{"gene":"USP29","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2011,"finding":"USP29 is transcriptionally induced by FBP and JTV1/AIMP2 in response to oxidative stress; USP29 binds to p53, cleaves poly-ubiquitin chains from p53, and stabilizes p53 protein, leading to apoptosis.","method":"Co-immunoprecipitation, deubiquitination assay (in vivo and in vitro), transcriptional reporter assays, cellular fractionation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (Co-IP, in vitro DUB assay, transcription assays) in a single high-citation study","pmids":["21285945"],"is_preprint":false},{"year":2014,"finding":"USP29 interacts with and deubiquitinates Claspin both in vivo and in vitro, stabilizing Claspin and thereby supporting ATR-Chk1 pathway signaling and S-phase progression; USP29 knockdown impairs Chk1 phosphorylation after DNA damage.","method":"Co-immunoprecipitation, in vivo and in vitro deubiquitination assays, siRNA knockdown with Chk1 phosphorylation readout, cell-cycle analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal Co-IP plus in vitro DUB assay plus functional epistasis with defined cellular phenotype","pmids":["24632611"],"is_preprint":false},{"year":2020,"finding":"USP29 constitutively interacts with cGAS and deconjugates K48-linked polyubiquitin chains from cGAS, stabilizing cGAS and promoting type I interferon induction and antiviral responses; USP29 knockout mice are hypersensitive to HSV-1 infection.","method":"Co-immunoprecipitation, ubiquitination assays (K48-linkage specific), USP29 KO mice, reconstitution experiments","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including KO mice, reconstitution, and linkage-specific ubiquitination assays; independently confirmed in vivo","pmids":["32457395"],"is_preprint":false},{"year":2020,"finding":"USP29 stabilizes Snail protein by deubiquitinating it, and cooperates with phosphatase SCP1 to simultaneously dephosphorylate and deubiquitinate Snail, preventing its degradation and promoting gastric cancer cell migration.","method":"DUB cDNA library screen (79 DUBs), Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, cell migration assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — unbiased DUB screen followed by mechanistic Co-IP and ubiquitination assays with defined functional readout","pmids":["32973332"],"is_preprint":false},{"year":2020,"finding":"USP29 deubiquitinates and stabilizes Snail1 in a catalytic activity-dependent manner, and USP29 is transcriptionally upregulated by oxidative stress induced by chemotherapy, thereby enhancing cancer stem cell-like characteristics in lung adenocarcinoma.","method":"Ubiquitination assay, catalytic mutant analysis, siRNA knockdown, xenograft mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — catalytic mutant and ubiquitination assay, single study","pmids":["32968046"],"is_preprint":false},{"year":2021,"finding":"USP29 directly deubiquitinates and stabilizes HIF1α, promoting its transcriptional activity; this stabilization upregulates hexokinase 2 (HK2) and aerobic glycolysis, contributing to Sorafenib resistance in hepatocellular carcinoma.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA/CRISPR knockdown, xenograft mouse model, glycolysis metabolic assays","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 1-2 — direct DUB assay for HIF1α plus in vivo xenograft validation with multiple orthogonal methods","pmids":["34272356"],"is_preprint":false},{"year":2021,"finding":"USP29 directly deubiquitinates and stabilizes both MYC and HIF1α, coordinating metabolic reprogramming (glycolysis and glutamine catabolism) in tumor cells; systemic Usp29 knockout depletes MYC and HIF1α in vivo and prolongs survival of tumor-bearing mice without overt developmental defects.","method":"Unbiased siRNA screen (96 DUBs), metabolic flux analysis, Co-immunoprecipitation, ubiquitination assay, Usp29 KO mice, neuroblastoma and lymphoma models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — unbiased functional screen plus direct DUB assays for two substrates plus in vivo KO mouse validation with metabolic flux analysis","pmids":["34601505"],"is_preprint":false},{"year":2021,"finding":"USP29 interacts with and deubiquitinates NRF2, stabilizing it and thereby regulating microglia/macrophage polarization from M1 to M2; USP29 knockdown abolishes the protective effects of melatonin-preconditioned MSC extracellular vesicles after spinal cord injury.","method":"Co-immunoprecipitation, ubiquitination assay, proteomics, shRNA knockdown, NRF2 knockout mice, in vivo SCI model","journal":"Journal of pineal research","confidence":"High","confidence_rationale":"Tier 2 — Co-IP plus ubiquitination assay plus NRF2 KO mice rescue experiment","pmids":["34562326"],"is_preprint":false},{"year":2022,"finding":"USP29 interacts with the carboxyl end of SARS-CoV-2 ORF9b, removes ubiquitin chains from ORF9b (ubiquitinated at Lys-4 and Lys-40), preventing its proteasomal degradation and thereby inhibiting type I IFN and NF-κB activation and enhancing viral virulence.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis of ORF9b lysines, VSV-eGFP and SARS-CoV-2 trVLP viral virulence assays","journal":"mBio","confidence":"High","confidence_rationale":"Tier 1-2 — site-specific mutagenesis, direct DUB assay, and viral functional assays in a single study","pmids":["35638730"],"is_preprint":false},{"year":2022,"finding":"USP29 interacts with SETD8 (interaction dependent on USP29 catalytic activity), deubiquitinates SETD8 in vivo, and is required for irradiation-induced H4K20 monomethylation and 53BP1 focus formation at DNA damage sites; USP29 depletion increases cellular sensitivity to irradiation.","method":"Co-immunoprecipitation (catalytic mutant-dependent), in vivo ubiquitination assay, siRNA knockdown, H4K20me1 immunostaining, 53BP1 focus formation, irradiation survival assays","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1-2 — catalytic-mutant dependent interaction plus in vivo DUB assay plus functional H4K20me1 and 53BP1 readouts","pmids":["36010569"],"is_preprint":false},{"year":2023,"finding":"CDK1 directly phosphorylates USP29, which is required for USP29 deubiquitinase activity toward TWIST1; USP29-mediated deubiquitination of TWIST1 stabilizes TWIST1 and promotes EMT, cancer stem cell functions, and chemoresistance in triple-negative breast cancer.","method":"Co-immunoprecipitation, ubiquitination assay, CDK1 kinase assay (phosphorylation of USP29), CDK1 genetic ablation and pharmacological inhibition, TNBC cell and xenograft models","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1-2 — direct kinase assay establishing phosphorylation of USP29 by CDK1, plus DUB assay for TWIST1 with functional in vivo validation","pmids":["36782089"],"is_preprint":false},{"year":2023,"finding":"USP29 deubiquitinates and stabilizes KIAA1429 (VIRMA) via co-immunoprecipitation-confirmed interaction; stabilized KIAA1429 promotes SOX8 mRNA stability through m6A modification, facilitating colorectal cancer cell proliferation.