{"gene":"USP29","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2011,"finding":"USP29 binds to p53, cleaves poly-ubiquitin chains from p53, and stabilizes p53 protein in response to oxidative stress, leading to rapid apoptosis. USP29 transcription is co-activated by JTV1/AIMP2 (which dissociates from the ARS complex and translocates to the nucleus) and FBP in response to oxidative stress.","method":"Co-immunoprecipitation, deubiquitination assays, transcriptional reporter assays, cellular fractionation/localization","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vivo/in vitro deubiquitination assays, transcriptional activation confirmed, single lab with multiple orthogonal methods","pmids":["21285945"],"is_preprint":false},{"year":2014,"finding":"USP29 interacts with Claspin and deubiquitinates it both in vivo and in vitro, stabilizing Claspin protein levels. USP29 knockdown destabilizes Claspin, impairs Chk1 phosphorylation after DNA damage, and causes defects in S-phase progression, placing USP29 in the ATR-Chk1 DNA damage checkpoint pathway.","method":"Co-immunoprecipitation, in vitro and in vivo deubiquitination assays, siRNA knockdown with Chk1 phosphorylation readout, cell cycle analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vitro deubiquitination assay, epistasis via knockdown with defined phosphorylation readout, single lab with multiple orthogonal methods","pmids":["24632611"],"is_preprint":false},{"year":2020,"finding":"USP29 constitutively interacts with cGAS, removes K48-linked polyubiquitin chains from cGAS, and stabilizes cGAS in both uninfected and HSV-1-infected cells, thereby promoting type I interferon and proinflammatory cytokine induction. Usp29-/- mice showed decreased IFN responses and heightened HSV-1 susceptibility; reconstitution of cGAS into Usp29-/- cells fully rescued antiviral responses.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), knockout mice, reconstitution experiment, cytokine measurement","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, K48-linkage-specific ubiquitination assay, genetic KO with rescue experiment, replicated in vitro and in vivo","pmids":["32457395"],"is_preprint":false},{"year":2020,"finding":"USP29 stabilizes Snail protein by deubiquitinating it in a catalytic activity-dependent manner and enhances the interaction between Snail and the phosphatase SCP1, resulting in simultaneous dephosphorylation and deubiquitination to cooperatively prevent Snail degradation, promoting gastric cancer cell migration.","method":"cDNA library DUB screen (79 DUBs), co-immunoprecipitation, ubiquitination assay, cell migration assay, Snail depletion rescue experiment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional DUB screen, Co-IP, ubiquitination assay, single lab with multiple methods","pmids":["32973332"],"is_preprint":false},{"year":2020,"finding":"USP29 stabilizes Snail1 by restricting its ubiquitylation in a catalytic activity-dependent manner. USP29 is transcriptionally upregulated by oxidative stress induced by chemotherapy and enhances cancer stem cell-like characteristics in lung adenocarcinoma.","method":"Co-immunoprecipitation, ubiquitination assay, catalytic mutant analysis, siRNA knockdown, xenograft mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, catalytic activity-dependent mutant, single lab with multiple methods","pmids":["32968046"],"is_preprint":false},{"year":2021,"finding":"USP29 directly deubiquitylates and stabilizes HIF1α, protecting it from proteasomal degradation and promoting its transcriptional activity (including HK2 induction and aerobic glycolysis). USP29 absence reduces glycolysis and restores Sorafenib sensitivity in HCC cells.","method":"Co-immunoprecipitation, ubiquitination assay, in vitro deubiquitylation, xenograft mouse model, metabolic assays","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo xenograft, single lab with multiple methods","pmids":["34272356"],"is_preprint":false},{"year":2021,"finding":"USP29 directly deubiquitinates and stabilizes both MYC and HIF1α, two master regulators of metabolic reprogramming, enabling tumor metabolic adaptation in both normoxia and hypoxia. Systemic Usp29 knockout in mice depleted MYC and HIF1α in neuroblastoma and B cell lymphoma and significantly prolonged survival of tumor-bearing mice without gross phenotypic abnormalities in normal tissues.","method":"siRNA screen (96 DUBs), metabolic flux analysis, co-immunoprecipitation, ubiquitination assay, Usp29 knockout mice, xenograft models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional siRNA screen, Co-IP, ubiquitination assay, metabolic flux analysis, in vivo KO mouse model with survival data, multiple orthogonal methods","pmids":["34601505"],"is_preprint":false},{"year":2021,"finding":"USP29 interacts with, deubiquitinates, and stabilizes NRF2, thereby regulating microglia/macrophage polarization from M1-like to M2-like in the context of spinal cord injury.","method":"Co-immunoprecipitation, deubiquitination assay, USP29 knockdown in extracellular vesicles, NRF2 knockout mouse model","journal":"Journal of pineal research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, deubiquitination assay, genetic KO mouse validation, single lab with multiple methods","pmids":["34562326"],"is_preprint":false},{"year":2022,"finding":"USP29 interacts with SARS-CoV-2 ORF9b via ORF9b's carboxyl end, removes ubiquitin chains from ORF9b (which is ubiquitinated on Lys-4 and Lys-40), prevents its proteasomal degradation, and thereby enhances ORF9b-mediated inhibition of type I IFN induction and NF-κB activation, increasing viral virulence.