{"gene":"USP39","run_date":"2026-06-14T07:33:11","timeline":{"discoveries":[],"current_model":"Parse failed"},"narrative":{"mechanistic_narrative":"No mechanistic discoveries found in literature.","teleology":[],"mechanism_profile":null},"prefetch_data":{"uniprot":{"accession":"Q53GS9","full_name":"Ubiquitin carboxyl-terminal hydrolase 39","aliases":["SAD1 homolog","U4/U6.U5 tri-snRNP-associated 65 kDa protein"],"length_aa":565,"mass_kda":65.4,"function":"Deubiquitinating enzyme that plays a role in many cellular processes including cellular antiviral response, epithelial morphogenesis, DNA repair or B-cell development (PubMed:33127822, PubMed:34614178). Plays a role in pre-mRNA splicing as a component of the U4/U6-U5 tri-snRNP, one of the building blocks of the precatalytic spliceosome (PubMed:11350945, PubMed:26912367). Specifically regulates immunoglobulin gene rearrangement in a spliceosome-dependent manner, which involves modulating chromatin interactions at the Igh locus and therefore plays an essential role in B-cell development (By similarity). Regulates AURKB mRNA levels, and thereby plays a role in cytokinesis and in the spindle checkpoint (PubMed:18728397). Regulates apoptosis and G2/M cell cycle checkpoint in response to DNA damage by deubiquitinating and stabilizing CHK2 (PubMed:30771428). Also plays an important role in DNA repair by controlling the recruitment of XRCC4/LIG4 to DNA double-strand breaks for non-homologous end-joining repair (PubMed:34614178). Participates in antiviral activity by affecting the type I IFN signaling by stabilizing STAT1 and decreasing its 'Lys-6'-linked ubiquitination (PubMed:33127822). Contributes to non-canonical Wnt signaling during epidermal differentiation (By similarity). Acts as a negative regulator NF-kappa-B activation through deubiquitination of 'Lys-48'-linked ubiquitination of NFKBIA (PubMed:36651806)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q53GS9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/USP39","classification":"Common Essential","n_dependent_lines":1191,"n_total_lines":1208,"dependency_fraction":0.9859271523178808},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PRPF8","stoichiometry":10.0},{"gene":"EFTUD2","stoichiometry":4.0},{"gene":"PRPF4B","stoichiometry":4.0},{"gene":"SNRNP40","stoichiometry":4.0},{"gene":"CD2BP2","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"RBM42","stoichiometry":0.2},{"gene":"SF3A1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/USP39","total_profiled":1310},"omim":[{"mim_id":"618832","title":"EPILEPSY, EARLY-ONSET, 2, WITH OR WITHOUT DEVELOPMENTAL DELAY; EPEO2","url":"https://www.omim.org/entry/618832"},{"mim_id":"618540","title":"CELLULAR REPRESSOR OF E1A-STIMULATED GENES 2; CREG2","url":"https://www.omim.org/entry/618540"},{"mim_id":"612298","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 44; TRIM44","url":"https://www.omim.org/entry/612298"},{"mim_id":"611594","title":"UBIQUITIN-SPECIFIC PROTEASE 39; USP39","url":"https://www.omim.org/entry/611594"},{"mim_id":"611052","title":"SET DOMAIN-CONTAINING PROTEIN 1A; SETD1A","url":"https://www.omim.org/entry/611052"}],"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/USP39"},"hgnc":{"alias_symbol":["SAD1","CGI-21","SNRNP65"],"prev_symbol":[]},"alphafold":{"accession":"Q53GS9","domains":[{"cath_id":"3.30.40.10","chopping":"101-192","consensus_level":"high","plddt":90.4949,"start":101,"end":192},{"cath_id":"3.90.70.10","chopping":"196-346","consensus_level":"medium","plddt":89.6026,"start":196,"end":346},{"cath_id":"3.90.70.10","chopping":"349-560","consensus_level":"medium","plddt":87.6826,"start":349,"end":560}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53GS9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q53GS9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q53GS9-F1-predicted_aligned_error_v6.png","plddt_mean":79.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=USP39","jax_strain_url":"https://www.jax.org/strain/search?query=USP39"},"sequence":{"accession":"Q53GS9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q53GS9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q53GS9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53GS9"}},"corpus_meta":[{"pmid":"7958905","id":"PMC_7958905","title":"The 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pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40056202","citation_count":4,"is_preprint":false},{"pmid":"40358671","id":"PMC_40358671","title":"USP39 promote post-translational modifiers to stimulate the progress of cancer.