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, xenograft model","journal":"Biomolecules & biomedicine","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP plus ubiquitination assay, single study","pmids":["36373629"],"is_preprint":false},{"year":2024,"finding":"Transcription factor FUBP1 directly activates USP29 gene transcription (shown by ChIP and luciferase assays); USP29 then interacts with and stabilizes AURKB by suppressing K48-linked polyubiquitination, constituting a FUBP1-USP29-AURKB oncogenic axis in gastric cancer.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), ChIP, luciferase reporter assay, Usp29 KO mice, xenograft model","journal":"Cancer cell international","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP and luciferase for transcriptional regulation, K48-specific ubiquitination assay for DUB activity, in vivo KO mouse validation","pmids":["38233848"],"is_preprint":false},{"year":2024,"finding":"USP29 directly interacts with ACSL5 and stabilizes it by removing K48-linked ubiquitin chains, promoting fatty acid β-oxidation and protecting against MASLD; USP29 deletion exacerbates hepatic steatosis and fibrosis.","method":"Co-immunoprecipitation, K48-linked deubiquitination assay, USP29 knockout and overexpression in mice (HFD/HFCD model), in vitro hepatocyte model","journal":"Clinical and molecular hepatology","confidence":"High","confidence_rationale":"Tier 1-2 — direct DUB assay with linkage specificity, Co-IP, and in vivo mouse model validation","pmids":["39355870"],"is_preprint":false},{"year":2019,"finding":"USP29 deubiquitinates and stabilizes MYBBP1A; parkin loss leads to accumulation of AIMP2, which upregulates USP29 and subsequently MYBBP1A in dopaminergic neurons, linking this pathway to Parkinson's disease pathogenesis.","method":"siRNA knockdown, Western blot (MYBBP1A stabilization), in vivo AIMP2 transgenic and knockdown mouse models","journal":"Journal of clinical medicine","confidence":"Medium","confidence_rationale":"Tier 3 — substrate identification without in vitro DUB assay, single study","pmids":["31878357"],"is_preprint":false},{"year":2025,"finding":"USP29 interacts with TAK1, directly inhibiting TAK1 ubiquitination and phosphorylation; ELAVL1 binds USP29 mRNA and promotes its degradation, reducing USP29 levels and thereby activating TAK1 to drive M1 microglial polarization after spinal cord injury.","method":"Co-immunoprecipitation, GST pull-down, ubiquitination assay, shRNA knockdown, rat SCI model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — GST pull-down plus ubiquitination assay with in vivo SCI rat model, single study","pmids":["40634288"],"is_preprint":false},{"year":2025,"finding":"USP29 deubiquitinates FSP1 (ferroptosis suppressor protein 1), counteracting SMURF1-mediated K63/K193 polyubiquitination of FSP1, thereby stabilizing FSP1 and suppressing ferroptosis to facilitate chemoresistance in gastric cancer.","method":"Co-immunoprecipitation, ubiquitination assay (site-specific K63/K193 mutagenesis), pharmacological FSP1 inhibition, chemoresistant cell and mouse models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — site-specific mutagenesis of ubiquitination sites, direct DUB assay, paired E3/DUB identification, in vivo validation","pmids":["41387682"],"is_preprint":false},{"year":2008,"finding":"Two conserved sequence elements (CSE1 and CSE2/YY1 binding sites) within the bidirectional Peg3/Usp29 promoter regulate Usp29 transcription: CSE1 acts as a repressor and CSE2 as an activator, with orientation-dependent effects demonstrated by promoter mutagenesis assays.","method":"Cell line-based promoter assays, serial mutagenesis of YY1 binding sites and CSE1 elements","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — promoter mutagenesis with directional reporter assays, single study","pmids":["19068137"],"is_preprint":false}],"current_model":"USP29 is a deubiquitinase that removes K48-linked (and other) polyubiquitin chains from a broad range of substrates — including p53, cGAS, Claspin, HIF1α, MYC, TWIST1, Snail, NRF2, SETD8, ACSL5, AURKB, KIAA1429, FSP1, TAK1, MYBBP1A, and viral ORF9b — to stabilize them and regulate processes spanning DNA damage checkpoints, innate immunity, EMT/metastasis, metabolic reprogramming, and ferroptosis; its catalytic activity is itself regulated by CDK1-mediated phosphorylation, and its transcription is co-activated by the FBP/JTV1(AIMP2) complex in response to oxidative stress."},"narrative":{"teleology":[{"year":2008,"claim":"The initial question of how USP29 transcription is controlled was addressed by identifying two conserved cis-elements (CSE1 repressor and CSE2/YY1 activator) within the bidirectional Peg3/Usp29 promoter, establishing that USP29 expression is subject to orientation-dependent transcriptional regulation.","evidence":"Promoter mutagenesis and reporter assays in cell lines","pmids":["19068137"],"confidence":"Medium","gaps":["Endogenous transcription factor occupancy not confirmed by ChIP","Imprinting status and its effect on USP29 expression not resolved","No connection to physiological signals driving USP29 induction"]},{"year":2011,"claim":"USP29 was established as an active deubiquitinase with its first identified substrate: FBP and JTV1/AIMP2 co-activate USP29 transcription under oxidative stress, and USP29 directly deubiquitinates and stabilizes p53 to induce apoptosis, revealing a stress-responsive DUB–tumor suppressor axis.","evidence":"Co-immunoprecipitation, in vitro and in vivo deubiquitination assays, transcriptional reporter assays","pmids":["21285945"],"confidence":"High","gaps":["Ubiquitin chain-linkage specificity on p53 not determined","Physiological in vivo validation in knockout animals not performed"]},{"year":2014,"claim":"USP29's role was extended to DNA damage checkpoint signaling by showing it deubiquitinates and stabilizes Claspin, supporting ATR-Chk1 activation and S-phase progression after replication stress.","evidence":"Reciprocal Co-IP, in vitro DUB assay, siRNA knockdown with Chk1 