{"gene":"USP34","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2011,"finding":"USP34 was identified in purified axin-containing protein complexes by LC-MS/MS and shown to stabilize axin by opposing its tankyrase-dependent ubiquitination, thereby functioning downstream of the β-catenin destruction complex to regulate Wnt/β-catenin signaling; RNAi knockdown of USP34 led to axin degradation and inhibition of β-catenin-mediated transcription.","method":"LC-MS/MS of purified axin complexes, RNA interference, Wnt/β-catenin reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal complex identification by MS, RNAi functional validation, epistasis placing USP34 downstream of destruction complex, replicated in multiple assays in one focused study","pmids":["21383061"],"is_preprint":false},{"year":2013,"finding":"USP34 stabilizes the E3 ubiquitin ligase RNF168 by deubiquitylation in response to DNA double-strand breaks; loss of USP34 causes rapid RNF168 degradation, attenuated DSB-associated ubiquitylation, defective recruitment of BRCA1 and 53BP1, and compromised cell survival after ionizing radiation.","method":"siRNA knockdown, immunofluorescence for DSB repair factors (BRCA1, 53BP1), clonogenic survival assay, ubiquitylation assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RNAi, ubiquitylation assay, recruitment assay, survival assay) in a single focused study","pmids":["23863847"],"is_preprint":false},{"year":2013,"finding":"In a genome-wide siRNA DUB screen in T lymphocytes, knockdown of USP34 selectively enhanced TCR-driven NF-κB activation, led to more pronounced degradation of the NF-κB inhibitor IκBα, and increased NF-κB DNA-binding activity, positioning USP34 as a negative regulator of NF-κB signaling downstream of TCR engagement.","method":"siRNA library screen, NF-κB reporter assay, IκBα degradation analysis, NF-κB DNA binding assay","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA screen with functional validation by multiple readouts, but no direct substrate identified for USP34 deubiquitylase activity in this context","pmids":["23590831"],"is_preprint":false},{"year":2018,"finding":"USP34 stabilizes both Smad1 and RUNX2 by deubiquitylation in mesenchymal stem cells; USP34 depletion inhibits osteogenic differentiation and BMP2 signaling responses, and depletion of Smurf1 (an E3 ligase for Smad1) restores the osteogenic potential of Usp34-deficient MSCs in vitro, placing USP34 in opposition to Smurf1-mediated degradation of Smad1/RUNX2.","method":"Conditional knockout in mice, siRNA knockdown, ubiquitylation assays, epistasis (Smurf1 co-depletion rescue), bone phenotype analysis (micro-CT, histology)","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO, in vitro mechanistic epistasis with Smurf1, ubiquitylation assays, multiple orthogonal readouts in one rigorous study","pmids":["30181118"],"is_preprint":false},{"year":2018,"finding":"USP34 was identified as an interaction partner of the E3 ligase gp78 by Co-IP/LC-MS/MS; USP34 knockdown facilitates proteasomal degradation of gp78 and consequently impairs gp78-mediated lipid droplet formation.","method":"Co-IP coupled to LC-MS/MS, siRNA knockdown, lipid droplet formation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP/MS identification plus functional consequence of KD, single lab, two orthogonal methods","pmids":["30585151"],"is_preprint":false},{"year":2024,"finding":"USP34 deubiquitinates and stabilizes the peptidyl-prolyl isomerase Pin1; this interaction is facilitated by Plk1-mediated phosphorylation of Pin1, and stabilized Pin1 promotes isomerization of the SUMO E2 enzyme Ubc9 (requiring CDK1-mediated phosphorylation of Ubc9), leading to elevated SUMO1-modified protein hypersumoylation that supports glioma stem cell maintenance.","method":"Co-immunoprecipitation, ubiquitylation assays, pharmacological inhibition (Plk1 inhibitor, CDK1 inhibitor), in vitro isomerization assay, orthotopic tumor xenograft","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple PTM contexts validated (phosphorylation, ubiquitination, sumoylation), in vivo xenograft, multiple orthogonal methods in one study","pmids":["38167292"],"is_preprint":false},{"year":2020,"finding":"USP34 interacts with SOX2, reduces its polyubiquitination, and stabilizes SOX2 protein (without affecting SOX2 mRNA), thereby promoting cell survival and cisplatin resistance in laryngeal squamous cell carcinoma cells.","method":"Co-immunoprecipitation, ubiquitylation assay, siRNA knockdown, overexpression rescue, cell viability assay","journal":"The Kaohsiung journal of medical sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus ubiquitylation assay, single lab, functional rescue included","pmids":["32783291"],"is_preprint":false},{"year":2021,"finding":"USP34 stabilizes the transcription factor NFIC by deubiquitylation in dental pulp cells; conditional deletion of Usp34 in dental mesenchymal cells reduces NFIC levels and impairs odontogenic differentiation, resulting in short root anomaly, and overexpression of NFIC partially restores the differentiation defect.","method":"Conditional knockout in mice, siRNA knockdown, overexpression rescue, ubiquitylation assay, histomorphometry","journal":"International journal of oral science","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with phenotype, in vitro mechanistic epistasis (NFIC rescue), ubiquitylation assay, multiple orthogonal methods","pmids":["33686052"],"is_preprint":false},{"year":2022,"finding":"In Drosophila, loss of Usp34 by siRNA abolishes homologous recombination at I-SceI-induced DSBs (DR-white assay), demonstrating an indispensable role for Usp34 specifically in homologous recombination-mediated DSB repair.","method":"siRNA knockdown, DR-white homologous recombination reporter assay, survival assay after UV/X-ray irradiation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean genetic reporter assay in Drosophila model with specific HR pathway readout, single