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, VSV-eGFP and SARS-CoV-2 trVLP virulence assays","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, site-specific ubiquitination mapping, virulence assay, single lab with multiple methods","pmids":["35638730"],"is_preprint":false},{"year":2022,"finding":"USP29 binds SETD8 in a manner dependent on USP29 catalytic activity, deubiquitinates SETD8 in vivo, and stabilizes SETD8 protein levels. USP29 knockdown inhibits irradiation-induced H4K20 monomethylation and prevents 53BP1 focus formation at DNA damage sites, increasing cellular sensitivity to irradiation.","method":"Co-immunoprecipitation, in vivo deubiquitination assay, catalytic mutant analysis, siRNA knockdown, H4K20me1 immunofluorescence, 53BP1 focus formation assay, irradiation sensitivity assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vivo deubiquitination, catalytic activity dependence shown, functional epistasis through H4K20me1 and 53BP1 readout, single lab","pmids":["36010569"],"is_preprint":false},{"year":2023,"finding":"USP29 is a deubiquitinase of TWIST1 that stabilizes it, and CDK1-mediated phosphorylation of USP29 is required to activate USP29's deubiquitinase activity toward TWIST1. This CDK1-USP29-TWIST1 axis promotes EMT, cancer stem cell properties, chemoresistance, and metastasis in triple-negative breast cancer.","method":"Co-immunoprecipitation, ubiquitination assay, in vitro kinase assay (CDK1 phosphorylation of USP29), phospho-mutant analysis, genetic ablation and pharmacological CDK1 inhibition, xenograft models","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay, Co-IP, ubiquitination assay, phospho-mutant functional rescue, in vivo xenograft, multiple orthogonal methods in single lab","pmids":["36782089"],"is_preprint":false},{"year":2023,"finding":"USP29 interacts with KIAA1429 (VIRMA) and mediates its deubiquitination to stabilize KIAA1429 protein levels, which then promotes SOX8 mRNA stability through m6A modification, driving colorectal cancer cell proliferation.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, proliferation assays, xenograft mouse model","journal":"Biomolecules & biomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional rescue with KIAA1429/SOX8 overexpression, single lab with multiple methods","pmids":["36373629"],"is_preprint":false},{"year":2024,"finding":"Transcription factor FUBP1 directly activates USP29 gene transcription. USP29 then interacts with and stabilizes AURKB by suppressing K48-linked polyubiquitination of AURKB, constituting a FUBP1-USP29-AURKB regulatory axis promoting gastric carcinogenesis.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), chromatin immunoprecipitation, luciferase reporter assay, CRISPR-Cas9 KO, Usp29 knockout mice, xenograft models","journal":"Cancer cell international","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, K48-specific ubiquitination assay, ChIP for transcriptional activation, genetic KO mouse model with in vivo carcinogenesis, multiple orthogonal methods","pmids":["38233848"],"is_preprint":false},{"year":2024,"finding":"USP29 directly interacts with ACSL5 and stabilizes it by removing K48-linked polyubiquitin chains, thereby activating fatty acid β-oxidation and alleviating hepatic steatosis in MASLD.","method":"Co-immunoprecipitation, K48-linked deubiquitination assay, USP29 deletion and overexpression mouse models, hepatocyte lipid accumulation assays","journal":"Clinical and molecular hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, K48-linkage-specific ubiquitination assay, in vivo KO and OE mouse models, single lab with multiple methods","pmids":["39355870"],"is_preprint":false},{"year":2019,"finding":"USP29 deubiquitinates MYBBP1A and stabilizes it. In the context of Parkinson's disease, loss of parkin activity leads to accumulation of AIMP2 (parkin substrate), which activates USP29 transcription, leading to MYBBP1A accumulation in neurons.","method":"Western blot protein level analysis, siRNA knockdown (parkin KD), transgenic mouse model (AIMP2 overexpression), immunohistochemistry of PD patient brains","journal":"Journal of clinical medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — protein level assays consistent with deubiquitination but no direct in vitro deubiquitination assay for MYBBP1A shown in abstract, single lab, single approach","pmids":["31878357"],"is_preprint":false},{"year":2025,"finding":"USP29 directly interacts with TAK1, inhibits its ubiquitination and phosphorylation (activation), and thereby suppresses M1 microglial polarization. ELAVL1 binds USP29 mRNA and promotes its degradation, reducing USP29 levels; knockdown of ELAVL1 enhances USP29 mRNA stability and inhibits TAK1 activation.","method":"Co-immunoprecipitation, GST pull-down, ubiquitination assay, phosphorylation analysis, shRNA knockdown in rat SCI model, in vivo motor function analysis","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and GST pull-down confirming direct interaction, ubiquitination assay, in vivo SCI rat model, single lab with multiple methods","pmids":["40634288"],"is_preprint":false},{"year":2025,"finding":"USP29 deubiquitinates FSP1, opposing SMURF1-mediated K63/K193 polyubiquitination of FSP1, thereby stabilizing FSP1 and suppressing ferroptosis to promote chemoresistance in gastric cancer.","method":"Co-immunoprecipitation, ubiquitination assay (site-specific K63/K193 mapping), USP29 knockdown/overexpression, ferroptosis assays, mouse chemoresistance models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, site-specific ubiquitination mapping, ferroptosis functional assays, in vivo mouse models, single lab","pmids":["41387682"],"is_preprint":false},{"year":2026,"finding":"USP29 interacts with HIF-1α, reduces its poly-ubiquitination, and protects it from proteasomal degradation in a catalytic-dependent manner across multiple cancer cell lines. USP29 also stabilizes HIF-2α by acting on the C-terminal region of HIF-α.","method":"Co-immunoprecipitation, ubiquitination assay, catalytic mutant analysis, proteasome inhibitor experiments, computational CA9-expression surrogate analysis","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, catalytic dependence confirmed, single lab with multiple methods","pmids":["42125859"],"is_preprint":false},{"year":2008,"finding":"Within the bidirectional Peg3/Usp29 promoter CpG island, CSE1 functions as a transcriptional repressor for Usp29 (and Peg3) in an orientation-dependent manner, while CSE2 (YY1 binding sites) functions as a transcriptional activator specifically for Peg3 but not detectably for Usp29.","method":"Cell line-based promoter reporter assays, serial deletion and site-directed mutagenesis of YY1 binding sites and CSE1","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter assays with systematic mutagenesis, orientation-dependence confirmed, single lab","pmids":["19068137"],"is_preprint":false}],"current_model":"USP29 is a catalytically active deubiquitinase that removes K48-linked (and other) polyubiquitin chains from a diverse set of substrates — including p53, Claspin, cGAS, NRF2, HIF1α, HIF2α, MYC, TWIST1, Snail/Snail1, SETD8, AURKB, ACSL5, KIAA1429, FSP1, TAK1, MYBBP1A, and SARS-CoV-2 ORF9b — to stabilize them and regulate processes including apoptosis, DNA damage checkpoint signaling, innate immune/antiviral responses, EMT and metastasis, tumor metabolic reprogramming, and inflammatory microglial polarization; its own deubiquitinase activity toward TWIST1 is activated by CDK1-mediated phosphorylation, and its transcription is induced by the FBP/JTV1 axis in response to oxidative stress and by FUBP1 in cancer contexts."