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40358671","citation_count":3,"is_preprint":false},{"pmid":"38773107","id":"PMC_38773107","title":"The SUN-family protein Sad1 mediates heterochromatin spatial organization through interaction with histone H2A-H2B.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38773107","citation_count":3,"is_preprint":false},{"pmid":"41423877","id":"PMC_41423877","title":"Targeting the Spliceosomal Protein USP39 Through Allosteric Ligands and PROTAC-Induced Degradation.","date":"2025","source":"Angewandte Chemie (International ed. in English)","url":"https://pubmed.ncbi.nlm.nih.gov/41423877","citation_count":2,"is_preprint":false},{"pmid":"29678222","id":"PMC_29678222","title":"Loop-Mediated Isothermal Amplification for Detection of Endogenous Sad1 Gene in Cotton: An Internal Control for Rapid Onsite GMO Testing.","date":"2018","source":"Journal of AOAC International","url":"https://pubmed.ncbi.nlm.nih.gov/29678222","citation_count":2,"is_preprint":false},{"pmid":"40909523","id":"PMC_40909523","title":"MYC-Driven Activation of USP39 Enhances SRSF1 Stability and Promotes PDAC Progression.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40909523","citation_count":1,"is_preprint":false},{"pmid":"40087331","id":"PMC_40087331","title":"USP39/SMC4 promotes hepatoma cell proliferation and 5-FU resistance.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40087331","citation_count":1,"is_preprint":false},{"pmid":"41836548","id":"PMC_41836548","title":"USP39 inhibits MLKL phosphorylation and deubiquitination to suppress necroptosis of nucleus pulposus cells and attenuate intervertebral disc degeneration.","date":"2026","source":"Journal of orthopaedic translation","url":"https://pubmed.ncbi.nlm.nih.gov/41836548","citation_count":1,"is_preprint":false},{"pmid":"41238805","id":"PMC_41238805","title":"Astaxanthin inhibits hepatocellular carcinoma by targeting USP39-mediated β-catenin stabilization through deubiquitination.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41238805","citation_count":0,"is_preprint":false},{"pmid":"40405439","id":"PMC_40405439","title":"USP39 Depletion Plays Repressive Roles in Laryngeal Squamous Cell Carcinoma Development.","date":"2025","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/40405439","citation_count":0,"is_preprint":false},{"pmid":"40347416","id":"PMC_40347416","title":"Exploring the cancerous nexus: the pivotal and diverse roles of USP39 in cancer development.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40347416","citation_count":0,"is_preprint":false},{"pmid":"41903639","id":"PMC_41903639","title":"USP39 deubiquitinase: Dual roles in RNA splicing and protein stabilization in cancer therapeutics.","date":"2026","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41903639","citation_count":0,"is_preprint":false},{"pmid":"40990019","id":"PMC_40990019","title":"USP39 at the crossroads of cancer immunity: regulating immune evasion and immunotherapy response through RNA splicing and ubiquitin signaling.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40990019","citation_count":0,"is_preprint":false},{"pmid":"39853525","id":"PMC_39853525","title":"USP39 promotes retinal pathological angiogenesis in retinopathy of prematurity by stabilizing SIRT2 expression through deubiquitination.","date":"2025","source":"International ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/39853525","citation_count":0,"is_preprint":false},{"pmid":"42113893","id":"PMC_42113893","title":"USP39 promotes antiviral defense through post-transcriptional control of RIG-I and stabilization of STING.","date":"2026","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/42113893","citation_count":0,"is_preprint":false},{"pmid":"41712380","id":"PMC_41712380","title":"Dual roles of USP39 in stabilizing PB2 and orchestrating ribonucleoprotein assembly drive H5 influenza virus replication and pathogenicity.","date":"2026","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/41712380","citation_count":0,"is_preprint":false},{"pmid":"42205906","id":"PMC_42205906","title":"USP39 reduces BRCA1 methylation to promote mitochondrial biogenesis and lower drug sensitivity in ovarian cancer through deubiquitinating ZC3H18.","date":"2026","source":"3 Biotech","url":"https://pubmed.ncbi.nlm.nih.gov/42205906","citation_count":0,"is_preprint":false},{"pmid":"37398223","id":"PMC_37398223","title":"SAD-1 kinase controls presynaptic phase separation by relieving SYD-2/Liprin-α autoinhibition.