lab","pmids":["35393473"],"is_preprint":false},{"year":2023,"finding":"An siRNA screen of 96 DUBs in endothelial and HeLa cells identified USP34 as a regulator of thrombin-GPCR (PAR1)-driven p38 MAPK signaling; USP34 knockdown decreased thrombin-stimulated p38 phosphorylation and reduced IL-6 cytokine expression, but had no effect on endothelial barrier permeability.","method":"siRNA library screen, p38 phosphorylation assay, IL-6 ELISA, endothelial permeability assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA screen with functional validation by multiple readouts, single lab; direct USP34 substrate in this pathway not identified","pmids":["37865315"],"is_preprint":false},{"year":2024,"finding":"USP34 knockdown in endothelial cells increases PAR1 (F2R) mRNA transcript levels, leading to elevated PAR1 cell surface abundance and altered thrombin-stimulated p38 activation; this effect is not due to altered PAR1 ubiquitination, internalization, or degradation, but to transcriptional regulation of the F2R gene.","method":"siRNA knockdown, flow cytometry, RT-PCR, receptor internalization and degradation assays, p38 phosphorylation assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple assays excluding alternative mechanisms, single lab; molecular mechanism linking USP34 to F2R transcription not defined","pmids":["39705380"],"is_preprint":false},{"year":2024,"finding":"USP34 mediates BPTF-regulated stabilization of FOXC1 via deubiquitylation; immunoprecipitation experiments showed that BPTF affects FOXC1 protein stability through USP34-dependent de-ubiquitylation, and FOXC1 overexpression rescues the phenotype of BPTF knockdown in glioma cells.","method":"Co-immunoprecipitation, ubiquitylation assay, western blot, lentiviral overexpression/knockdown, functional rescue","journal":"Histology and histopathology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitylation assay plus functional rescue, single lab","pmids":["38686761"],"is_preprint":false},{"year":2025,"finding":"USP34 interacts with c-Myc, reduces its ubiquitination, and stabilizes the c-Myc protein; USP34 knockdown enhances c-Myc ubiquitination and degradation, and reduces aerobic glycolysis in hepatocellular carcinoma cells; overexpression of c-Myc reverses si-USP34-mediated phenotypic effects.","method":"Co-immunoprecipitation, ubiquitylation assay, siRNA knockdown, CCK-8, glycolysis assays, overexpression rescue","journal":"The Turkish journal of gastroenterology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus ubiquitylation assay and functional rescue, single lab","pmids":["40260316"],"is_preprint":false},{"year":2026,"finding":"USP34 deubiquitinates and stabilizes ANT1 (adenine nucleotide translocase 1) in TMJ chondrocytes; USP34 deficiency in chondrocyte-specific Usp34 KO mice leads to impaired ANT1-dependent initiation of PINK1-Parkin mitophagy and age-dependent TMJ osteoarthritis; USP34 overexpression protects chondrocytes against cellular injury.","method":"Chondrocyte-specific conditional KO mouse model, micro-CT/histomorphometry, Co-IP, ubiquitylation assay, mitophagy assays, overexpression studies","journal":"JBMR plus","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with phenotype, direct substrate identification (ANT1) by Co-IP and ubiquitylation assay, pathway placement upstream of PINK1-Parkin, multiple orthogonal methods","pmids":["41631201"],"is_preprint":false},{"year":2026,"finding":"USP34 stabilizes eIF3m protein through deubiquitylation in triple-negative breast cancer cells; stabilized eIF3m binds the 5'UTR of MTCH2 mRNA to upregulate MTCH2 expression, thereby maintaining mitochondrial function and promoting TNBC proliferation.","method":"Co-immunoprecipitation, GST pulldown, RNA immunoprecipitation, RNA pulldown, ubiquitylation assay, siRNA knockdown, mitochondrial function assays","journal":"Journal of histotechnology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple binding assays (Co-IP, GST pulldown, RIP) plus functional readouts, single lab","pmids":["42023842"],"is_preprint":false}],"current_model":"USP34 is a deubiquitylase that stabilizes multiple substrates—including axin (opposing tankyrase-dependent ubiquitination in Wnt signaling), RNF168 (promoting DSB repair ubiquitin signaling), Smad1/RUNX2 (supporting BMP2-driven osteogenesis), Pin1 (driving SUMO1 hypersumoylation in glioma stem cells), NFIC, ANT1, SOX2, FOXC1, c-Myc, eIF3m, and gp78—by removing polyubiquitin chains to prevent proteasomal degradation, and it additionally regulates NF-κB activity downstream of TCR engagement, GPCR-p38 MAPK signaling, and homologous recombination-mediated DNA repair."},"narrative":{"mechanistic_narrative":"USP34 is a deubiquitylase that controls the abundance of diverse substrate proteins by removing polyubiquitin chains to oppose their proteasomal degradation, thereby acting as a positive or negative tuning node across developmental signaling, DNA repair, and cancer-associated pathways [PMID:21383061, PMID:30181118, PMID:23863847]. Its founding role is in Wnt/β-catenin signaling, where it was purified in axin-containing complexes and stabilizes axin by counteracting tankyrase-dependent ubiquitination, functioning downstream of the β-catenin destruction complex [PMID:21383061]. In the DNA damage response, USP34 stabilizes the E3 ligase RNF168 to sustain double-strand-break ubiquitin signaling and the recruitment of BRCA1 and 53BP1, with loss compromising survival after ionizing radiation [PMID:23863847], consistent with an indispensable requirement for Usp34 in homologous recombination repair [PMID:35393473]. A recurring theme is opposition to specific E3 ligases: USP34 stabilizes Smad1 and RUNX2 against Smurf1-mediated degradation to drive BMP2 osteogenesis [PMID:30181118], stabilizes the transcription factor NFIC to support odontogenic differentiation [PMID:33686052], and stabilizes ANT1 to enable PINK1-Parkin mitophagy in chondrocytes [PMID:41631201]; conditional