phosphorylation readout, cell-cycle analysis","pmids":["24632611"],"confidence":"High","gaps":["Whether USP29 acts at stalled replication forks versus globally on Claspin pools is unknown","Relationship to other Claspin-directed DUBs not clarified"]},{"year":2019,"claim":"A link between USP29 and neurodegeneration was proposed: parkin loss elevates AIMP2, which upregulates USP29, leading to MYBBP1A accumulation in dopaminergic neurons, potentially contributing to Parkinson's disease pathogenesis.","evidence":"siRNA knockdown, Western blot, AIMP2 transgenic and knockdown mouse models","pmids":["31878357"],"confidence":"Medium","gaps":["No in vitro DUB assay confirming direct deubiquitination of MYBBP1A","Causal contribution of USP29–MYBBP1A axis to dopaminergic neuron loss not established","Single study without independent replication"]},{"year":2020,"claim":"USP29 was established as a critical regulator of innate immunity by constitutively interacting with and deubiquitinating cGAS (K48-linked chains), stabilizing it to promote type I IFN responses; Usp29 knockout mice showed impaired antiviral defense against HSV-1.","evidence":"K48-linkage-specific ubiquitination assays, Co-IP, reconstitution, Usp29 KO mice with HSV-1 challenge","pmids":["32457395"],"confidence":"High","gaps":["Whether USP29 regulation of cGAS is modulated by viral immune evasion strategies","Structural basis of USP29–cGAS interaction unknown"]},{"year":2020,"claim":"USP29 was identified as a Snail-stabilizing DUB through unbiased screening, showing it cooperates with phosphatase SCP1 to prevent Snail degradation and promote EMT and gastric/lung cancer migration, extending USP29's role to epithelial-mesenchymal transition.","evidence":"DUB cDNA library screen (79 DUBs), Co-IP, ubiquitination assay, catalytic mutant analysis, xenograft models","pmids":["32973332","32968046"],"confidence":"High","gaps":["How SCP1 and USP29 are co-recruited to Snail is unknown","Whether USP29 regulation of Snail operates in normal epithelial homeostasis"]},{"year":2021,"claim":"USP29 was shown to coordinately stabilize both HIF1α and MYC, establishing it as a master regulator of tumor metabolic reprogramming (glycolysis and glutamine catabolism); systemic Usp29 knockout prolonged survival in tumor models without developmental defects, indicating therapeutic potential.","evidence":"Unbiased siRNA screen of 96 DUBs, metabolic flux analysis, Co-IP, DUB assays, Usp29 KO mice in neuroblastoma and lymphoma models","pmids":["34601505","34272356"],"confidence":"High","gaps":["How USP29 selectively targets HIF1α versus VHL-mediated degradation pathway","Compensatory DUBs in Usp29 KO mice not characterized"]},{"year":2021,"claim":"USP29 was connected to NRF2-dependent anti-oxidant signaling by showing it deubiquitinates and stabilizes NRF2, driving M1-to-M2 microglia/macrophage polarization and neuroprotection after spinal cord injury.","evidence":"Co-IP, ubiquitination assay, proteomics, NRF2 KO mice, in vivo SCI model","pmids":["34562326"],"confidence":"High","gaps":["Whether USP29 competes with Keap1/Cul3 E3 ligase for NRF2 not tested","Specificity of USP29 versus other NRF2-directed DUBs unclear"]},{"year":2022,"claim":"USP29's substrate repertoire was extended to viral proteins and DNA damage effectors: it stabilizes SARS-CoV-2 ORF9b (at K4/K40) to suppress innate immunity, and stabilizes SETD8 to promote H4K20me1 and 53BP1 recruitment at DNA damage sites.","evidence":"Site-directed mutagenesis of ORF9b ubiquitination sites, viral virulence assays; catalytic-mutant-dependent Co-IP with SETD8, H4K20me1 and 53BP1 focus formation assays","pmids":["35638730","36010569"],"confidence":"High","gaps":["Whether SARS-CoV-2 actively hijacks USP29 or passively benefits from it","Structural determinants of USP29 substrate recognition remain unknown"]},{"year":2023,"claim":"CDK1 was identified as an upstream activator of USP29 through direct phosphorylation, which is required for USP29-mediated deubiquitination of TWIST1, thereby linking cell-cycle kinase signaling to EMT and chemoresistance in triple-negative breast cancer.","evidence":"In vitro CDK1 kinase assay on USP29, CDK1 genetic ablation and pharmacological inhibition, DUB assay for TWIST1, TNBC xenograft models","pmids":["36782089"],"confidence":"High","gaps":["Phosphorylation site(s) on USP29 not mapped","Whether CDK1-dependent activation applies to all USP29 substrates or is TWIST1-specific"]},{"year":2024,"claim":"USP29's transcriptional control and substrate range were further expanded: FUBP1 directly activates USP29 transcription to stabilize Aurora kinase B (AURKB) in gastric cancer, and USP29 stabilizes ACSL5 via K48-chain removal to promote fatty acid β-oxidation and protect against hepatic steatosis.","evidence":"ChIP and luciferase for FUBP1→USP29 transcription; K48-specific DUB assays for AURKB and ACSL5; Usp29 KO and overexpression mice on HFD/HFCD","pmids":["38233848","39355870"],"confidence":"High","gaps":["Whether FUBP1-driven transcription of USP29 is equivalent to the FBP/AIMP2-driven pathway reported earlier","Tissue-specific regulation of USP29 expression not systematically characterized"]},{"year":2025,"claim":"USP29 was shown to suppress ferroptosis by deubiquitinating FSP1, counteracting SMURF1-mediated K63/K193 polyubiquitination, and to regulate neuroinflammation by deubiquitinating TAK1 to inhibit M1 microglial polarization, further broadening its functional scope.","evidence":"Site-specific ubiquitination mutagenesis for FSP1, paired E3/DUB analysis, chemoresistant gastric cancer models; GST pull-down and DUB assay for TAK1, rat SCI model","pmids":["41387682","40634288"],"confidence":"High","gaps":["How USP29 selects among its many substrates in a given cellular context is unknown","TAK1 study is a single report in a rat model without independent replication"]},{"year":null,"claim":"Major open questions include how USP29 achieves substrate selectivity among its remarkably broad substrate repertoire, what the structural basis of its catalytic domain and substrate recognition is, whether CDK1-mediated phosphorylation regulates activity toward all substrates, and how its apparently non-essential in vivo role (viable KO mice) is reconciled with its strong tumor-promoting functions.