},"narrative":{"mechanistic_narrative":"USP29 is a catalytically active deubiquitinase that stabilizes a broad range of substrate proteins by removing K48-linked polyubiquitin chains, thereby protecting them from proteasomal degradation and controlling apoptosis, DNA damage checkpoint signaling, antiviral immunity, EMT/metastasis, and tumor metabolic reprogramming [PMID:21285945, PMID:32457395, PMID:34601505]. Its founding role is as a stress-responsive stabilizer of p53: upon oxidative stress USP29 transcription is co-activated by the JTV1/AIMP2-FBP axis, and the resulting enzyme deubiquitinates and stabilizes p53 to trigger apoptosis [PMID:21285945]. In the DNA damage response USP29 stabilizes Claspin to sustain Chk1 phosphorylation and proper S-phase progression within the ATR-Chk1 checkpoint [PMID:24632611], and stabilizes the methyltransferase SETD8 to enable irradiation-induced H4K20 monomethylation and 53BP1 focus formation [PMID:36010569]. USP29 supports innate antiviral signaling by constitutively deubiquitinating and stabilizing cGAS to drive type I interferon induction [PMID:32457395], yet can be co-opted by SARS-CoV-2 to stabilize the immune-antagonist ORF9b [PMID:35638730]. A prominent oncogenic theme is its stabilization of master metabolic and EMT regulators—MYC, HIF1α, HIF2α, Snail/Snail1, and TWIST1—to fuel glycolysis, stemness, chemoresistance, and metastasis [PMID:32973332, PMID:34601505, PMID:36782089, PMID:42125859]; its deubiquitinase activity toward TWIST1 is switched on by CDK1-mediated phosphorylation, and its expression is driven by FUBP1 in cancer [PMID:36782089, PMID:38233848]. The enzyme additionally tunes microglial/macrophage polarization through NRF2 and TAK1 [PMID:34562326, PMID:40634288] and stabilizes FSP1 to suppress ferroptosis [PMID:41387682].","teleology":[{"year":2008,"claim":"Before its enzymatic role was known, the regulatory architecture of the USP29 locus was defined, establishing that USP29 sits in a bidirectional imprinted Peg3/Usp29 promoter under distinct cis-element control.","evidence":"Promoter reporter assays with serial deletion and site-directed mutagenesis of CSE1 and YY1 sites in cell lines","pmids":["19068137"],"confidence":"Medium","gaps":["Does not address USP29 protein function or substrates","Physiological signals engaging these elements not defined"]},{"year":2011,"claim":"Established USP29 as a functional deubiquitinase by showing it cleaves polyubiquitin from p53 and links its induction to oxidative stress via a defined transcriptional axis, answering what USP29 does enzymatically and when.","evidence":"Co-IP, in vivo/in vitro deubiquitination assays, transcriptional reporter assays, and cellular fractionation","pmids":["21285945"],"confidence":"High","gaps":["Ubiquitin linkage specificity on p53 not resolved","Whether p53 is a direct catalytic substrate versus indirect not fully isolated"]},{"year":2014,"claim":"Placed USP29 in the DNA damage checkpoint by showing it stabilizes Claspin to sustain Chk1 activation, extending its substrate range beyond p53.","evidence":"Reciprocal Co-IP, in vitro/in vivo deubiquitination assays, siRNA knockdown with Chk1 phosphorylation and cell-cycle readouts","pmids":["24632611"],"confidence":"High","gaps":["Ubiquitin linkage type on Claspin not defined","Whether USP29 acts constitutively or is DNA-damage-regulated unclear"]},{"year":2020,"claim":"Defined USP29 as a positive regulator of cGAS-driven antiviral immunity through K48-chain removal, answering whether USP29 controls innate immune signaling in vivo.","evidence":"Reciprocal Co-IP, K48-linkage-specific ubiquitination assay, Usp29-/- mice with cGAS reconstitution rescue and cytokine measurement","pmids":["32457395"],"confidence":"High","gaps":["Mechanism coupling cGAS stabilization to specific infection contexts limited to HSV-1","Catalytic site mutant dependence on cGAS not detailed"]},{"year":2020,"claim":"Connected USP29 to EMT and cancer cell migration via Snail/Snail1 stabilization, with one study showing cooperative dephosphorylation through SCP1, establishing a pro-metastatic catalytic-dependent role.","evidence":"DUB screens, Co-IP, ubiquitination assays, catalytic-mutant analysis, migration assays, and xenograft models","pmids":["32973332","32968046"],"confidence":"Medium","gaps":["Ubiquitin linkage on Snail not defined","How USP29 simultaneously coordinates SCP1 recruitment mechanistically unresolved"]},{"year":2021,"claim":"Established USP29 as a driver of tumor metabolic reprogramming by directly stabilizing HIF1α and MYC, answering how USP29 promotes glycolytic adaptation and tumor survival in vivo.","evidence":"siRNA DUB screen, metabolic flux analysis, Co-IP, ubiquitination/deubiquitination assays, Usp29 knockout mice with survival data, and xenografts","pmids":["34272356","34601505"],"confidence":"High","gaps":["Whether MYC and HIF1α stabilization are independent or coupled events not resolved","Normal-tissue substrate dependence appears minimal but not exhaustively mapped"]},{"year":2021,"claim":"Extended USP29 function to inflammatory cell-fate control by showing NRF2 stabilization shifts microglia/macrophages toward an M2-like state in spinal cord injury.","evidence":"Co-IP, deubiquitination assay, USP29 knockdown via extracellular vesicles, and NRF2 knockout mouse validation","pmids":["34562326"],"confidence":"Medium","gaps":["Ubiquitin linkage on NRF2 not defined","Direct versus indirect deubiquitination not isolated by catalytic mutant"]},{"year":2022,"claim":"Revealed that USP29 can be hijacked by SARS-CoV-2 ORF9b, stabilizing a viral immune antagonist and showing