knockout mice reveal skeletal, dental, and joint phenotypes from these activities [PMID:30181118, PMID:33686052, PMID:41631201]. In cancer contexts USP34 stabilizes a range of pro-tumorigenic factors—Pin1 (driving Ubc9 isomerization and SUMO1 hypersumoylation in glioma stem cells) [PMID:38167292], SOX2 [PMID:32783291], FOXC1 [PMID:38686761], c-Myc [PMID:40260316], and eIF3m [PMID:42023842]. USP34 also acts as a negative regulator of TCR-driven NF-κB activation [PMID:23590831] and modulates thrombin-PAR1-p38 MAPK signaling, in the latter case through transcriptional control of F2R rather than receptor deubiquitination [PMID:37865315, PMID:39705380].","teleology":[{"year":2011,"claim":"Established USP34's founding function by asking how axin stability is maintained against tankyrase-driven turnover, placing a deubiquitylase within the Wnt/β-catenin destruction-complex axis.","evidence":"LC-MS/MS of purified axin complexes with RNAi and Wnt reporter assays","pmids":["21383061"],"confidence":"High","gaps":["Direct in vitro deubiquitylation of axin by USP34 not reconstituted","Chain-type specificity of USP34 not defined"]},{"year":2013,"claim":"Extended USP34 into the DNA damage response by showing it stabilizes the E3 ligase RNF168 to sustain DSB ubiquitin signaling and downstream repair-factor recruitment.","evidence":"siRNA knockdown, immunofluorescence for BRCA1/53BP1, ubiquitylation and clonogenic survival assays","pmids":["23863847"],"confidence":"High","gaps":["Whether USP34 acts directly on RNF168 ubiquitin chains vs indirectly not fully resolved","Recruitment dynamics of USP34 to damage sites unknown"]},{"year":2013,"claim":"Identified USP34 as a negative regulator of TCR-driven NF-κB signaling, expanding its roles beyond stabilization to immune signal attenuation.","evidence":"Genome-wide siRNA DUB screen in T lymphocytes with NF-κB reporter, IκBα degradation and DNA-binding readouts","pmids":["23590831"],"confidence":"Medium","gaps":["No direct USP34 substrate identified in the NF-κB pathway","Screen-based hit without reciprocal biochemical validation"]},{"year":2018,"claim":"Demonstrated an in vivo developmental role by showing USP34 opposes Smurf1-mediated degradation of Smad1/RUNX2 to enable BMP2-driven osteogenesis.","evidence":"Conditional KO mice, Smurf1 co-depletion epistasis rescue, ubiquitylation assays, micro-CT/histology","pmids":["30181118"],"confidence":"High","gaps":["Direct biochemical deubiquitylation of Smad1/RUNX2 not reconstituted","Tissue-specificity of the USP34-Smurf1 antagonism unclear"]},{"year":2018,"claim":"Linked USP34 to ER-associated/lipid biology by identifying gp78 as an interactor whose stability and lipid-droplet function depend on USP34.","evidence":"Co-IP/LC-MS/MS, siRNA knockdown, lipid droplet formation assay","pmids":["30585151"],"confidence":"Medium","gaps":["Single lab, no reciprocal validation of direct deubiquitylation","Mechanism connecting gp78 stability to lipid droplets incomplete"]},{"year":2020,"claim":"Began establishing USP34 as a stabilizer of oncogenic transcription factors by showing it deubiquitylates SOX2 to promote survival and cisplatin resistance.","evidence":"Co-IP, ubiquitylation assay, siRNA knockdown, overexpression rescue, viability assay","pmids":["32783291"],"confidence":"Medium","gaps":["Single-lab Co-IP without reciprocal validation","Specificity of USP34 for SOX2 vs other factors not benchmarked"]},{"year":2021,"claim":"Showed an in vivo dental developmental requirement, with USP34 stabilizing NFIC to drive odontogenic differentiation and prevent short root anomaly.","evidence":"Conditional KO mice, siRNA, NFIC overexpression rescue, ubiquitylation assay, histomorphometry","pmids":["33686052"],"confidence":"High","gaps":["Direct deubiquitylation of NFIC not reconstituted in vitro","Upstream regulators directing USP34 to NFIC unknown"]},{"year":2022,"claim":"Defined the DNA-repair role more precisely by showing Usp34 is indispensable specifically for homologous recombination at induced DSBs in Drosophila.","evidence":"siRNA knockdown, DR-white HR reporter, survival after UV/X-ray","pmids":["35393473"],"confidence":"Medium","gaps":["Molecular substrate of Usp34 in HR not identified in this system","Conservation of the exact mechanism to human cells not shown here"]},{"year":2023,"claim":"Connected USP34 to GPCR signaling by identifying it as a regulator of thrombin-PAR1-driven p38 MAPK activation and IL-6 production.","evidence":"siRNA DUB screen in endothelial/HeLa cells, p38 phosphorylation assay, IL-6 ELISA, permeability assay","pmids":["37865315"],"confidence":"Medium","gaps":["Direct USP34 substrate in the PAR1-p38 pathway not identified","Mechanism of selectivity for p38 vs barrier function unexplained"]},{"year":2024,"claim":"Resolved part of the PAR1 mechanism by showing USP34 acts via transcriptional control of F2R rather than receptor ubiquitination or trafficking.","evidence":"siRNA, flow cytometry, RT-PCR, internalization/degradation assays, p38 phosphorylation assay","pmids":["39705380"],"confidence":"Medium","gaps":["Molecular link between USP34 and F2R transcription undefined","Whether this reflects a deubiquitylase-dependent activity unknown"]},{"year":2024,"claim":"Defined a PTM-gated cancer mechanism in which USP34 stabilizes Pin1 (facilitated by Plk1 phosphorylation), driving Ubc9 isomerization and SUMO1 hypersumoylation in glioma stem cells.","evidence":"Reciprocal Co-IP, ubiquitylation assays, Plk1/CDK1 inhibition, in vitro isomerization, orthotopic xenograft","pmids":["38167292"],"confidence":"High","gaps":["How Plk1 phosphorylation licenses USP34-Pin1 binding mechanistically not fully detailed","Generality of the hypersumoylation axis beyond glioma stem cells unknown"]},{"year":2024,"claim":"Added FOXC1 to the USP34 substrate set, placing USP34 downstream of BPTF in controlling FOXC1 stability in glioma.","evidence":"Co-IP, ubiquitylation assay, western blot, lentiviral