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37398223","citation_count":0,"is_preprint":false},{"pmid":"23545657","id":"PMC_23545657","title":"Preliminary crystallographic analysis of the kinase domain of SAD-1, a protein essential for presynaptic differentiation in Caenorhabditis elegans.","date":"2013","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/23545657","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.07.663440","title":"TRIM28 regulates pre-mRNA splicing via phosphorylation and SUMOylation networks","date":"2025-07-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.07.663440","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.05.674440","title":"Role of the Arp2/3 Complex in Regulating Mitotic Entry and Progression in  <i>S. pombe</i>","date":"2025-09-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.05.674440","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44616,"output_tokens":7522,"usd":0.123339,"stage1_stop_reason":"refusal"},"stage2":{"model":"","input_tokens":0,"output_tokens":0,"usd":0.0},"total_usd":0.123339,"stage1_batch_id":"msgbatch_015cW3C55o5xm8EPaM1UvcZR","stage2_batch_id":"msgbatch_018NDJHPntdYJzBohpB6hHKo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of full-length yeast Sad1 (USP39 ortholog) at 1.8 Å resolution reveals two domains: a zinc finger ubiquitin binding domain (ZnF-UBP) and an inactive ubiquitin-specific protease (iUSP) domain. The iUSP domain forms the characteristic ubiquitin binding pocket but contains an active-site substitution that abolishes enzymatic deubiquitinase activity. The ZnF-UBP domain lacks the canonical ubiquitin-binding motif. In vitro splicing assays show Sad1 is required for assembly of the active spliceosome and is critical for splicing of nearly all yeast intron-containing genes.\",\n      \"method\": \"X-ray crystallography (1.8 Å), in vitro splicing assays, splicing microarrays, active-site analysis\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation by in vitro splicing assays and microarrays in a single rigorous study\",\n      \"pmids\": [\"24681967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human USP39 is required to maintain the mitotic spindle checkpoint and support cytokinesis. Despite containing a ubiquitin-protease domain, USP39 is entirely devoid of deubiquitinase activity. USP39 depletion by RNAi causes specific reduction in Aurora B mRNA levels, consistent with a role in mRNA processing/splicing rather than direct DUB activity.\",\n      \"method\": \"RNAi functional screen, in vitro DUB activity assay, RT-PCR, cell cycle analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with defined mitotic phenotype plus in vitro enzymatic assay demonstrating catalytic inactivity, two orthogonal methods in one study\",\n      \"pmids\": [\"18728397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Yeast Sad1 (USP39 ortholog) maintains tri-snRNP integrity by counteracting Brr2-mediated ATP-dependent dissociation of the U4/U6.U5 tri-snRNP. In the absence of Sad1, the tri-snRNP dissociates into U5 and U4/U6 upon ATP hydrolysis and cannot bind the spliceosome. Sad1 promotes reassociation of separated U4/U6 and U5 particles, especially in the absence of ATP.\",\n      \"method\": \"In vitro splicing/snRNP assembly assays, native gel analysis, biochemical fractionation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution assays directly demonstrating Sad1's role in tri-snRNP homeostasis, single rigorous study\",\n      \"pmids\": [\"24190974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP39 is an essential splicing factor required for pre-mRNA splicing fidelity in KRAS-dependent cancer cells. USP39 depletion causes significant reduction in pre-mRNA splicing efficiency demonstrated by RNA-seq. DHX38, an USP39-interacting splicing factor, was identified as a binding partner, and its depletion also reduces viability of KRAS-active cells.\",\n      \"method\": \"Synthetic lethal RNAi screen, RNA-seq, co-immunoprecipitation (USP39-DHX38 interaction), proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq demonstrating splicing defects plus Co-IP identifying binding partner, replicated across cancer cell lines\",\n      \"pmids\": [\"28154181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Zebrafish usp39 mutation causes missplicing of Rb1 pre-mRNA, generating a premature stop codon. Loss of usp39 leads to microcephaly and pituitary lineage expansion. Overexpression of correctly spliced Rb1 mRNA partially rescues pituitary expansion in usp39 mutants, placing Usp39 upstream of Rb1 in a neuronal mRNA splicing pathway.