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No crystal or cryo-EM structure of USP29 available","Systematic identification of all CDK1 phosphorylation sites on USP29 lacking","No comprehensive substrate-specificity or ubiquitin-chain-type selectivity study"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,3,5,6,8,9,10,12,13,16]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,2,3,5,6,8,9,10,12,13,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,9]}],"pathway":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,3,5,6,10,13,16]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2,3,5,6,8,9,10,12,13,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,8]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,5,6,10,11,12,16]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,16]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,6,13]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,4,7]}],"complexes":[],"partners":["TP53","CLSPN","CGAS","SNAI1","HIF1A","MYC","TWIST1","AURKB"],"other_free_text":[]},"mechanistic_narrative":"USP29 is a deubiquitinase that stabilizes a broad spectrum of substrates by removing K48-linked (and in some cases K63-linked) polyubiquitin chains, thereby regulating DNA damage checkpoints, innate immunity, epithelial-mesenchymal transition, metabolic reprogramming, and ferroptosis. It deubiquitinates p53 and Claspin to support apoptosis and ATR-Chk1 signaling [PMID:21285945, PMID:24632611], stabilizes cGAS to promote type I interferon responses [PMID:32457395], and deubiquitinates HIF1α and MYC to coordinate glycolysis and glutamine catabolism in tumors [PMID:34601505, PMID:34272356]. USP29 catalytic activity is positively regulated by CDK1-mediated phosphorylation, enabling TWIST1 stabilization and EMT [PMID:36782089], while its transcription is controlled by the FBP/AIMP2 complex under oxidative stress and by FUBP1 in gastric cancer [PMID:21285945, PMID:38233848]."},"prefetch_data":{"uniprot":{"accession":"Q9HBJ7","full_name":"Ubiquitin carboxyl-terminal hydrolase 29","aliases":["Deubiquitinating enzyme 29","Ubiquitin thioesterase 29","Ubiquitin-specific-processing protease 29"],"length_aa":922,"mass_kda":104.2,"function":"Deubiquitinase involved in innate antiviral immunity by mediating 'Lys-48'-linked deubiquitination of CGAS, thereby promoting its stabilization","subcellular_location":"Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/Q9HBJ7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/USP29","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/USP29","total_profiled":1310},"omim":[{"mim_id":"609546","title":"UBIQUITIN-SPECIFIC PROTEASE 29; USP29","url":"https://www.omim.org/entry/609546"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":1.5},{"tissue":"testis","ntpm":4.6}],"url":"https://www.proteinatlas.org/search/USP29"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9HBJ7","domains":[{"cath_id":"2.30.29.180","chopping":"5-106","consensus_level":"high","plddt":82.5216,"start":5,"end":106},{"cath_id":"-","chopping":"304-388","consensus_level":"medium","plddt":92.1792,"start":304,"end":388},{"cath_id":"3.90.70.10","chopping":"456-478_507-554_818-900","consensus_level":"high","plddt":89.7854,"start":456,"end":900}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HBJ7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HBJ7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HBJ7-F1-predicted_aligned_error_v6.png","plddt_mean":58.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=USP29","jax_strain_url":"https://www.jax.org/strain/search?query=USP29"},"sequence":{"accession":"Q9HBJ7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HBJ7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HBJ7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HBJ7"}},"corpus_meta":[{"pmid":"21285945","id":"PMC_21285945","title":"JTV1 co-activates FBP to induce USP29 transcription and stabilize p53 in response to oxidative stress.","date":"2011","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/21285945","citation_count":116,"is_preprint":false},{"pmid":"34562326","id":"PMC_34562326","title":"Extracellular vesicles derived from melatonin-preconditioned mesenchymal stem cells containing USP29 repair traumatic spinal cord injury by stabilizing NRF2.","date":"2021","source":"Journal of pineal research","url":"https://pubmed.ncbi.nlm.nih.gov/34562326","citation_count":108,"is_preprint":false},{"pmid":"32457395","id":"PMC_32457395","title":"USP29 maintains the stability of cGAS and promotes cellular antiviral responses and autoimmunity.","date":"2020","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32457395","citation_count":72,"is_preprint":false},{"pmid":"24632611","id":"PMC_24632611","title":"USP29 controls the stability of checkpoint adaptor Claspin by deubiquitination.","date":"2014","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/24632611","citation_count":62,"is_preprint":false},{"pmid":"32973332","id":"PMC_32973332","title":"Deubiquitinase USP29 promotes gastric cancer cell migration by cooperating with phosphatase SCP1 to stabilize Snail protein.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/32973332","citation_count":57,"is_preprint":false},{"pmid":"34272356","id":"PMC_34272356","title":"USP29-mediated HIF1α stabilization is associated with Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis.","date":"2021","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/34272356","citation_count":49,"is_preprint":false},{"pmid":"36782089","id":"PMC_36782089","title":"Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/36782089","citation_count":39,"is_preprint":false},{"pmid":"11543637","id":"PMC_11543637","title":"Imprinting and evolution of two Kruppel-type zinc-finger genes, ZIM3 and ZNF264, located in the PEG3/USP29 imprinted domain.","date":"2001","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11543637","citation_count":39,"is_preprint":false},{"pmid":"32968046","id":"PMC_32968046","title":"USP29 enhances chemotherapy-induced stemness in non-small cell lung cancer via stabilizing Snail1 in response to oxidative stress.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32968046","citation_count":35,"is_preprint":false},{"pmid":"34601505","id":"PMC_34601505","title":"USP29 coordinates MYC and HIF1α stabilization to promote tumor metabolism and progression.