knockdown/overexpression, functional rescue","pmids":["38686761"],"confidence":"Medium","gaps":["Single-lab evidence without reciprocal validation","How BPTF directs USP34 to FOXC1 not defined"]},{"year":2025,"claim":"Implicated USP34 in tumor metabolism by showing it stabilizes c-Myc and sustains aerobic glycolysis in hepatocellular carcinoma.","evidence":"Co-IP, ubiquitylation assay, siRNA, glycolysis assays, c-Myc overexpression rescue","pmids":["40260316"],"confidence":"Medium","gaps":["Direct deubiquitylation of c-Myc not reconstituted","Single-lab evidence"]},{"year":2026,"claim":"Demonstrated an in vivo mitochondrial-quality-control role, with USP34 stabilizing ANT1 to enable PINK1-Parkin mitophagy and protect against TMJ osteoarthritis.","evidence":"Chondrocyte-specific conditional KO mice, micro-CT/histomorphometry, Co-IP, ubiquitylation assay, mitophagy and overexpression studies","pmids":["41631201"],"confidence":"High","gaps":["Direct in vitro deubiquitylation of ANT1 not shown","How ANT1 levels gate PINK1-Parkin initiation not mechanistically detailed"]},{"year":2026,"claim":"Extended the substrate repertoire to translation/mitochondrial maintenance by showing USP34 stabilizes eIF3m, which binds MTCH2 5'UTR to support TNBC proliferation.","evidence":"Co-IP, GST pulldown, RIP, RNA pulldown, ubiquitylation assay, siRNA, mitochondrial function assays","pmids":["42023842"],"confidence":"Medium","gaps":["Single-lab evidence without reciprocal validation","Direct deubiquitylation of eIF3m not reconstituted"]},{"year":null,"claim":"The biochemical determinants of USP34 substrate selectivity, polyubiquitin chain-type specificity, and structural basis for its broad substrate range remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the USP34 catalytic domain in the timeline","No defined recognition motif explaining its diverse substrate set","Whether non-catalytic/scaffolding activities account for transcriptional and NF-κB effects unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,5,6,7,11,12,13,14]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,3,13]}],"localization":[],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,9,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,3,5,6,7,12,13,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,7]}],"complexes":[],"partners":["AXIN1","RNF168","SMAD1","RUNX2","PIN1","SOX2","FOXC1","ANT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q70CQ2","full_name":"Ubiquitin carboxyl-terminal hydrolase 34","aliases":["Deubiquitinating enzyme 34","Ubiquitin thioesterase 34","Ubiquitin-specific-processing protease 34"],"length_aa":3546,"mass_kda":404.2,"function":"Ubiquitin hydrolase that can remove conjugated ubiquitin from AXIN1 and AXIN2, thereby acting as a regulator of Wnt signaling pathway. Acts as an activator of the Wnt signaling pathway downstream of the beta-catenin destruction complex by deubiquitinating and stabilizing AXIN1 and AXIN2, leading to promote nuclear accumulation of AXIN1 and AXIN2 and positively regulate beta-catenin (CTNBB1)-mediated transcription. Recognizes and hydrolyzes the peptide bond at the C-terminal Gly of ubiquitin. Involved in the processing of poly-ubiquitin precursors as well as that of ubiquitinated proteins","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q70CQ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/USP34","classification":"Not Classified","n_dependent_lines":43,"n_total_lines":1208,"dependency_fraction":0.03559602649006623},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CSNK1A1","stoichiometry":0.2},{"gene":"GLUL","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/USP34","total_profiled":1310},"omim":[{"mim_id":"615295","title":"UBIQUITIN-SPECIFIC PROTEASE 34; USP34","url":"https://www.omim.org/entry/615295"},{"mim_id":"603816","title":"AXIS INHIBITOR 1; AXIN1","url":"https://www.omim.org/entry/603816"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/USP34"},"hgnc":{"alias_symbol":["KIAA0570","KIAA0729"],"prev_symbol":[]},"alphafold":{"accession":"Q70CQ2","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q70CQ2","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=USP34","jax_strain_url":"https://www.jax.org/strain/search?query=USP34"},"sequence":{"accession":"Q70CQ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q70CQ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q70CQ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q70CQ2"}},"corpus_meta":[{"pmid":"21383061","id":"PMC_21383061","title":"The ubiquitin-specific protease USP34 regulates axin stability and Wnt/β-catenin signaling.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21383061","citation_count":115,"is_preprint":false},{"pmid":"30181118","id":"PMC_30181118","title":"Ubiquitin-specific protease USP34 controls osteogenic differentiation and bone formation by regulating BMP2 signaling.","date":"2018","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/30181118","citation_count":69,"is_preprint":false},{"pmid":"23863847","id":"PMC_23863847","title":"The ubiquitin specific protease USP34 promotes ubiquitin signaling at DNA double-strand breaks.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23863847","citation_count":60,"is_preprint":false},{"pmid":"38167292","id":"PMC_38167292","title":"Stabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38167292","citation_count":37,"is_preprint":false},{"pmid":"23590831","id":"PMC_23590831","title":"Negative regulation of NF-κB signaling in T lymphocytes by the ubiquitin-specific protease USP34.","date":"2013","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/23590831","citation_count":27,"is_preprint":false},{"pmid":"28499884","id":"PMC_28499884","title":"Inhibition of ubiquitin-specific protease 34 (USP34) induces epithelial-mesenchymal transition and promotes stemness in mammary epithelial cells.","date":"2017","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/28499884","citation_count":22,"is_preprint":false},{"pmid":"30686807","id":"PMC_30686807","title":"USP34 Regulated Human Pancreatic Cancer Cell Survival via AKT and PKC Pathways.","date":"2019","source":"Biological & pharmaceutical 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sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32363724","citation_count":5,"is_preprint":false},{"pmid":"35198563","id":"PMC_35198563","title":"Whole-Exome Sequencing Implicates the USP34 rs777591A > G Intron Variant in Chronic Obstructive Pulmonary Disease in a Kashi Cohort.