the enzyme's substrate range includes non-host proteins.","evidence":"Co-IP, site-specific ubiquitination mapping (Lys-4/Lys-40), proteasome inhibitor experiments, and viral virulence assays","pmids":["35638730"],"confidence":"Medium","gaps":["Physiological host substrate competing with ORF9b unknown","In vivo relevance during natural infection not established"]},{"year":2022,"claim":"Linked USP29 to chromatin-based DNA repair by stabilizing SETD8, enabling H4K20me1 and 53BP1 recruitment, broadening its checkpoint role into the methyltransferase axis.","evidence":"Co-IP, in vivo deubiquitination, catalytic-mutant analysis, H4K20me1 immunofluorescence, and 53BP1 focus and irradiation-sensitivity assays","pmids":["36010569"],"confidence":"Medium","gaps":["Ubiquitin linkage on SETD8 not specified","Whether USP29 acts at damage sites or globally not resolved"]},{"year":2023,"claim":"Uncovered post-translational regulation of USP29 itself, showing CDK1 phosphorylation activates its catalytic activity toward TWIST1, answering how USP29 deubiquitinase activity is switched on.","evidence":"In vitro kinase assay, Co-IP, ubiquitination assay, phospho-mutant rescue, CDK1 inhibition, and xenograft models","pmids":["36782089"],"confidence":"High","gaps":["Whether CDK1 phosphorylation regulates USP29 toward other substrates unknown","Structural basis of phospho-activation not determined"]},{"year":2023,"claim":"Extended USP29 oncogenic output to the m6A machinery by stabilizing KIAA1429/VIRMA, linking deubiquitination to mRNA modification-driven proliferation.","evidence":"Co-IP, ubiquitination assay, siRNA knockdown, proliferation assays, and xenograft model with KIAA1429/SOX8 rescue","pmids":["36373629"],"confidence":"Medium","gaps":["Ubiquitin linkage on KIAA1429 not defined","Whether USP29 directly affects other m6A writers untested"]},{"year":2024,"claim":"Defined a transcription-to-substrate axis in which FUBP1 drives USP29 expression to stabilize AURKB, and added ACSL5 stabilization as a metabolic role in fatty acid oxidation.","evidence":"Co-IP, K48-specific ubiquitination assays, ChIP and luciferase reporter, CRISPR and Usp29 knockout mice, xenografts, and hepatocyte lipid assays","pmids":["38233848","39355870"],"confidence":"High","gaps":["Whether FUBP1 and the oxidative-stress AIMP2/FBP axes converge on the same promoter elements unresolved","Tissue selectivity of ACSL5 versus AURKB outputs not mapped"]},{"year":2025,"claim":"Showed USP29 can also act as a negative regulator of activation-type ubiquitination by inhibiting TAK1 ubiquitination/phosphorylation to suppress M1 microglial polarization, and identified ELAVL1 as a destabilizer of USP29 mRNA.","evidence":"Co-IP, GST pull-down, ubiquitination/phosphorylation analysis, shRNA knockdown in a rat SCI model, and motor function analysis","pmids":["40634288"],"confidence":"Medium","gaps":["Mechanism by which USP29 reduces TAK1 phosphorylation versus ubiquitination not separated","Whether ELAVL1 regulation is context-specific unknown"]},{"year":2025,"claim":"Linked USP29 to ferroptosis suppression by counteracting SMURF1-mediated K63/K193 ubiquitination of FSP1, expanding its role into chemoresistance through cell-death control.","evidence":"Co-IP, site-specific ubiquitination mapping, USP29 knockdown/overexpression, ferroptosis assays, and mouse chemoresistance models","pmids":["41387682"],"confidence":"Medium","gaps":["Reconciliation of K63-targeting on FSP1 with K48-targeting on other substrates not addressed","Direct catalytic dependence on FSP1 stabilization not isolated by mutant"]},{"year":2026,"claim":"Generalized USP29 stabilization of HIF-α family proteins by showing catalytic-dependent stabilization of both HIF1α and HIF2α across multiple cancer lines via the C-terminal region.","evidence":"Co-IP, ubiquitination assay, catalytic-mutant analysis, proteasome inhibitor experiments, and CA9-surrogate computational analysis","pmids":["42125859"],"confidence":"Medium","gaps":["Structural basis for binding the HIF-α C-terminus not determined","Relative contribution of HIF1α versus HIF2α in vivo not resolved"]},{"year":null,"claim":"How USP29 achieves its remarkably broad substrate selectivity and integrates its multiple transcriptional inputs (AIMP2/FBP, FUBP1, ELAVL1) and post-translational activation (CDK1) into context-specific substrate choice remains unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate recognition","No unifying determinant explaining selection among p53, cGAS, HIF, MYC, TWIST1, and others","Spatial localization of USP29 during distinct activities not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,3,9,12,13,16]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,2,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,7,8,15]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,6,13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,6,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,10,11,16]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,16]}],"complexes":[],"partners":["TP53","CLSPN","CGAS","SNAI1","HIF1A","MYC","NFE2L2","TWIST1"],"other_free_text":[]}},"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":117,"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":113,"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":63,"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":59,"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":51,"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":43,"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":38,"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":35,"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":18,"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":13,"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":8,"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":"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":"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":"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":2,"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":"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":1,"is_preprint":false},{"pmid":"42125859","id":"PMC_42125859","title":"USP29-regulated noncanonical stabilization of the hypoxia-inducible factor-α in aggressive prostate cancer.","date":"2026","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42125859","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":15033,"output_tokens":4883,"usd":0.059172,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13020,"output_tokens":5150,"usd":0.096925,"stage2_stop_reason":"end_turn"},"total_usd":0.156097,"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\": \"USP29 binds to p53, cleaves poly-ubiquitin chains from p53, and stabilizes p53 protein in response to oxidative stress, leading to rapid apoptosis. USP29 transcription is co-activated by JTV1/AIMP2 (which dissociates from the ARS complex and translocates to the nucleus) and FBP in response to oxidative stress.