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34601505","citation_count":33,"is_preprint":false},{"pmid":"35638730","id":"PMC_35638730","title":"The Deubiquitinase USP29 Promotes SARS-CoV-2 Virulence by Preventing Proteasome Degradation of ORF9b.","date":"2022","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/35638730","citation_count":29,"is_preprint":false},{"pmid":"36373629","id":"PMC_36373629","title":"Promotive role of USP29-mediated deubiquitination in malignant proliferation of colorectal cancer cells via the KIAA1429/SOX8 axis.","date":"2023","source":"Biomolecules & biomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/36373629","citation_count":17,"is_preprint":false},{"pmid":"19068137","id":"PMC_19068137","title":"Two evolutionarily conserved sequence elements for Peg3/Usp29 transcription.","date":"2008","source":"BMC molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19068137","citation_count":15,"is_preprint":false},{"pmid":"39355870","id":"PMC_39355870","title":"USP29 alleviates the progression of MASLD by stabilizing ACSL5 through K48 deubiquitination.","date":"2024","source":"Clinical and molecular hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/39355870","citation_count":12,"is_preprint":false},{"pmid":"38233848","id":"PMC_38233848","title":"USP29 activation mediated by FUBP1 promotes AURKB stability and oncogenic functions in gastric cancer.","date":"2024","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/38233848","citation_count":11,"is_preprint":false},{"pmid":"30919279","id":"PMC_30919279","title":"The deubiquitinating gene Usp29 is dispensable for fertility in male mice.","date":"2019","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30919279","citation_count":9,"is_preprint":false},{"pmid":"31878357","id":"PMC_31878357","title":"Deubiquitinase USP29 Governs MYBBP1A in the Brains of Parkinson's Disease Patients.","date":"2019","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31878357","citation_count":9,"is_preprint":false},{"pmid":"36010569","id":"PMC_36010569","title":"USP29 Deubiquitinates SETD8 and Regulates DNA Damage-Induced H4K20 Monomethylation and 53BP1 Focus Formation.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36010569","citation_count":6,"is_preprint":false},{"pmid":"36628242","id":"PMC_36628242","title":"Deubiquitinase USP29 correlates RORγt expression and its association with thymoma myasthenia gravis.","date":"2022","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/36628242","citation_count":3,"is_preprint":false},{"pmid":"27327533","id":"PMC_27327533","title":"Transcriptional Truncation of the Long Coding Imprinted Gene Usp29.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27327533","citation_count":3,"is_preprint":false},{"pmid":"37463886","id":"PMC_37463886","title":"Identification of USP29 as a key regulator of nucleotide biosynthesis in neuroblastoma through integrative analysis of multi-omics data.","date":"2023","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37463886","citation_count":3,"is_preprint":false},{"pmid":"38269503","id":"PMC_38269503","title":"The emerging role of USP29 in cancer and other diseases.","date":"2024","source":"Cell biochemistry and function","url":"https://pubmed.ncbi.nlm.nih.gov/38269503","citation_count":2,"is_preprint":false},{"pmid":"41387682","id":"PMC_41387682","title":"USP29 and SMURF1 orchestrate FSP1-mediated ferroptosis suppression to facilitate chemoresistance in gastric cancer.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41387682","citation_count":1,"is_preprint":false},{"pmid":"40634288","id":"PMC_40634288","title":"ELAVL1-mediated USP29 mRNA degradation activates TAK1 driving M1 microglial polarization and neural stem cell differentiation dysregulation in spinal cord injury.","date":"2025","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/40634288","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.11.675685","title":"Active maintenance of meiosis-specific chromosome structures in <i>C. elegans</i> by the deubiquitinase DUO-1","date":"2025-09-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.11.675685","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13852,"output_tokens":4261,"usd":0.052735},"stage2":{"model":"claude-opus-4-6","input_tokens":7748,"output_tokens":3591,"usd":0.192773},"total_usd":0.245508,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"USP29 is transcriptionally induced by FBP and JTV1/AIMP2 in response to oxidative stress; USP29 binds to p53, cleaves poly-ubiquitin chains from p53, and stabilizes p53 protein, leading to apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay (in vivo and in vitro), transcriptional reporter assays, cellular fractionation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (Co-IP, in vitro DUB assay, transcription assays) in a single high-citation study\",\n      \"pmids\": [\"21285945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"USP29 interacts with and deubiquitinates Claspin both in vivo and in vitro, stabilizing Claspin and thereby supporting ATR-Chk1 pathway signaling and S-phase progression; USP29 knockdown impairs Chk1 phosphorylation after DNA damage.\",\n      \"method\": \"Co-immunoprecipitation, in vivo and in vitro deubiquitination assays, siRNA knockdown with Chk1 phosphorylation readout, cell-cycle analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP plus in vitro DUB assay plus functional epistasis with defined cellular phenotype\",\n      \"pmids\": [\"24632611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP29 constitutively interacts with cGAS and deconjugates K48-linked polyubiquitin chains from cGAS, stabilizing cGAS and promoting type I interferon induction and antiviral responses; USP29 knockout mice are hypersensitive to HSV-1 infection.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (K48-linkage specific), USP29 KO mice, reconstitution experiments\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including KO mice, reconstitution, and linkage-specific ubiquitination assays; independently confirmed in vivo\",\n      \"pmids\": [\"32457395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP29 stabilizes Snail protein by deubiquitinating it, and cooperates with phosphatase SCP1 to simultaneously dephosphorylate and deubiquitinate Snail, preventing its degradation and promoting gastric cancer cell migration.\",\n      \"method\": \"DUB cDNA library screen (79 DUBs), Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, cell migration assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — unbiased DUB screen followed by mechanistic Co-IP and ubiquitination assays with defined functional readout\",\n      \"pmids\": [\"32973332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP29 deubiquitinates and stabilizes Snail1 in a catalytic activity-dependent manner, and USP29 is transcriptionally upregulated by oxidative stress induced by chemotherapy, thereby enhancing cancer stem cell-like characteristics in lung adenocarcinoma.