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35198563","citation_count":5,"is_preprint":false},{"pmid":"39705380","id":"PMC_39705380","title":"USP34 regulates endothelial PAR1 mRNA transcript expression and cellular signaling.","date":"2024","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/39705380","citation_count":2,"is_preprint":false},{"pmid":"38686761","id":"PMC_38686761","title":"BPTF promotes glioma development through USP34-mediated de-ubiquitination of FOXC1.","date":"2024","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/38686761","citation_count":1,"is_preprint":false},{"pmid":"41631201","id":"PMC_41631201","title":"USP34 attenuates cartilage degradation in temporomandibular joint osteoarthritis by ANT1-mediated mitophagy.","date":"2026","source":"JBMR plus","url":"https://pubmed.ncbi.nlm.nih.gov/41631201","citation_count":1,"is_preprint":false},{"pmid":"39050773","id":"PMC_39050773","title":"Rare Case of de Novo 2p15 Microdeletion Syndrome with Deletion Covering XPO1 and USP34 Genes Diagnosed in a Child - A Case Report.","date":"2024","source":"The application of clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39050773","citation_count":1,"is_preprint":false},{"pmid":"40260316","id":"PMC_40260316","title":"The Knockdown of USP34 Inhibits the Progression of Hepatocellular Carcinoma by Accelerating c-Myc Degradation.","date":"2025","source":"The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/40260316","citation_count":0,"is_preprint":false},{"pmid":"42023842","id":"PMC_42023842","title":"USP34 modulates mitochondrial function in triple-negative breast cancer cells through the eIf3m/MTCH2 axis.","date":"2026","source":"Journal of histotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/42023842","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13197,"output_tokens":3860,"usd":0.048745,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11602,"output_tokens":4683,"usd":0.087542,"stage2_stop_reason":"end_turn"},"total_usd":0.136287,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"USP34 was identified in purified axin-containing protein complexes by LC-MS/MS and shown to stabilize axin by opposing its tankyrase-dependent ubiquitination, thereby functioning downstream of the β-catenin destruction complex to regulate Wnt/β-catenin signaling; RNAi knockdown of USP34 led to axin degradation and inhibition of β-catenin-mediated transcription.\",\n      \"method\": \"LC-MS/MS of purified axin complexes, RNA interference, Wnt/β-catenin reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal complex identification by MS, RNAi functional validation, epistasis placing USP34 downstream of destruction complex, replicated in multiple assays in one focused study\",\n      \"pmids\": [\"21383061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"USP34 stabilizes the E3 ubiquitin ligase RNF168 by deubiquitylation in response to DNA double-strand breaks; loss of USP34 causes rapid RNF168 degradation, attenuated DSB-associated ubiquitylation, defective recruitment of BRCA1 and 53BP1, and compromised cell survival after ionizing radiation.\",\n      \"method\": \"siRNA knockdown, immunofluorescence for DSB repair factors (BRCA1, 53BP1), clonogenic survival assay, ubiquitylation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RNAi, ubiquitylation assay, recruitment assay, survival assay) in a single focused study\",\n      \"pmids\": [\"23863847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In a genome-wide siRNA DUB screen in T lymphocytes, knockdown of USP34 selectively enhanced TCR-driven NF-κB activation, led to more pronounced degradation of the NF-κB inhibitor IκBα, and increased NF-κB DNA-binding activity, positioning USP34 as a negative regulator of NF-κB signaling downstream of TCR engagement.\",\n      \"method\": \"siRNA library screen, NF-κB reporter assay, IκBα degradation analysis, NF-κB DNA binding assay\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA screen with functional validation by multiple readouts, but no direct substrate identified for USP34 deubiquitylase activity in this context\",\n      \"pmids\": [\"23590831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP34 stabilizes both Smad1 and RUNX2 by deubiquitylation in mesenchymal stem cells; USP34 depletion inhibits osteogenic differentiation and BMP2 signaling responses, and depletion of Smurf1 (an E3 ligase for Smad1) restores the osteogenic potential of Usp34-deficient MSCs in vitro, placing USP34 in opposition to Smurf1-mediated degradation of Smad1/RUNX2.\",\n      \"method\": \"Conditional knockout in mice, siRNA knockdown, ubiquitylation assays, epistasis (Smurf1 co-depletion rescue), bone phenotype analysis (micro-CT, histology)\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO, in vitro mechanistic epistasis with Smurf1, ubiquitylation assays, multiple orthogonal readouts in one rigorous study\",\n      \"pmids\": [\"30181118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP34 was identified as an interaction partner of the E3 ligase gp78 by Co-IP/LC-MS/MS; USP34 knockdown facilitates proteasomal degradation of gp78 and consequently impairs gp78-mediated lipid droplet formation.