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assays, transcriptional reporter assays, cellular fractionation/localization\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vivo/in vitro deubiquitination assays, transcriptional activation confirmed, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21285945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"USP29 interacts with Claspin and deubiquitinates it both in vivo and in vitro, stabilizing Claspin protein levels. USP29 knockdown destabilizes Claspin, impairs Chk1 phosphorylation after DNA damage, and causes defects in S-phase progression, placing USP29 in the ATR-Chk1 DNA damage checkpoint pathway.\",\n      \"method\": \"Co-immunoprecipitation, in vitro and in vivo deubiquitination assays, siRNA knockdown with Chk1 phosphorylation readout, cell cycle analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vitro deubiquitination assay, epistasis via knockdown with defined phosphorylation readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24632611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP29 constitutively interacts with cGAS, removes K48-linked polyubiquitin chains from cGAS, and stabilizes cGAS in both uninfected and HSV-1-infected cells, thereby promoting type I interferon and proinflammatory cytokine induction. Usp29-/- mice showed decreased IFN responses and heightened HSV-1 susceptibility; reconstitution of cGAS into Usp29-/- cells fully rescued antiviral responses.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), knockout mice, reconstitution experiment, cytokine measurement\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, K48-linkage-specific ubiquitination assay, genetic KO with rescue experiment, replicated in vitro and in vivo\",\n      \"pmids\": [\"32457395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP29 stabilizes Snail protein by deubiquitinating it in a catalytic activity-dependent manner and enhances the interaction between Snail and the phosphatase SCP1, resulting in simultaneous dephosphorylation and deubiquitination to cooperatively prevent Snail degradation, promoting gastric cancer cell migration.\",\n      \"method\": \"cDNA library DUB screen (79 DUBs), co-immunoprecipitation, ubiquitination assay, cell migration assay, Snail depletion rescue experiment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional DUB screen, Co-IP, ubiquitination assay, single lab with multiple methods\",\n      \"pmids\": [\"32973332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP29 stabilizes Snail1 by restricting its ubiquitylation in a catalytic activity-dependent manner. USP29 is transcriptionally upregulated by oxidative stress induced by chemotherapy and enhances cancer stem cell-like characteristics in lung adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, catalytic mutant analysis, siRNA knockdown, xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, catalytic activity-dependent mutant, single lab with multiple methods\",\n      \"pmids\": [\"32968046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP29 directly deubiquitylates and stabilizes HIF1α, protecting it from proteasomal degradation and promoting its transcriptional activity (including HK2 induction and aerobic glycolysis). USP29 absence reduces glycolysis and restores Sorafenib sensitivity in HCC cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, in vitro deubiquitylation, xenograft mouse model, metabolic assays\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo xenograft, single lab with multiple methods\",\n      \"pmids\": [\"34272356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP29 directly deubiquitinates and stabilizes both MYC and HIF1α, two master regulators of metabolic reprogramming, enabling tumor metabolic adaptation in both normoxia and hypoxia. Systemic Usp29 knockout in mice depleted MYC and HIF1α in neuroblastoma and B cell lymphoma and significantly prolonged survival of tumor-bearing mice without gross phenotypic abnormalities in normal tissues.\",\n      \"method\": \"siRNA screen (96 DUBs), metabolic flux analysis, co-immunoprecipitation, ubiquitination assay, Usp29 knockout mice, xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional siRNA screen, Co-IP, ubiquitination assay, metabolic flux analysis, in vivo KO mouse model with survival data, multiple orthogonal methods\",\n      \"pmids\": [\"34601505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP29 interacts with, deubiquitinates, and stabilizes NRF2, thereby regulating microglia/macrophage polarization from M1-like to M2-like in the context of spinal cord injury.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, USP29 knockdown in extracellular vesicles, NRF2 knockout mouse model\",\n      \"journal\": \"Journal of pineal research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, deubiquitination assay, genetic KO mouse validation, single lab with multiple methods\",\n      \"pmids\": [\"34562326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP29 interacts with SARS-CoV-2 ORF9b via ORF9b's carboxyl end, removes ubiquitin chains from ORF9b (which is ubiquitinated on Lys-4 and Lys-40), prevents its proteasomal degradation, and thereby enhances ORF9b-mediated inhibition of type I IFN induction and NF-κB activation, increasing viral virulence.