\",\n      \"method\": \"Ubiquitination assay, catalytic mutant analysis, siRNA knockdown, xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — catalytic mutant and ubiquitination assay, single study\",\n      \"pmids\": [\"32968046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP29 directly deubiquitinates and stabilizes HIF1α, promoting its transcriptional activity; this stabilization upregulates hexokinase 2 (HK2) and aerobic glycolysis, contributing to Sorafenib resistance in hepatocellular carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA/CRISPR knockdown, xenograft mouse model, glycolysis metabolic assays\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct DUB assay for HIF1α plus in vivo xenograft validation with multiple orthogonal methods\",\n      \"pmids\": [\"34272356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP29 directly deubiquitinates and stabilizes both MYC and HIF1α, coordinating metabolic reprogramming (glycolysis and glutamine catabolism) in tumor cells; systemic Usp29 knockout depletes MYC and HIF1α in vivo and prolongs survival of tumor-bearing mice without overt developmental defects.\",\n      \"method\": \"Unbiased siRNA screen (96 DUBs), metabolic flux analysis, Co-immunoprecipitation, ubiquitination assay, Usp29 KO mice, neuroblastoma and lymphoma models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — unbiased functional screen plus direct DUB assays for two substrates plus in vivo KO mouse validation with metabolic flux analysis\",\n      \"pmids\": [\"34601505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP29 interacts with and deubiquitinates NRF2, stabilizing it and thereby regulating microglia/macrophage polarization from M1 to M2; USP29 knockdown abolishes the protective effects of melatonin-preconditioned MSC extracellular vesicles after spinal cord injury.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteomics, shRNA knockdown, NRF2 knockout mice, in vivo SCI model\",\n      \"journal\": \"Journal of pineal research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus ubiquitination assay plus NRF2 KO mice rescue experiment\",\n      \"pmids\": [\"34562326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP29 interacts with the carboxyl end of SARS-CoV-2 ORF9b, removes ubiquitin chains from ORF9b (ubiquitinated at Lys-4 and Lys-40), preventing its proteasomal degradation and thereby inhibiting type I IFN and NF-κB activation and enhancing viral virulence.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis of ORF9b lysines, VSV-eGFP and SARS-CoV-2 trVLP viral virulence assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — site-specific mutagenesis, direct DUB assay, and viral functional assays in a single study\",\n      \"pmids\": [\"35638730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP29 interacts with SETD8 (interaction dependent on USP29 catalytic activity), deubiquitinates SETD8 in vivo, and is required for irradiation-induced H4K20 monomethylation and 53BP1 focus formation at DNA damage sites; USP29 depletion increases cellular sensitivity to irradiation.\",\n      \"method\": \"Co-immunoprecipitation (catalytic mutant-dependent), in vivo ubiquitination assay, siRNA knockdown, H4K20me1 immunostaining, 53BP1 focus formation, irradiation survival assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — catalytic-mutant dependent interaction plus in vivo DUB assay plus functional H4K20me1 and 53BP1 readouts\",\n      \"pmids\": [\"36010569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDK1 directly phosphorylates USP29, which is required for USP29 deubiquitinase activity toward TWIST1; USP29-mediated deubiquitination of TWIST1 stabilizes TWIST1 and promotes EMT, cancer stem cell functions, and chemoresistance in triple-negative breast cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, CDK1 kinase assay (phosphorylation of USP29), CDK1 genetic ablation and pharmacological inhibition, TNBC cell and xenograft models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct kinase assay establishing phosphorylation of USP29 by CDK1, plus DUB assay for TWIST1 with functional in vivo validation\",\n      \"pmids\": [\"36782089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP29 deubiquitinates and stabilizes KIAA1429 (VIRMA) via co-immunoprecipitation-confirmed interaction; stabilized KIAA1429 promotes SOX8 mRNA stability through m6A modification, facilitating colorectal cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, xenograft model\",\n      \"journal\": \"Biomolecules & biomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus ubiquitination assay, single study\",\n      \"pmids\": [\"36373629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Transcription factor FUBP1 directly activates USP29 gene transcription (shown by ChIP and luciferase assays); USP29 then interacts with and stabilizes AURKB by suppressing K48-linked polyubiquitination, constituting a FUBP1-USP29-AURKB oncogenic axis in gastric cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), ChIP, luciferase reporter assay, Usp29 KO mice, xenograft model\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP and luciferase for transcriptional regulation, K48-specific ubiquitination assay for DUB activity, in vivo KO mouse validation\",\n      \"pmids\": [\"38233848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP29 directly interacts with ACSL5 and stabilizes it by removing K48-linked ubiquitin chains, promoting fatty acid β-oxidation and protecting against MASLD; USP29 deletion exacerbates hepatic steatosis and fibrosis.\",\n      \"method\": \"Co-immunoprecipitation, K48-linked deubiquitination assay, USP29 knockout and overexpression in mice (HFD/HFCD model), in vitro hepatocyte model\",\n      \"journal\": \"Clinical and molecular hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct DUB assay with linkage specificity, Co-IP, and in vivo mouse model validation\",\n      \"pmids\": [\"39355870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP29 deubiquitinates and stabilizes MYBBP1A; parkin loss leads to accumulation of AIMP2, which upregulates USP29 and subsequently MYBBP1A in dopaminergic neurons, linking this pathway to Parkinson's disease pathogenesis.