\",\n      \"method\": \"Co-IP coupled to LC-MS/MS, siRNA knockdown, lipid droplet formation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP/MS identification plus functional consequence of KD, single lab, two orthogonal methods\",\n      \"pmids\": [\"30585151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP34 deubiquitinates and stabilizes the peptidyl-prolyl isomerase Pin1; this interaction is facilitated by Plk1-mediated phosphorylation of Pin1, and stabilized Pin1 promotes isomerization of the SUMO E2 enzyme Ubc9 (requiring CDK1-mediated phosphorylation of Ubc9), leading to elevated SUMO1-modified protein hypersumoylation that supports glioma stem cell maintenance.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, pharmacological inhibition (Plk1 inhibitor, CDK1 inhibitor), in vitro isomerization assay, orthotopic tumor xenograft\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple PTM contexts validated (phosphorylation, ubiquitination, sumoylation), in vivo xenograft, multiple orthogonal methods in one study\",\n      \"pmids\": [\"38167292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP34 interacts with SOX2, reduces its polyubiquitination, and stabilizes SOX2 protein (without affecting SOX2 mRNA), thereby promoting cell survival and cisplatin resistance in laryngeal squamous cell carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay, siRNA knockdown, overexpression rescue, cell viability assay\",\n      \"journal\": \"The Kaohsiung journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus ubiquitylation assay, single lab, functional rescue included\",\n      \"pmids\": [\"32783291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP34 stabilizes the transcription factor NFIC by deubiquitylation in dental pulp cells; conditional deletion of Usp34 in dental mesenchymal cells reduces NFIC levels and impairs odontogenic differentiation, resulting in short root anomaly, and overexpression of NFIC partially restores the differentiation defect.\",\n      \"method\": \"Conditional knockout in mice, siRNA knockdown, overexpression rescue, ubiquitylation assay, histomorphometry\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with phenotype, in vitro mechanistic epistasis (NFIC rescue), ubiquitylation assay, multiple orthogonal methods\",\n      \"pmids\": [\"33686052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Drosophila, loss of Usp34 by siRNA abolishes homologous recombination at I-SceI-induced DSBs (DR-white assay), demonstrating an indispensable role for Usp34 specifically in homologous recombination-mediated DSB repair.\",\n      \"method\": \"siRNA knockdown, DR-white homologous recombination reporter assay, survival assay after UV/X-ray irradiation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean genetic reporter assay in Drosophila model with specific HR pathway readout, single lab\",\n      \"pmids\": [\"35393473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"An siRNA screen of 96 DUBs in endothelial and HeLa cells identified USP34 as a regulator of thrombin-GPCR (PAR1)-driven p38 MAPK signaling; USP34 knockdown decreased thrombin-stimulated p38 phosphorylation and reduced IL-6 cytokine expression, but had no effect on endothelial barrier permeability.\",\n      \"method\": \"siRNA library screen, p38 phosphorylation assay, IL-6 ELISA, endothelial permeability assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA screen with functional validation by multiple readouts, single lab; direct USP34 substrate in this pathway not identified\",\n      \"pmids\": [\"37865315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP34 knockdown in endothelial cells increases PAR1 (F2R) mRNA transcript levels, leading to elevated PAR1 cell surface abundance and altered thrombin-stimulated p38 activation; this effect is not due to altered PAR1 ubiquitination, internalization, or degradation, but to transcriptional regulation of the F2R gene.\",\n      \"method\": \"siRNA knockdown, flow cytometry, RT-PCR, receptor internalization and degradation assays, p38 phosphorylation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple assays excluding alternative mechanisms, single lab; molecular mechanism linking USP34 to F2R transcription not defined\",\n      \"pmids\": [\"39705380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP34 mediates BPTF-regulated stabilization of FOXC1 via deubiquitylation; immunoprecipitation experiments showed that BPTF affects FOXC1 protein stability through USP34-dependent de-ubiquitylation, and FOXC1 overexpression rescues the phenotype of BPTF knockdown in glioma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay, western blot, lentiviral overexpression/knockdown, functional rescue\",\n      \"journal\": \"Histology and histopathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitylation assay plus functional rescue, single lab\",\n      \"pmids\": [\"38686761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP34 interacts with c-Myc, reduces its ubiquitination, and stabilizes the c-Myc protein; USP34 knockdown enhances c-Myc ubiquitination and degradation, and reduces aerobic glycolysis in hepatocellular carcinoma cells; overexpression of c-Myc reverses si-USP34-mediated phenotypic effects.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay, siRNA knockdown, CCK-8, glycolysis assays, overexpression rescue\",\n      \"journal\": \"The Turkish journal of gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus ubiquitylation assay and functional rescue, single lab\",\n      \"pmids\": [\"40260316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP34 deubiquitinates and stabilizes ANT1 (adenine nucleotide translocase 1) in TMJ chondrocytes; USP34 deficiency in chondrocyte-specific Usp34 KO mice leads to impaired ANT1-dependent initiation of PINK1-Parkin mitophagy and age-dependent TMJ osteoarthritis; USP34 overexpression protects chondrocytes against cellular injury.