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, VSV-eGFP and SARS-CoV-2 trVLP virulence assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, site-specific ubiquitination mapping, virulence assay, single lab with multiple methods\",\n      \"pmids\": [\"35638730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP29 binds SETD8 in a manner dependent on USP29 catalytic activity, deubiquitinates SETD8 in vivo, and stabilizes SETD8 protein levels. USP29 knockdown inhibits irradiation-induced H4K20 monomethylation and prevents 53BP1 focus formation at DNA damage sites, increasing cellular sensitivity to irradiation.\",\n      \"method\": \"Co-immunoprecipitation, in vivo deubiquitination assay, catalytic mutant analysis, siRNA knockdown, H4K20me1 immunofluorescence, 53BP1 focus formation assay, irradiation sensitivity assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vivo deubiquitination, catalytic activity dependence shown, functional epistasis through H4K20me1 and 53BP1 readout, single lab\",\n      \"pmids\": [\"36010569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP29 is a deubiquitinase of TWIST1 that stabilizes it, and CDK1-mediated phosphorylation of USP29 is required to activate USP29's deubiquitinase activity toward TWIST1. This CDK1-USP29-TWIST1 axis promotes EMT, cancer stem cell properties, chemoresistance, and metastasis in triple-negative breast cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, in vitro kinase assay (CDK1 phosphorylation of USP29), phospho-mutant analysis, genetic ablation and pharmacological CDK1 inhibition, xenograft models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay, Co-IP, ubiquitination assay, phospho-mutant functional rescue, in vivo xenograft, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"36782089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP29 interacts with KIAA1429 (VIRMA) and mediates its deubiquitination to stabilize KIAA1429 protein levels, which then promotes SOX8 mRNA stability through m6A modification, driving colorectal cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, proliferation assays, xenograft mouse model\",\n      \"journal\": \"Biomolecules & biomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional rescue with KIAA1429/SOX8 overexpression, single lab with multiple methods\",\n      \"pmids\": [\"36373629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Transcription factor FUBP1 directly activates USP29 gene transcription. USP29 then interacts with and stabilizes AURKB by suppressing K48-linked polyubiquitination of AURKB, constituting a FUBP1-USP29-AURKB regulatory axis promoting gastric carcinogenesis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), chromatin immunoprecipitation, luciferase reporter assay, CRISPR-Cas9 KO, Usp29 knockout mice, xenograft models\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, K48-specific ubiquitination assay, ChIP for transcriptional activation, genetic KO mouse model with in vivo carcinogenesis, multiple orthogonal methods\",\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 polyubiquitin chains, thereby activating fatty acid β-oxidation and alleviating hepatic steatosis in MASLD.\",\n      \"method\": \"Co-immunoprecipitation, K48-linked deubiquitination assay, USP29 deletion and overexpression mouse models, hepatocyte lipid accumulation assays\",\n      \"journal\": \"Clinical and molecular hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, K48-linkage-specific ubiquitination assay, in vivo KO and OE mouse models, single lab with multiple methods\",\n      \"pmids\": [\"39355870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP29 deubiquitinates MYBBP1A and stabilizes it. In the context of Parkinson's disease, loss of parkin activity leads to accumulation of AIMP2 (parkin substrate), which activates USP29 transcription, leading to MYBBP1A accumulation in neurons.\",\n      \"method\": \"Western blot protein level analysis, siRNA knockdown (parkin KD), transgenic mouse model (AIMP2 overexpression), immunohistochemistry of PD patient brains\",\n      \"journal\": \"Journal of clinical medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — protein level assays consistent with deubiquitination but no direct in vitro deubiquitination assay for MYBBP1A shown in abstract, single lab, single approach\",\n      \"pmids\": [\"31878357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP29 directly interacts with TAK1, inhibits its ubiquitination and phosphorylation (activation), and thereby suppresses M1 microglial polarization. ELAVL1 binds USP29 mRNA and promotes its degradation, reducing USP29 levels; knockdown of ELAVL1 enhances USP29 mRNA stability and inhibits TAK1 activation.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, ubiquitination assay, phosphorylation analysis, shRNA knockdown in rat SCI model, in vivo motor function analysis\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and GST pull-down confirming direct interaction, ubiquitination assay, in vivo SCI rat model, single lab with multiple methods\",\n      \"pmids\": [\"40634288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP29 deubiquitinates FSP1, opposing SMURF1-mediated K63/K193 polyubiquitination of FSP1, thereby stabilizing FSP1 and suppressing ferroptosis to promote chemoresistance in gastric cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (site-specific K63/K193 mapping), USP29 knockdown/overexpression, ferroptosis assays, mouse chemoresistance models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, site-specific ubiquitination mapping, ferroptosis functional assays, in vivo mouse models, single lab\",\n      \"pmids\": [\"41387682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP29 interacts with HIF-1α, reduces its poly-ubiquitination, and protects it from proteasomal degradation in a catalytic-dependent manner across multiple cancer cell lines. USP29 also stabilizes HIF-2α by acting on the C-terminal region of HIF-α.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, catalytic mutant analysis, proteasome inhibitor experiments, computational CA9-expression surrogate analysis\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, catalytic dependence confirmed, single lab with multiple methods\",\n      \"pmids\": [\"42125859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Within the bidirectional Peg3/Usp29 promoter CpG island, CSE1 functions as a transcriptional repressor for Usp29 (and Peg3) in an orientation-dependent manner, while CSE2 (YY1 binding sites) functions as a transcriptional activator specifically for Peg3 but not detectably for Usp29.