (=UBP1) in B cells/CSR. INCLUDE.\n- Paper [19]: NF2d9 (LBP-1a) = UBP1 binding to PREX. INCLUDE.\n- Paper [20]: Trypanosome TcUBP1. EXCLUDE.\n- Paper [21]: Plasmodium UBP-1. EXCLUDE.\n- Paper [22]: Trypanosome UBP1 proteomics. EXCLUDE.\n- Paper [23]: Ustilago maydis UBP1 - fungal protein, symbol collision. EXCLUDE.\n- Paper [24]: Trypanosome UBP1. EXCLUDE.\n- Paper [25]: Yeast Ubp1 PCNA deubiquitylase. EXCLUDE (yeast deubiquitinase, not ortholog of human TF UBP1).\n- Paper [26]: MED16-UBP1-TFCP2 complex. This IS about human UBP1/LBP-1a. INCLUDE.\n- Paper [27]: Xenopus Ubp1 in ionocyte specification. This mentions Ubp1 in context consistent with the grainyhead/TFCP2 family. INCLUDE cautiously.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"LBP-1a (UBP1) is exclusively localized to the cytosol when expressed alone, but undergoes nuclear translocation upon co-expression with LBP-1b. Heterodimerization with LBP-1b, which contains a nuclear localization signal (NLS) encoded by exon 6, is required for nuclear localization of LBP-1a. Once in the nucleus, LBP-1a accumulates in PML bodies, with the N-terminal region of LBP-1a being sufficient for PML body accumulation.\",\n      \"method\": \"YFP-fusion subcellular localization imaging in COS-7 cells, co-expression experiments, NLS mapping by domain deletion\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell imaging with functional co-expression rescue, domain mapping, single lab with two orthogonal methods (imaging + deletion analysis)\",\n      \"pmids\": [\"16115195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"LBP-1a (UBP1) knockout mice develop intrauterine growth retardation and die by embryonic day 11.5 due to a defect in extraembryonic angiogenesis. In LBP-1a−/− placentas, allantoic blood vessels fail to branch into the labyrinthine layer, and yolk sac capillary tubes fail to connect into a vascular network. Tetraploid complementation studies excluded a primary trophoblast defect, placing the angiogenic role of LBP-1a in endothelial cells.\",\n      \"method\": \"Germline knockout mouse, histological analysis of placenta and yolk sac vasculature, tetraploid complementation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous in vivo loss-of-function with defined vascular phenotype, complementation experiment to localize defect, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"15282311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NF2d9 (LBP-1a/UBP1) binds directly to the positive regulatory element (PREX) upstream of the XRE in the CYP2A8 gene, as demonstrated by gel mobility shift assay. Overexpression of NF2d9 enhanced both PREX- and XRE-driven CYP2A8 transcriptional induction in luciferase reporter assays, indicating that LBP-1a/UBP1 functions as a transcriptional activator at this locus by interacting with PREX and indirectly with XRE.\",\n      \"method\": \"Gel mobility shift assay (EMSA), luciferase reporter gene assay with overexpression\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct DNA-binding assay plus reporter assay, single lab, single study\",\n      \"pmids\": [\"15716014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LBP-1a (UBP1) is the predominant LSF/LBP-1 family member in B lymphocytes and binds genomic switch (S) regions Smu and Salpha (but not Sgamma1) in an isotype-specific manner in vivo, as shown by ChIP. LPS stimulation dramatically decreases LBP-1a occupancy at S regions. Inhibition of LSF/LBP-1 activity in bone marrow chimeric mice increases CSR efficiency specifically to IgA but not IgG1, establishing LBP-1a as an isotype-specific repressor of class switch recombination acting through direct S-region binding.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) in primary splenic B cells, bone marrow chimeric mice with in vitro stimulation, isotype-specific CSR measurement\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal evidence from ChIP (direct binding) and in vivo loss-of-function (chimeric mice) with specific phenotypic readout, multiple orthogonal methods\",\n      \"pmids\": [\"19384868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The UBP1 locus was identified as a blood pressure determinant. UBP1 (LBP-1a) plays a role in cholesterol and steroid metabolism via transcriptional activation of CYP11A, the rate-limiting enzyme in pregnenolone and aldosterone biosynthesis, linking UBP1 transcriptional activity to blood pressure regulation.