\",\n      \"method\": \"Chondrocyte-specific conditional KO mouse model, micro-CT/histomorphometry, Co-IP, ubiquitylation assay, mitophagy assays, overexpression studies\",\n      \"journal\": \"JBMR plus\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with phenotype, direct substrate identification (ANT1) by Co-IP and ubiquitylation assay, pathway placement upstream of PINK1-Parkin, multiple orthogonal methods\",\n      \"pmids\": [\"41631201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP34 stabilizes eIF3m protein through deubiquitylation in triple-negative breast cancer cells; stabilized eIF3m binds the 5'UTR of MTCH2 mRNA to upregulate MTCH2 expression, thereby maintaining mitochondrial function and promoting TNBC proliferation.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, RNA immunoprecipitation, RNA pulldown, ubiquitylation assay, siRNA knockdown, mitochondrial function assays\",\n      \"journal\": \"Journal of histotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple binding assays (Co-IP, GST pulldown, RIP) plus functional readouts, single lab\",\n      \"pmids\": [\"42023842\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"USP34 is a deubiquitylase that stabilizes multiple substrates—including axin (opposing tankyrase-dependent ubiquitination in Wnt signaling), RNF168 (promoting DSB repair ubiquitin signaling), Smad1/RUNX2 (supporting BMP2-driven osteogenesis), Pin1 (driving SUMO1 hypersumoylation in glioma stem cells), NFIC, ANT1, SOX2, FOXC1, c-Myc, eIF3m, and gp78—by removing polyubiquitin chains to prevent proteasomal degradation, and it additionally regulates NF-κB activity downstream of TCR engagement, GPCR-p38 MAPK signaling, and homologous recombination-mediated DNA repair.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"USP34 is a deubiquitylase that controls the abundance of diverse substrate proteins by removing polyubiquitin chains to oppose their proteasomal degradation, thereby acting as a positive or negative tuning node across developmental signaling, DNA repair, and cancer-associated pathways [#0, #3, #1]. Its founding role is in Wnt/\\u03b2-catenin signaling, where it was purified in axin-containing complexes and stabilizes axin by counteracting tankyrase-dependent ubiquitination, functioning downstream of the \\u03b2-catenin destruction complex [#0]. In the DNA damage response, USP34 stabilizes the E3 ligase RNF168 to sustain double-strand-break ubiquitin signaling and the recruitment of BRCA1 and 53BP1, with loss compromising survival after ionizing radiation [#1], consistent with an indispensable requirement for Usp34 in homologous recombination repair [#8]. A recurring theme is opposition to specific E3 ligases: USP34 stabilizes Smad1 and RUNX2 against Smurf1-mediated degradation to drive BMP2 osteogenesis [#3], stabilizes the transcription factor NFIC to support odontogenic differentiation [#7], and stabilizes ANT1 to enable PINK1-Parkin mitophagy in chondrocytes [#13]; conditional knockout mice reveal skeletal, dental, and joint phenotypes from these activities [#3, #7, #13]. In cancer contexts USP34 stabilizes a range of pro-tumorigenic factors\\u2014Pin1 (driving Ubc9 isomerization and SUMO1 hypersumoylation in glioma stem cells) [#5], SOX2 [#6], FOXC1 [#11], c-Myc [#12], and eIF3m [#14]. USP34 also acts as a negative regulator of TCR-driven NF-\\u03baB activation [#2] and modulates thrombin-PAR1-p38 MAPK signaling, in the latter case through transcriptional control of F2R rather than receptor deubiquitination [#9, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established USP34's founding function by asking how axin stability is maintained against tankyrase-driven turnover, placing a deubiquitylase within the Wnt/\\u03b2-catenin destruction-complex axis.\",\n      \"evidence\": \"LC-MS/MS of purified axin complexes with RNAi and Wnt reporter assays\",\n      \"pmids\": [\"21383061\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct in vitro deubiquitylation of axin by USP34 not reconstituted\", \"Chain-type specificity of USP34 not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended USP34 into the DNA damage response by showing it stabilizes the E3 ligase RNF168 to sustain DSB ubiquitin signaling and downstream repair-factor recruitment.\",\n      \"evidence\": \"siRNA knockdown, immunofluorescence for BRCA1/53BP1, ubiquitylation and clonogenic survival assays\",\n      \"pmids\": [\"23863847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP34 acts directly on RNF168 ubiquitin chains vs indirectly not fully resolved\", \"Recruitment dynamics of USP34 to damage sites unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified USP34 as a negative regulator of TCR-driven NF-\\u03baB signaling, expanding its roles beyond stabilization to immune signal attenuation.\",\n      \"evidence\": \"Genome-wide siRNA DUB screen in T lymphocytes with NF-\\u03baB reporter, I\\u03baB\\u03b1 degradation and DNA-binding readouts\",\n      \"pmids\": [\"23590831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct USP34 substrate identified in the NF-\\u03baB pathway\", \"Screen-based hit without reciprocal biochemical validation\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated an in vivo developmental role by showing USP34 opposes Smurf1-mediated degradation of Smad1/RUNX2 to enable BMP2-driven osteogenesis.\",\n      \"evidence\": \"Conditional KO mice, Smurf1 co-depletion epistasis rescue, ubiquitylation assays, micro-CT/histology\",\n      \"pmids\": [\"30181118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical deubiquitylation of Smad1/RUNX2 not reconstituted\", \"Tissue-specificity of the USP34-Smurf1 antagonism unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked USP34 to ER-associated/lipid biology by identifying gp78 as an interactor whose stability and lipid-droplet function depend on USP34.\",\n      \"evidence\": \"Co-IP/LC-MS/MS, siRNA knockdown, lipid droplet formation assay\",\n      \"pmids\": [\"30585151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no reciprocal validation of direct deubiquitylation\", \"Mechanism connecting gp78 stability to lipid droplets incomplete\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Began establishing USP34 as a stabilizer of oncogenic transcription factors by showing it deubiquitylates SOX2 to promote survival and cisplatin resistance.