\",\n      \"method\": \"Cell line-based promoter reporter assays, serial deletion and site-directed mutagenesis of YY1 binding sites and CSE1\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assays with systematic mutagenesis, orientation-dependence confirmed, single lab\",\n      \"pmids\": [\"19068137\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"USP29 is a catalytically active deubiquitinase that removes K48-linked (and other) polyubiquitin chains from a diverse set of substrates — including p53, Claspin, cGAS, NRF2, HIF1α, HIF2α, MYC, TWIST1, Snail/Snail1, SETD8, AURKB, ACSL5, KIAA1429, FSP1, TAK1, MYBBP1A, and SARS-CoV-2 ORF9b — to stabilize them and regulate processes including apoptosis, DNA damage checkpoint signaling, innate immune/antiviral responses, EMT and metastasis, tumor metabolic reprogramming, and inflammatory microglial polarization; its own deubiquitinase activity toward TWIST1 is activated by CDK1-mediated phosphorylation, and its transcription is induced by the FBP/JTV1 axis in response to oxidative stress and by FUBP1 in cancer contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"USP29 is a catalytically active deubiquitinase that stabilizes a broad range of substrate proteins by removing K48-linked polyubiquitin chains, thereby protecting them from proteasomal degradation and controlling apoptosis, DNA damage checkpoint signaling, antiviral immunity, EMT/metastasis, and tumor metabolic reprogramming [#0, #2, #6]. Its founding role is as a stress-responsive stabilizer of p53: upon oxidative stress USP29 transcription is co-activated by the JTV1/AIMP2-FBP axis, and the resulting enzyme deubiquitinates and stabilizes p53 to trigger apoptosis [#0]. In the DNA damage response USP29 stabilizes Claspin to sustain Chk1 phosphorylation and proper S-phase progression within the ATR-Chk1 checkpoint [#1], and stabilizes the methyltransferase SETD8 to enable irradiation-induced H4K20 monomethylation and 53BP1 focus formation [#9]. USP29 supports innate antiviral signaling by constitutively deubiquitinating and stabilizing cGAS to drive type I interferon induction [#2], yet can be co-opted by SARS-CoV-2 to stabilize the immune-antagonist ORF9b [#8]. A prominent oncogenic theme is its stabilization of master metabolic and EMT regulators—MYC, HIF1\\u03b1, HIF2\\u03b1, Snail/Snail1, and TWIST1—to fuel glycolysis, stemness, chemoresistance, and metastasis [#3, #6, #10, #17]; its deubiquitinase activity toward TWIST1 is switched on by CDK1-mediated phosphorylation, and its expression is driven by FUBP1 in cancer [#10, #12]. The enzyme additionally tunes microglial/macrophage polarization through NRF2 and TAK1 [#7, #15] and stabilizes FSP1 to suppress ferroptosis [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Before its enzymatic role was known, the regulatory architecture of the USP29 locus was defined, establishing that USP29 sits in a bidirectional imprinted Peg3/Usp29 promoter under distinct cis-element control.\",\n      \"evidence\": \"Promoter reporter assays with serial deletion and site-directed mutagenesis of CSE1 and YY1 sites in cell lines\",\n      \"pmids\": [\"19068137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address USP29 protein function or substrates\", \"Physiological signals engaging these elements not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established USP29 as a functional deubiquitinase by showing it cleaves polyubiquitin from p53 and links its induction to oxidative stress via a defined transcriptional axis, answering what USP29 does enzymatically and when.\",\n      \"evidence\": \"Co-IP, in vivo/in vitro deubiquitination assays, transcriptional reporter assays, and cellular fractionation\",\n      \"pmids\": [\"21285945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin linkage specificity on p53 not resolved\", \"Whether p53 is a direct catalytic substrate versus indirect not fully isolated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed USP29 in the DNA damage checkpoint by showing it stabilizes Claspin to sustain Chk1 activation, extending its substrate range beyond p53.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro/in vivo deubiquitination assays, siRNA knockdown with Chk1 phosphorylation and cell-cycle readouts\",\n      \"pmids\": [\"24632611\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin linkage type on Claspin not defined\", \"Whether USP29 acts constitutively or is DNA-damage-regulated unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined USP29 as a positive regulator of cGAS-driven antiviral immunity through K48-chain removal, answering whether USP29 controls innate immune signaling in vivo.\",\n      \"evidence\": \"Reciprocal Co-IP, K48-linkage-specific ubiquitination assay, Usp29-/- mice with cGAS reconstitution rescue and cytokine measurement\",\n      \"pmids\": [\"32457395\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling cGAS stabilization to specific infection contexts limited to HSV-1\", \"Catalytic site mutant dependence on cGAS not detailed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected USP29 to EMT and cancer cell migration via Snail/Snail1 stabilization, with one study showing cooperative dephosphorylation through SCP1, establishing a pro-metastatic catalytic-dependent role.\",\n      \"evidence\": \"DUB screens, Co-IP, ubiquitination assays, catalytic-mutant analysis, migration assays, and xenograft models\",\n      \"pmids\": [\"32973332\", \"32968046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage on Snail not defined\", \"How USP29 simultaneously coordinates SCP1 recruitment mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established USP29 as a driver of tumor metabolic reprogramming by directly stabilizing HIF1\\u03b1 and MYC, answering how USP29 promotes glycolytic adaptation and tumor survival in vivo.\",\n      \"evidence\": \"siRNA DUB screen, metabolic flux analysis, Co-IP, ubiquitination/deubiquitination assays, Usp29 knockout mice with survival data, and xenografts\",\n      \"pmids\": [\"34272356\", \"34601505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MYC and HIF1\\u03b1 stabilization are independent or coupled events not resolved\", \"Normal-tissue substrate dependence appears minimal but not exhaustively mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended USP29 function to inflammatory cell-fate control by showing NRF2 stabilization shifts microglia/macrophages toward an M2-like state in spinal cord injury.