\",\n      \"method\": \"QTL mapping in BXD recombinant inbred mouse strains, human association study, functional annotation of UBP1 as CYP11A transcriptional activator\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic association plus stated functional role as CYP11A activator, but the direct transcriptional activation experiment for CYP11A is not described in detail in the abstract; single study\",\n      \"pmids\": [\"19662162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MED16, a dissociable subunit of the Mediator complex, forms a subcomplex with transcription factors UBP1 and TFCP2. This interaction was identified by protein purification coupled with mass spectrometry. The MED16-UBP1 complex modulates transcriptional activation or repression in a promoter-position-dependent manner: transcription is activated when the UBP1-TFCP2 binding motif is proximal to the TSS, but repressed when the motif overlaps the TSS. MED16 and UBP1 cooperatively bind the HIV-1 transcriptional start site to inhibit preinitiation complex assembly, reinforcing viral latency.\",\n      \"method\": \"Protein purification with mass spectrometry, gene expression analysis, genomic-scale binding analysis, HIV-1 transcription reporter assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein purification/MS for complex identification plus functional reporter assays and genomic analysis; preprint, single lab, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.08.12.669905\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Xenopus laevis embryonic development, Ubp1 cooperates with Foxi1 and Dmrt2 in a multi-step process of ionocyte specification and differentiation. Foxi1 at high levels induces ISC specification in cooperation with Ubp1, placing Ubp1 as a co-factor in the transcriptional program governing ionocyte fate.\",\n      \"method\": \"Xenopus gain- and loss-of-function experiments, transcriptional analysis during embryonic epidermis development\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional cooperation inferred from Xenopus developmental assays, preprint, no direct biochemical characterization of Ubp1 mechanism, single study\",\n      \"pmids\": [\"bio_10.1101_2024.10.27.620464\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"UBP1 (LBP-1a) is a member of the TFCP2/Grainyhead subfamily of transcription factors that resides in the cytoplasm unless heterodimerized with its splicing variant LBP-1b, which supplies a nuclear localization signal; once nuclear, UBP1 accumulates at PML bodies and functions as a context-dependent transcriptional regulator—directly binding DNA elements (including immunoglobulin switch regions and the CYP2A8 PREX element) to repress class switch recombination in an isotype-specific manner and activate steroidogenic gene expression (CYP11A), and forming a subcomplex with Mediator subunit MED16 and TFCP2 to activate or repress transcription depending on the position of the UBP1-TFCP2 binding motif relative to the transcription start site; in vivo, LBP-1a is essential for extraembryonic angiogenesis, with its loss causing placental labyrinthine and yolk sac vascular defects leading to embryonic lethality.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBP1 (LBP-1a) is a sequence-specific DNA-binding transcription factor of the LSF/LBP-1 family that acts as a context-dependent activator or repressor and is required for extraembryonic vascular development [#1, #2, #3]. Its nuclear access is conditional: expressed alone it is confined to the cytosol, and only heterodimerization with the splice variant LBP-1b, which provides a nuclear localization signal, drives nuclear translocation, after which UBP1 accumulates at PML bodies via its N-terminal region [#0]. In the nucleus UBP1 directs distinct gene programs through direct DNA binding—occupying the PREX element upstream of the CYP2A8 gene to enhance its transcription [#2] and binding immunoglobulin switch regions Smu and Salpha in an isotype-specific manner to repress class switch recombination, with loss of LSF/LBP-1 activity selectively increasing IgA switching [#3]. The direction of its regulatory output depends on promoter geometry: in a subcomplex with the Mediator subunit MED16 and TFCP2, UBP1 activates transcription when its binding motif lies proximal to the transcription start site but represses when the motif overlaps the start site, a mechanism that enforces HIV-1 latency by blocking preinitiation complex assembly [#5]. Genetically, LBP-1a knockout mice die by embryonic day 11.5 from failed extraembryonic angiogenesis—placental labyrinthine and yolk sac vascular networks fail to form—a defect mapped to endothelial cells by tetraploid complementation [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing whether UBP1 has an essential physiological role, in vivo loss-of-function defined it as a non-redundant regulator of extraembryonic blood vessel formation.