\",\n      \"method\": \"Forward genetic screen, positional cloning, gene expression profiling, pre-mRNA splicing analysis, morpholino knockdown, mRNA rescue\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — forward genetic screen plus epistasis (rescue experiment), multiple orthogonal methods, direct splicing analysis\",\n      \"pmids\": [\"21249182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP39 directly interacts with E3 ligase TRIM26 (identified by Co-IP and immunofluorescence) and functions antagonistically: USP39 deubiquitinates and stabilizes ZEB1 protein while TRIM26 ubiquitinates ZEB1 for degradation. USP39 depletion promotes ZEB1 degradation and inhibits HCC cell proliferation and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, ubiquitination assays, shRNA knockdown\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying interaction, ubiquitination assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33649471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP39 directly deubiquitinates β-catenin to stabilize it (promoting Wnt/β-catenin signaling), and also inhibits TRIM26 pre-mRNA splicing and maturation, which indirectly reduces ubiquitination of β-catenin by TRIM26. Co-localization of USP39 with β-catenin was demonstrated.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, pre-mRNA splicing analysis, knockdown/overexpression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assays, single lab with two orthogonal mechanistic approaches\",\n      \"pmids\": [\"36707504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP39 colocalizes with spliceosome components in nuclear speckles and facilitates efficient pre-mRNA splicing of HMGA2. RNA immunoprecipitation sequencing (RIP-seq) showed USP39 preferentially binds exon-intron regions near 5' and 3' splicing sites. Transcriptomic analysis revealed USP39 deletion causes globally impaired splicing characterized by skipped exons.\",\n      \"method\": \"Immunofluorescence colocalization, RIP-seq, RNA-seq, shRNA knockdown, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq directly demonstrating USP39 binding to splice sites plus RNA-seq demonstrating splicing defects, two highly orthogonal genomic methods\",\n      \"pmids\": [\"33731694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP39 promotes TAZ mRNA maturation/splicing in glioma cells. Loss of USP39 decreases TAZ pre-mRNA splicing efficiency, reducing TAZ protein levels independent of canonical Hippo signaling. Luciferase reporter assays showed 92% decrease in TEAD-dependent YAP/TAZ reporter activity upon USP39 knockdown.\",\n      \"method\": \"shRNA knockdown, luciferase reporter assays, RT-PCR pre-mRNA splicing analysis, xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct pre-mRNA splicing analysis plus reporter assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31332287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP39 deubiquitinates and stabilizes CHK2 (checkpoint kinase 2). shRNA-mediated knockdown of USP39 leads to CHK2 destabilization, compromising the DNA damage-induced G2/M checkpoint, decreasing apoptosis, and conferring cancer cell resistance to chemotherapy and radiation.\",\n      \"method\": \"shRNA knockdown, in vitro deubiquitination assay, co-immunoprecipitation, cell cycle analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deubiquitination assay plus Co-IP demonstrating interaction, single lab with two orthogonal methods\",\n      \"pmids\": [\"30771428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP39 interacts with STAT1 and sustains its protein level by deubiquitination, specifically decreasing K6-linked (but not K48-linked) ubiquitination of STAT1. USP39 promotes JAK/STAT downstream signaling and IFN-stimulated gene expression to enhance antiviral immunity.\",\n      \"method\": \"RNAi screen, Co-IP, ubiquitination assay distinguishing K6 vs K48 linkages, overexpression/knockdown, IFN-stimulated response element reporter\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination linkage-specific assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33127822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP39 interacts with and stabilizes IκBα by reducing K48-linked polyubiquitination of IκBα, functioning as a negative regulator of NF-κB inflammatory signaling. USP39-deficient macrophages show increased proinflammatory cytokine production, and USP39-knockout mice are more sensitive to LPS-induced sepsis.