\",\n      \"evidence\": \"Co-IP, ubiquitylation assay, siRNA knockdown, overexpression rescue, viability assay\",\n      \"pmids\": [\"32783291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP without reciprocal validation\", \"Specificity of USP34 for SOX2 vs other factors not benchmarked\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed an in vivo dental developmental requirement, with USP34 stabilizing NFIC to drive odontogenic differentiation and prevent short root anomaly.\",\n      \"evidence\": \"Conditional KO mice, siRNA, NFIC overexpression rescue, ubiquitylation assay, histomorphometry\",\n      \"pmids\": [\"33686052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct deubiquitylation of NFIC not reconstituted in vitro\", \"Upstream regulators directing USP34 to NFIC unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the DNA-repair role more precisely by showing Usp34 is indispensable specifically for homologous recombination at induced DSBs in Drosophila.\",\n      \"evidence\": \"siRNA knockdown, DR-white HR reporter, survival after UV/X-ray\",\n      \"pmids\": [\"35393473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular substrate of Usp34 in HR not identified in this system\", \"Conservation of the exact mechanism to human cells not shown here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected USP34 to GPCR signaling by identifying it as a regulator of thrombin-PAR1-driven p38 MAPK activation and IL-6 production.\",\n      \"evidence\": \"siRNA DUB screen in endothelial/HeLa cells, p38 phosphorylation assay, IL-6 ELISA, permeability assay\",\n      \"pmids\": [\"37865315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct USP34 substrate in the PAR1-p38 pathway not identified\", \"Mechanism of selectivity for p38 vs barrier function unexplained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved part of the PAR1 mechanism by showing USP34 acts via transcriptional control of F2R rather than receptor ubiquitination or trafficking.\",\n      \"evidence\": \"siRNA, flow cytometry, RT-PCR, internalization/degradation assays, p38 phosphorylation assay\",\n      \"pmids\": [\"39705380\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between USP34 and F2R transcription undefined\", \"Whether this reflects a deubiquitylase-dependent activity unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a PTM-gated cancer mechanism in which USP34 stabilizes Pin1 (facilitated by Plk1 phosphorylation), driving Ubc9 isomerization and SUMO1 hypersumoylation in glioma stem cells.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitylation assays, Plk1/CDK1 inhibition, in vitro isomerization, orthotopic xenograft\",\n      \"pmids\": [\"38167292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Plk1 phosphorylation licenses USP34-Pin1 binding mechanistically not fully detailed\", \"Generality of the hypersumoylation axis beyond glioma stem cells unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added FOXC1 to the USP34 substrate set, placing USP34 downstream of BPTF in controlling FOXC1 stability in glioma.\",\n      \"evidence\": \"Co-IP, ubiquitylation assay, western blot, lentiviral knockdown/overexpression, functional rescue\",\n      \"pmids\": [\"38686761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence without reciprocal validation\", \"How BPTF directs USP34 to FOXC1 not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated USP34 in tumor metabolism by showing it stabilizes c-Myc and sustains aerobic glycolysis in hepatocellular carcinoma.\",\n      \"evidence\": \"Co-IP, ubiquitylation assay, siRNA, glycolysis assays, c-Myc overexpression rescue\",\n      \"pmids\": [\"40260316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct deubiquitylation of c-Myc not reconstituted\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated an in vivo mitochondrial-quality-control role, with USP34 stabilizing ANT1 to enable PINK1-Parkin mitophagy and protect against TMJ osteoarthritis.\",\n      \"evidence\": \"Chondrocyte-specific conditional KO mice, micro-CT/histomorphometry, Co-IP, ubiquitylation assay, mitophagy and overexpression studies\",\n      \"pmids\": [\"41631201\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct in vitro deubiquitylation of ANT1 not shown\", \"How ANT1 levels gate PINK1-Parkin initiation not mechanistically detailed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended the substrate repertoire to translation/mitochondrial maintenance by showing USP34 stabilizes eIF3m, which binds MTCH2 5'UTR to support TNBC proliferation.\",\n      \"evidence\": \"Co-IP, GST pulldown, RIP, RNA pulldown, ubiquitylation assay, siRNA, mitochondrial function assays\",\n      \"pmids\": [\"42023842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence without reciprocal validation\", \"Direct deubiquitylation of eIF3m not reconstituted\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical determinants of USP34 substrate selectivity, polyubiquitin chain-type specificity, and structural basis for its broad substrate range remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the USP34 catalytic domain in the timeline\", \"No defined recognition motif explaining its diverse substrate set\", \"Whether non-catalytic/scaffolding activities account for transcriptional and NF-\\u03baB effects unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 5, 6, 7, 11, 12, 13, 14]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 3, 13]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 9, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3, 5, 6, 7, 12, 13, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AXIN1\", \"RNF168\", \"SMAD1\", \"RUNX2\", \"PIN1\", \"SOX2\", \"FOXC1\", \"ANT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}