\",\n      \"evidence\": \"germline knockout mouse with placental/yolk sac histology and tetraploid complementation\",\n      \"pmids\": [\"15282311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The direct transcriptional targets driving the endothelial angiogenic program are not identified\", \"Whether the vascular role depends on LBP-1b heterodimerization is untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"To determine a molecular activity, UBP1 was shown to bind a defined promoter element and activate transcription, establishing it as a direct DNA-binding transcriptional activator at a metabolic gene.\",\n      \"evidence\": \"EMSA and luciferase reporter assays with overexpression at the CYP2A8 PREX/XRE locus\",\n      \"pmids\": [\"15716014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single locus and single study\", \"Cofactors mediating activation not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Addressing how a cytosolic factor reaches its DNA targets, imaging revealed that UBP1 nuclear entry is gated by heterodimerization with the NLS-bearing splice variant LBP-1b, followed by PML body accumulation.\",\n      \"evidence\": \"YFP-fusion live-cell localization in COS-7 cells with co-expression rescue and NLS/domain deletion mapping\",\n      \"pmids\": [\"16115195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of PML body accumulation unknown\", \"Whether endogenous LBP-1b stoichiometry controls UBP1 nuclear access in vivo not shown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"To define UBP1 function in the immune system, ChIP and in vivo perturbation showed it binds switch regions in an isotype-specific manner and represses class switch recombination to IgA.\",\n      \"evidence\": \"ChIP in primary B cells and bone marrow chimeric mice with isotype-specific CSR readout\",\n      \"pmids\": [\"19384868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of repression at S regions not resolved\", \"Why occupancy is lost upon LPS stimulation is unexplained\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linking UBP1 to physiology, genetic mapping associated the locus with blood pressure and attributed a role in steroidogenesis via CYP11A activation.\",\n      \"evidence\": \"QTL mapping in BXD mice plus human association and functional annotation as a CYP11A activator\",\n      \"pmids\": [\"19662162\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct CYP11A transcriptional activation experiment not detailed\", \"Causal link between UBP1 genotype and blood pressure not mechanistically established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extending UBP1 to developmental gene regulation, Xenopus assays placed it as a cofactor with Foxi1 and Dmrt2 in ionocyte specification.\",\n      \"evidence\": \"gain- and loss-of-function in Xenopus embryonic epidermis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.10.27.620464\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical characterization of Ubp1 in this program\", \"Direct target genes and binding sites not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolving how UBP1's activator-versus-repressor output is determined, purification and reporter assays defined a MED16-UBP1-TFCP2 subcomplex whose effect depends on motif position relative to the TSS, with TSS-overlapping binding repressing HIV-1 to enforce latency.\",\n      \"evidence\": \"protein purification/mass spectrometry, genomic binding analysis, and HIV-1 transcription reporter assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.08.12.669905\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab, not peer-reviewed\", \"Structural basis for position-dependent switching not determined\", \"Generality of the rule beyond HIV-1 and tested loci unproven\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how UBP1's distinct context-dependent roles—angiogenesis, CSR repression, steroidogenesis, and latency control—are coordinated by its dimerization state, cofactor availability, and promoter geometry across cell types.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model connecting LBP-1b dimerization to target selection\", \"Endothelial angiogenic targets unidentified\", \"No structural model of the UBP1-TFCP2-MED16 complex\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 3, 5]}\n    ],\n    \"complexes\": [\"MED16-UBP1-TFCP2 subcomplex\"],\n    \"partners\": [\"LBP-1b\", \"MED16\", \"TFCP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}