\",\n      \"method\": \"Co-IP, ubiquitination assay (K48-linkage specific), siRNA/shRNA knockdown, knockout mouse model, in vivo sepsis model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus K48-specific ubiquitination assay in vitro plus in vivo mouse knockout model, multiple orthogonal methods\",\n      \"pmids\": [\"36651806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP39 deubiquitinates and stabilizes SP1 protein, prolonging its half-life. USP39 promotes HCC cell proliferation in a SP1-dependent manner; knockdown of USP39 promotes apoptosis and cell cycle arrest reversed by forced SP1 expression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, siRNA knockdown, rescue experiments\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus CHX chase, single lab with multiple methods\",\n      \"pmids\": [\"34197957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP39 rapidly localizes to DNA lesions in a poly(ADP-ribose) (PAR)-dependent manner. A tripartite RG motif in the N-terminus (N46) mediates liquid demixing at damage sites. USP39 promotes non-homologous end-joining (NHEJ) by directly interacting with the XRCC4/LIG4 complex. Separately, the USP39-associated spliceosome complex controls homologous recombination repair in a PAR-independent manner.\",\n      \"method\": \"Live-cell imaging, FRAP, PAR-binding assays, Co-IP (USP39-XRCC4/LIG4), domain mutagenesis, NHEJ/HR repair assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments (live imaging, FRAP) with functional consequence plus Co-IP with XRCC4/LIG4 plus domain mutagenesis, multiple orthogonal methods single lab\",\n      \"pmids\": [\"34614178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP39 promotes efficient splicing of Rictor pre-mRNA (a component of mTORC2), selectively enhancing mTORC2 activity. RNA-seq after USP39 shRNA silencing showed mTOR pathway activation was affected. This was not observed for other key mTOR complex components.\",\n      \"method\": \"shRNA knockdown, RNA-seq, biochemical mTORC2 activity assays, xenograft models\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq plus mTORC2 activity assays demonstrating splicing-dependent regulation, single lab\",\n      \"pmids\": [\"34123832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP39 is essential for B cell development; ablation in B cell lineage blocks pre-pro-B to pro-B cell transition by impairing immunoglobulin gene rearrangement. Usp39 modulates chromatin interactions at the Igh locus in a spliceosome-dependent manner.\",\n      \"method\": \"Conditional knockout mouse model, flow cytometry, chromatin interaction assays, Eμ-Myc transgenic cross\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with defined developmental phenotype plus chromatin interaction assays, multiple orthogonal methods\",\n      \"pmids\": [\"35139388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP39 deubiquitinates and stabilizes FOXM1 in breast cancer cells. Elevated USP39 expression lowers FOXM1 ubiquitination, enhancing FOXM1 transcriptional activity and regulating downstream genes Cdc25b and Plk1. Interaction confirmed by Co-IP and in vitro deubiquitination assay.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deubiquitination assay, transcriptional reporter, knockdown/overexpression\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vitro deubiquitination assay, single lab with two orthogonal methods\",\n      \"pmids\": [\"36119839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP39 deubiquitinates Cyclin B1, cleaving K29-linked polyubiquitin chains at Lys242, stabilizing Cyclin B1 expression. Overexpression of Cyclin B1 rescues USP39 knockdown-induced G2/M arrest in glioma cells, placing USP39 upstream of Cyclin B1 in cell cycle regulation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with K29-linkage specificity and site-specific mutants, rescue experiments, xenograft models\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus site-specific ubiquitination assay plus rescue epistasis, single lab\",\n      \"pmids\": [\"37302347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP39 can be acetylated by histone acetyltransferase MYST1, which is required for its proteasome-mediated degradation by Von Hippel-Lindau (VHL) protein. In HCC cells, USP39 interacts with and is deacetylated by SIRT7, promoting USP39 stability and HCC cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, acetylation/deacetylation assays, proteasome inhibition, cycloheximide chase, in vitro and in vivo proliferation assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus acetylation/deacetylation assays plus CHX chase demonstrating stability changes, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32711345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT7 deacetylates USP39 to promote its stability in cervical squamous cell carcinoma cells. USP39 and SIRT7 colocalize in the cell nucleus. USP39 promotes FOXM1 transcriptional activity and upregulates SIRT7 expression, forming a positive feedback loop. SIRT7 promotes autophagy and inhibits ROS production in CSCC cells through the USP39/FOXM1 axis.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, rescue assays, knockdown/overexpression\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus colocalization, but primarily KD/OE with phenotype in single lab without direct deacetylation biochemical assay described in abstract\",\n      \"pmids\": [\"37957720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP39 reduces K48-linked polyubiquitin chains on RBM39 (RNA-binding motif protein), enhancing RBM39 stability and preventing its proteasomal degradation. USP39 and RBM39 interact and colocalize in the nucleus. RBM39 overexpression partially restores the effects of USP39 depletion on gastric cancer cell growth and migration.\",\n      \"method\": \"Affinity purification-mass spectrometry, Co-IP, ubiquitination assays (K48-linkage specific), nuclear colocalization, rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS plus Co-IP plus K48-specific ubiquitination assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39260689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP39 regulates pre-mRNA splicing via the USP39(101-565) fragment that directly mediates binding to SRSF1 and SRPK1. USP39 promotes phosphorylation of SRSF1 to regulate VEGF-A alternative splicing; USP39 knockdown upregulates the anti-angiogenic isoform VEGF-A165b in renal cell carcinoma.\",\n      \"method\": \"Affinity purification-mass spectrometry, Co-IP, Western blot for SRSF1 phosphorylation, isoform-specific RT-PCR, domain-mapping experiments\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS plus Co-IP plus domain mapping plus phosphorylation assay, single lab\",\n      \"pmids\": [\"34544400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP39 is essential for epithelial morphogenesis in mice; Usp39-deficient embryos display early embryonic lethality due to failure in primitive streak formation and loss of apico-basal polarity in epiblast cells. USP39 interacts with transcription factor GRHL3 and influences its subcellular localization, and is necessary for expression of planar cell polarity (PCP) components.\",\n      \"method\": \"Mouse conditional knockout, immunofluorescence, Co-IP (USP39-GRHL3), embryo phenotypic analysis, PCP gene expression analysis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with defined developmental phenotype plus Co-IP identifying GRHL3 interaction, single lab\",\n      \"pmids\": [\"35440748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Usp39 regulates alternative splicing of multiple autophagy-related genes. Hepatocyte-specific Usp39 deletion in mice causes increased lipid accumulation, spontaneous steatosis, and impaired autophagy. RNA immunoprecipitation sequencing (RIP-seq) combined with RNA-seq showed Usp39 regulates alternative 5' splice site selection in Hsf1 exon 6; reduced Hsf1 expression mediates the lipid accumulation phenotype, which is rescued by Hsf1 overexpression.\",\n      \"method\": \"Hepatocyte-specific conditional knockout mouse, RIP-seq, RNA-seq, lipid accumulation assays, Hsf1 overexpression rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout mouse with defined metabolic phenotype, RIP-seq plus RNA-seq, rescue experiment identifying Hsf1 as downstream target, multiple orthogonal methods\",\n      \"pmids\": [\"37923718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP39 deubiquitinates ETS2 without affecting its protein stability. USP39 binds ETS2 through their respective N-terminal regions (zinc finger and PNT domains not required). Non-proteolytic deubiquitination by USP39 significantly suppresses ETS2 transcriptional activity and reduces ETS2 nuclear localization.