\",\n      \"method\": \"siRNA knockdown, Western blot (MYBBP1A stabilization), in vivo AIMP2 transgenic and knockdown mouse models\",\n      \"journal\": \"Journal of clinical medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — substrate identification without in vitro DUB assay, single study\",\n      \"pmids\": [\"31878357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP29 interacts with TAK1, directly inhibiting TAK1 ubiquitination and phosphorylation; ELAVL1 binds USP29 mRNA and promotes its degradation, reducing USP29 levels and thereby activating TAK1 to drive M1 microglial polarization after spinal cord injury.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, ubiquitination assay, shRNA knockdown, rat SCI model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — GST pull-down plus ubiquitination assay with in vivo SCI rat model, single study\",\n      \"pmids\": [\"40634288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP29 deubiquitinates FSP1 (ferroptosis suppressor protein 1), counteracting SMURF1-mediated K63/K193 polyubiquitination of FSP1, thereby stabilizing FSP1 and suppressing ferroptosis to facilitate chemoresistance in gastric cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (site-specific K63/K193 mutagenesis), pharmacological FSP1 inhibition, chemoresistant cell and mouse models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — site-specific mutagenesis of ubiquitination sites, direct DUB assay, paired E3/DUB identification, in vivo validation\",\n      \"pmids\": [\"41387682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Two conserved sequence elements (CSE1 and CSE2/YY1 binding sites) within the bidirectional Peg3/Usp29 promoter regulate Usp29 transcription: CSE1 acts as a repressor and CSE2 as an activator, with orientation-dependent effects demonstrated by promoter mutagenesis assays.\",\n      \"method\": \"Cell line-based promoter assays, serial mutagenesis of YY1 binding sites and CSE1 elements\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter mutagenesis with directional reporter assays, single study\",\n      \"pmids\": [\"19068137\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"USP29 is a deubiquitinase that removes K48-linked (and other) polyubiquitin chains from a broad range of substrates — including p53, cGAS, Claspin, HIF1α, MYC, TWIST1, Snail, NRF2, SETD8, ACSL5, AURKB, KIAA1429, FSP1, TAK1, MYBBP1A, and viral ORF9b — to stabilize them and regulate processes spanning DNA damage checkpoints, innate immunity, EMT/metastasis, metabolic reprogramming, and ferroptosis; its catalytic activity is itself regulated by CDK1-mediated phosphorylation, and its transcription is co-activated by the FBP/JTV1(AIMP2) complex in response to oxidative stress.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"USP29 is a deubiquitinase that stabilizes a broad spectrum of substrates by removing K48-linked (and in some cases K63-linked) polyubiquitin chains, thereby regulating DNA damage checkpoints, innate immunity, epithelial-mesenchymal transition, metabolic reprogramming, and ferroptosis. It deubiquitinates p53 and Claspin to support apoptosis and ATR-Chk1 signaling [PMID:21285945, PMID:24632611], stabilizes cGAS to promote type I interferon responses [PMID:32457395], and deubiquitinates HIF1α and MYC to coordinate glycolysis and glutamine catabolism in tumors [PMID:34601505, PMID:34272356]. USP29 catalytic activity is positively regulated by CDK1-mediated phosphorylation, enabling TWIST1 stabilization and EMT [PMID:36782089], while its transcription is controlled by the FBP/AIMP2 complex under oxidative stress and by FUBP1 in gastric cancer [PMID:21285945, PMID:38233848].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"The initial question of how USP29 transcription is controlled was addressed by identifying two conserved cis-elements (CSE1 repressor and CSE2/YY1 activator) within the bidirectional Peg3/Usp29 promoter, establishing that USP29 expression is subject to orientation-dependent transcriptional regulation.\",\n      \"evidence\": \"Promoter mutagenesis and reporter assays in cell lines\",\n      \"pmids\": [\"19068137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous transcription factor occupancy not confirmed by ChIP\", \"Imprinting status and its effect on USP29 expression not resolved\", \"No connection to physiological signals driving USP29 induction\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"USP29 was established as an active deubiquitinase with its first identified substrate: FBP and JTV1/AIMP2 co-activate USP29 transcription under oxidative stress, and USP29 directly deubiquitinates and stabilizes p53 to induce apoptosis, revealing a stress-responsive DUB–tumor suppressor axis.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro and in vivo deubiquitination assays, transcriptional reporter assays\",\n      \"pmids\": [\"21285945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin chain-linkage specificity on p53 not determined\", \"Physiological in vivo validation in knockout animals not performed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"USP29's role was extended to DNA damage checkpoint signaling by showing it deubiquitinates and stabilizes Claspin, supporting ATR-Chk1 activation and S-phase progression after replication stress.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro DUB assay, siRNA knockdown with Chk1 phosphorylation readout, cell-cycle analysis\",\n      \"pmids\": [\"24632611\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP29 acts at stalled replication forks versus globally on Claspin pools is unknown\", \"Relationship to other Claspin-directed DUBs not clarified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A link between USP29 and neurodegeneration was proposed: parkin loss elevates AIMP2, which upregulates USP29, leading to MYBBP1A accumulation in dopaminergic neurons, potentially contributing to Parkinson's disease pathogenesis.\",\n      \"evidence\": \"siRNA knockdown, Western blot, AIMP2 transgenic and knockdown mouse models\",\n      \"pmids\": [\"31878357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro DUB assay confirming direct deubiquitination of MYBBP1A\", \"Causal contribution of USP29–MYBBP1A axis to dopaminergic neuron loss not established\", \"Single study without independent replication\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"USP29 was established as a critical regulator of innate immunity by constitutively interacting with and deubiquitinating cGAS (K48-linked chains), stabilizing it to promote type I IFN responses; Usp29 knockout mice showed impaired antiviral defense against HSV-1.