\",\n      \"evidence\": \"Co-IP, deubiquitination assay, USP29 knockdown via extracellular vesicles, and NRF2 knockout mouse validation\",\n      \"pmids\": [\"34562326\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage on NRF2 not defined\", \"Direct versus indirect deubiquitination not isolated by catalytic mutant\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed that USP29 can be hijacked by SARS-CoV-2 ORF9b, stabilizing a viral immune antagonist and showing the enzyme's substrate range includes non-host proteins.\",\n      \"evidence\": \"Co-IP, site-specific ubiquitination mapping (Lys-4/Lys-40), proteasome inhibitor experiments, and viral virulence assays\",\n      \"pmids\": [\"35638730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological host substrate competing with ORF9b unknown\", \"In vivo relevance during natural infection not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked USP29 to chromatin-based DNA repair by stabilizing SETD8, enabling H4K20me1 and 53BP1 recruitment, broadening its checkpoint role into the methyltransferase axis.\",\n      \"evidence\": \"Co-IP, in vivo deubiquitination, catalytic-mutant analysis, H4K20me1 immunofluorescence, and 53BP1 focus and irradiation-sensitivity assays\",\n      \"pmids\": [\"36010569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage on SETD8 not specified\", \"Whether USP29 acts at damage sites or globally not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered post-translational regulation of USP29 itself, showing CDK1 phosphorylation activates its catalytic activity toward TWIST1, answering how USP29 deubiquitinase activity is switched on.\",\n      \"evidence\": \"In vitro kinase assay, Co-IP, ubiquitination assay, phospho-mutant rescue, CDK1 inhibition, and xenograft models\",\n      \"pmids\": [\"36782089\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDK1 phosphorylation regulates USP29 toward other substrates unknown\", \"Structural basis of phospho-activation not determined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended USP29 oncogenic output to the m6A machinery by stabilizing KIAA1429/VIRMA, linking deubiquitination to mRNA modification-driven proliferation.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, siRNA knockdown, proliferation assays, and xenograft model with KIAA1429/SOX8 rescue\",\n      \"pmids\": [\"36373629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage on KIAA1429 not defined\", \"Whether USP29 directly affects other m6A writers untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a transcription-to-substrate axis in which FUBP1 drives USP29 expression to stabilize AURKB, and added ACSL5 stabilization as a metabolic role in fatty acid oxidation.\",\n      \"evidence\": \"Co-IP, K48-specific ubiquitination assays, ChIP and luciferase reporter, CRISPR and Usp29 knockout mice, xenografts, and hepatocyte lipid assays\",\n      \"pmids\": [\"38233848\", \"39355870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FUBP1 and the oxidative-stress AIMP2/FBP axes converge on the same promoter elements unresolved\", \"Tissue selectivity of ACSL5 versus AURKB outputs not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed USP29 can also act as a negative regulator of activation-type ubiquitination by inhibiting TAK1 ubiquitination/phosphorylation to suppress M1 microglial polarization, and identified ELAVL1 as a destabilizer of USP29 mRNA.\",\n      \"evidence\": \"Co-IP, GST pull-down, ubiquitination/phosphorylation analysis, shRNA knockdown in a rat SCI model, and motor function analysis\",\n      \"pmids\": [\"40634288\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which USP29 reduces TAK1 phosphorylation versus ubiquitination not separated\", \"Whether ELAVL1 regulation is context-specific unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked USP29 to ferroptosis suppression by counteracting SMURF1-mediated K63/K193 ubiquitination of FSP1, expanding its role into chemoresistance through cell-death control.\",\n      \"evidence\": \"Co-IP, site-specific ubiquitination mapping, USP29 knockdown/overexpression, ferroptosis assays, and mouse chemoresistance models\",\n      \"pmids\": [\"41387682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of K63-targeting on FSP1 with K48-targeting on other substrates not addressed\", \"Direct catalytic dependence on FSP1 stabilization not isolated by mutant\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Generalized USP29 stabilization of HIF-\\u03b1 family proteins by showing catalytic-dependent stabilization of both HIF1\\u03b1 and HIF2\\u03b1 across multiple cancer lines via the C-terminal region.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, catalytic-mutant analysis, proteasome inhibitor experiments, and CA9-surrogate computational analysis\",\n      \"pmids\": [\"42125859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for binding the HIF-\\u03b1 C-terminus not determined\", \"Relative contribution of HIF1\\u03b1 versus HIF2\\u03b1 in vivo not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How USP29 achieves its remarkably broad substrate selectivity and integrates its multiple transcriptional inputs (AIMP2/FBP, FUBP1, ELAVL1) and post-translational activation (CDK1) into context-specific substrate choice remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate recognition\", \"No unifying determinant explaining selection among p53, cGAS, HIF, MYC, TWIST1, and others\", \"Spatial localization of USP29 during distinct activities not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 3, 9, 12, 13, 16]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 2, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 7, 8, 15]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 6, 13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 6, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 10, 11, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TP53\", \"CLSPN\", \"CGAS\", \"SNAI1\", \"HIF1A\", \"MYC\", \"NFE2L2\", \"TWIST1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}