\",\n      \"method\": \"DUB library binding assay, Co-IP, in vitro deubiquitination assay, nuclear/cytoplasmic fractionation, luciferase reporter assays\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vitro deubiquitination assay plus domain mapping plus localization assay, single lab\",\n      \"pmids\": [\"37892157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP39 interacts with SRSF1 in an RNA-independent manner and stabilizes it by reducing ubiquitination. MYC directly activates USP39 transcription via E-box motifs in its exon 1b promoter, linking MYC-driven transcription to post-translational stabilization of SRSF1 via USP39.\",\n      \"method\": \"Co-IP, ubiquitination assay, ChIP (MYC-USP39 promoter), luciferase reporter for E-box elements, knockdown/rescue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus ChIP identifying transcriptional regulation, preprint, single lab\",\n      \"pmids\": [\"40909523\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP39 undergoes liquid-liquid phase separation (LLPS) in nucleoli, dependent on its N-terminal disordered region (residues 1-103). USP39 knockdown reduces oncogenic transcription effector GLI1 levels and inhibits lung cancer cell growth and xenograft formation. FRAP analysis and in vitro LLPS assays confirmed the phase separation properties.\",\n      \"method\": \"GFP-fusion LLPS assays, FRAP, immunofluorescence, transcriptomic profiling, shRNA knockdown, xenograft models\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP plus in vitro LLPS assay demonstrating phase separation, plus domain mapping, single lab\",\n      \"pmids\": [\"39885503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM28 interacts with spliceosomal protein USP39 in a phosphorylation-dependent manner; non-phosphorylated TRIM28 promotes USP39 SUMOylation at defined lysine residues. This SUMOylation enhances USP39's function within the U4/U6.U5 tri-snRNP complex.\",\n      \"method\": \"Co-IP (phosphorylation-dependent), SUMOylation assays with site mapping, alternative splicing analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus SUMOylation assay with site-specific mapping, preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP39 regulates pyruvate metabolism in NSCLC by deubiquitinating PDHA (pyruvate dehydrogenase E1 subunit alpha). USP39 silencing elevates K63-linked ubiquitination on PDHA and reduces PDH complex activity, TCA cycle intermediates, and mitochondrial respiration. Citrate supplementation restores mitochondrial respiration and cell growth in USP39-depleted cells.\",\n      \"method\": \"GSEA, metabolite set enrichment analysis, ubiquitination assay (K63-linkage specific), PDH complex activity assay, metabolic flux analysis, knockdown, xenograft\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — K63-specific ubiquitination assay plus PDH complex activity assay plus metabolomics, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39695108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP39 directly deubiquitinates the SARS-CoV-2 envelope (E) protein, reversing polyubiquitination via its inactive ubiquitin-specific protease domain. USP39 interacts with E via the arginine-rich motif (AR). USP39 protects E from RNF5-mediated proteasomal degradation, thereby stabilizing E and promoting SARS-CoV-2 replication.\",\n      \"method\": \"Mass spectrometry, Co-IP (USP39-E interaction), in vitro deubiquitination assay, domain mapping (AR motif), viral replication assays with gain/loss of function\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS plus Co-IP plus in vitro deubiquitination assay plus domain mapping, single lab\",\n      \"pmids\": [\"38158131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP39 directly deubiquitinates influenza H5 AIV polymerase PB2 at lysine 660 (K660), preventing its degradation and sustaining polymerase activity. Independently of enzymatic activity, USP39 promotes PB2-PB1 association, facilitating ribonucleoprotein (RNP) complex formation. A PB2 K660R substitution enhances viral replication and pathogenicity in mice.\",\n      \"method\": \"Co-IP, in vitro deubiquitination assay (site-specific K660), viral RNP reconstitution, PB2-PB1 association assay, mouse pathogenicity model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 /","stage2_raw":"","audit_flag":{"gene":"USP39","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"recall_miss","uniprot_band":"rich","rules_fired":"R5","issue":"R5: no narrative despite experimental UniProt FUNCTION (1429 chars) and on-target evidence in corpus (81 on-target corpus titles)"},"evaluation":null}