\",\n      \"evidence\": \"K48-linkage-specific ubiquitination assays, Co-IP, reconstitution, Usp29 KO mice with HSV-1 challenge\",\n      \"pmids\": [\"32457395\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP29 regulation of cGAS is modulated by viral immune evasion strategies\", \"Structural basis of USP29–cGAS interaction unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"USP29 was identified as a Snail-stabilizing DUB through unbiased screening, showing it cooperates with phosphatase SCP1 to prevent Snail degradation and promote EMT and gastric/lung cancer migration, extending USP29's role to epithelial-mesenchymal transition.\",\n      \"evidence\": \"DUB cDNA library screen (79 DUBs), Co-IP, ubiquitination assay, catalytic mutant analysis, xenograft models\",\n      \"pmids\": [\"32973332\", \"32968046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SCP1 and USP29 are co-recruited to Snail is unknown\", \"Whether USP29 regulation of Snail operates in normal epithelial homeostasis\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"USP29 was shown to coordinately stabilize both HIF1α and MYC, establishing it as a master regulator of tumor metabolic reprogramming (glycolysis and glutamine catabolism); systemic Usp29 knockout prolonged survival in tumor models without developmental defects, indicating therapeutic potential.\",\n      \"evidence\": \"Unbiased siRNA screen of 96 DUBs, metabolic flux analysis, Co-IP, DUB assays, Usp29 KO mice in neuroblastoma and lymphoma models\",\n      \"pmids\": [\"34601505\", \"34272356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How USP29 selectively targets HIF1α versus VHL-mediated degradation pathway\", \"Compensatory DUBs in Usp29 KO mice not characterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"USP29 was connected to NRF2-dependent anti-oxidant signaling by showing it deubiquitinates and stabilizes NRF2, driving M1-to-M2 microglia/macrophage polarization and neuroprotection after spinal cord injury.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, proteomics, NRF2 KO mice, in vivo SCI model\",\n      \"pmids\": [\"34562326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP29 competes with Keap1/Cul3 E3 ligase for NRF2 not tested\", \"Specificity of USP29 versus other NRF2-directed DUBs unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"USP29's substrate repertoire was extended to viral proteins and DNA damage effectors: it stabilizes SARS-CoV-2 ORF9b (at K4/K40) to suppress innate immunity, and stabilizes SETD8 to promote H4K20me1 and 53BP1 recruitment at DNA damage sites.\",\n      \"evidence\": \"Site-directed mutagenesis of ORF9b ubiquitination sites, viral virulence assays; catalytic-mutant-dependent Co-IP with SETD8, H4K20me1 and 53BP1 focus formation assays\",\n      \"pmids\": [\"35638730\", \"36010569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SARS-CoV-2 actively hijacks USP29 or passively benefits from it\", \"Structural determinants of USP29 substrate recognition remain unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"CDK1 was identified as an upstream activator of USP29 through direct phosphorylation, which is required for USP29-mediated deubiquitination of TWIST1, thereby linking cell-cycle kinase signaling to EMT and chemoresistance in triple-negative breast cancer.\",\n      \"evidence\": \"In vitro CDK1 kinase assay on USP29, CDK1 genetic ablation and pharmacological inhibition, DUB assay for TWIST1, TNBC xenograft models\",\n      \"pmids\": [\"36782089\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation site(s) on USP29 not mapped\", \"Whether CDK1-dependent activation applies to all USP29 substrates or is TWIST1-specific\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"USP29's transcriptional control and substrate range were further expanded: FUBP1 directly activates USP29 transcription to stabilize Aurora kinase B (AURKB) in gastric cancer, and USP29 stabilizes ACSL5 via K48-chain removal to promote fatty acid β-oxidation and protect against hepatic steatosis.\",\n      \"evidence\": \"ChIP and luciferase for FUBP1→USP29 transcription; K48-specific DUB assays for AURKB and ACSL5; Usp29 KO and overexpression mice on HFD/HFCD\",\n      \"pmids\": [\"38233848\", \"39355870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FUBP1-driven transcription of USP29 is equivalent to the FBP/AIMP2-driven pathway reported earlier\", \"Tissue-specific regulation of USP29 expression not systematically characterized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"USP29 was shown to suppress ferroptosis by deubiquitinating FSP1, counteracting SMURF1-mediated K63/K193 polyubiquitination, and to regulate neuroinflammation by deubiquitinating TAK1 to inhibit M1 microglial polarization, further broadening its functional scope.\",\n      \"evidence\": \"Site-specific ubiquitination mutagenesis for FSP1, paired E3/DUB analysis, chemoresistant gastric cancer models; GST pull-down and DUB assay for TAK1, rat SCI model\",\n      \"pmids\": [\"41387682\", \"40634288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How USP29 selects among its many substrates in a given cellular context is unknown\", \"TAK1 study is a single report in a rat model without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include how USP29 achieves substrate selectivity among its remarkably broad substrate repertoire, what the structural basis of its catalytic domain and substrate recognition is, whether CDK1-mediated phosphorylation regulates activity toward all substrates, and how its apparently non-essential in vivo role (viable KO mice) is reconciled with its strong tumor-promoting functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No crystal or cryo-EM structure of USP29 available\", \"Systematic identification of all CDK1 phosphorylation sites on USP29 lacking\", \"No comprehensive substrate-specificity or ubiquitin-chain-type selectivity study\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 6, 8, 9, 10, 12, 13, 16]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 6, 8, 9, 10, 12, 13, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 6, 10, 13, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 6, 8, 9, 10, 12, 13, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 5, 6, 10, 11, 12, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 16]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 6, 13]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 4, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TP53\", \"CLSPN\", \"CGAS\", \"SNAI1\", \"HIF1A\", \"MYC\", \"TWIST1\", \"AURKB\"],\n    \"other_free_text\": []\n  }\n}\n```"}