Affinage

USP29

Ubiquitin carboxyl-terminal hydrolase 29 · UniProt Q9HBJ7

Length
922 aa
Mass
104.2 kDa
Annotated
2026-06-11
25 papers in source corpus 19 papers cited in narrative 19 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2008 Medium

    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

    PMID:19068137

    Open questions at the time
    • Does not address USP29 protein function or substrates
    • Physiological signals engaging these elements not defined
  2. 2011 High

    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

    PMID:21285945

    Open questions at the time
    • Ubiquitin linkage specificity on p53 not resolved
    • Whether p53 is a direct catalytic substrate versus indirect not fully isolated
  3. 2014 High

    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

    PMID:24632611

    Open questions at the time
    • Ubiquitin linkage type on Claspin not defined
    • Whether USP29 acts constitutively or is DNA-damage-regulated unclear
  4. 2020 High

    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

    PMID:32457395

    Open questions at the time
    • Mechanism coupling cGAS stabilization to specific infection contexts limited to HSV-1
    • Catalytic site mutant dependence on cGAS not detailed
  5. 2020 Medium

    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

    PMID:32968046 PMID:32973332

    Open questions at the time
    • Ubiquitin linkage on Snail not defined
    • How USP29 simultaneously coordinates SCP1 recruitment mechanistically unresolved
  6. 2021 High

    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

    PMID:34272356 PMID:34601505

    Open questions at the time
    • Whether MYC and HIF1α stabilization are independent or coupled events not resolved
    • Normal-tissue substrate dependence appears minimal but not exhaustively mapped
  7. 2021 Medium

    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

    PMID:34562326

    Open questions at the time
    • Ubiquitin linkage on NRF2 not defined
    • Direct versus indirect deubiquitination not isolated by catalytic mutant
  8. 2022 Medium

    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

    PMID:35638730

    Open questions at the time
    • Physiological host substrate competing with ORF9b unknown
    • In vivo relevance during natural infection not established
  9. 2022 Medium

    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

    PMID:36010569

    Open questions at the time
    • Ubiquitin linkage on SETD8 not specified
    • Whether USP29 acts at damage sites or globally not resolved
  10. 2023 High

    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

    PMID:36782089

    Open questions at the time
    • Whether CDK1 phosphorylation regulates USP29 toward other substrates unknown
    • Structural basis of phospho-activation not determined
  11. 2023 Medium

    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

    PMID:36373629

    Open questions at the time
    • Ubiquitin linkage on KIAA1429 not defined
    • Whether USP29 directly affects other m6A writers untested
  12. 2024 High

    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

    PMID:38233848 PMID:39355870

    Open questions at the time
    • 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
  13. 2025 Medium

    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

    PMID:40634288

    Open questions at the time
    • Mechanism by which USP29 reduces TAK1 phosphorylation versus ubiquitination not separated
    • Whether ELAVL1 regulation is context-specific unknown
  14. 2025 Medium

    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

    PMID:41387682

    Open questions at the time
    • Reconciliation of K63-targeting on FSP1 with K48-targeting on other substrates not addressed
    • Direct catalytic dependence on FSP1 stabilization not isolated by mutant
  15. 2026 Medium

    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

    PMID:42125859

    Open questions at the time
    • Structural basis for binding the HIF-α C-terminus not determined
    • Relative contribution of HIF1α versus HIF2α in vivo not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016787 hydrolase activity 3
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-168256 Immune System 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1430728 Metabolism 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2
Partners
CGASCLSPNHIF1AMYCNFE2L2SNAI1TP53TWIST1

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 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. Co-immunoprecipitation, deubiquitination assays, transcriptional reporter assays, cellular fractionation/localization The EMBO journal High 21285945
2014 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. Co-immunoprecipitation, in vitro and in vivo deubiquitination assays, siRNA knockdown with Chk1 phosphorylation readout, cell cycle analysis Oncogene High 24632611
2020 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. Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), knockout mice, reconstitution experiment, cytokine measurement Cell research High 32457395
2020 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. cDNA library DUB screen (79 DUBs), co-immunoprecipitation, ubiquitination assay, cell migration assay, Snail depletion rescue experiment Oncogene Medium 32973332
2020 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. Co-immunoprecipitation, ubiquitination assay, catalytic mutant analysis, siRNA knockdown, xenograft mouse model Cell death & disease Medium 32968046
2021 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. Co-immunoprecipitation, ubiquitination assay, in vitro deubiquitylation, xenograft mouse model, metabolic assays Oncogenesis Medium 34272356
2021 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. siRNA screen (96 DUBs), metabolic flux analysis, co-immunoprecipitation, ubiquitination assay, Usp29 knockout mice, xenograft models Oncogene High 34601505
2021 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. Co-immunoprecipitation, deubiquitination assay, USP29 knockdown in extracellular vesicles, NRF2 knockout mouse model Journal of pineal research Medium 34562326
2022 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. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, VSV-eGFP and SARS-CoV-2 trVLP virulence assays mBio Medium 35638730
2022 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. Co-immunoprecipitation, in vivo deubiquitination assay, catalytic mutant analysis, siRNA knockdown, H4K20me1 immunofluorescence, 53BP1 focus formation assay, irradiation sensitivity assay Cells Medium 36010569
2023 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. Co-immunoprecipitation, ubiquitination assay, in vitro kinase assay (CDK1 phosphorylation of USP29), phospho-mutant analysis, genetic ablation and pharmacological CDK1 inhibition, xenograft models Advanced science High 36782089
2023 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. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, proliferation assays, xenograft mouse model Biomolecules & biomedicine Medium 36373629
2024 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. Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), chromatin immunoprecipitation, luciferase reporter assay, CRISPR-Cas9 KO, Usp29 knockout mice, xenograft models Cancer cell international High 38233848
2024 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. Co-immunoprecipitation, K48-linked deubiquitination assay, USP29 deletion and overexpression mouse models, hepatocyte lipid accumulation assays Clinical and molecular hepatology Medium 39355870
2019 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. Western blot protein level analysis, siRNA knockdown (parkin KD), transgenic mouse model (AIMP2 overexpression), immunohistochemistry of PD patient brains Journal of clinical medicine Low 31878357
2025 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. Co-immunoprecipitation, GST pull-down, ubiquitination assay, phosphorylation analysis, shRNA knockdown in rat SCI model, in vivo motor function analysis Cell death discovery Medium 40634288
2025 USP29 deubiquitinates FSP1, opposing SMURF1-mediated K63/K193 polyubiquitination of FSP1, thereby stabilizing FSP1 and suppressing ferroptosis to promote chemoresistance in gastric cancer. Co-immunoprecipitation, ubiquitination assay (site-specific K63/K193 mapping), USP29 knockdown/overexpression, ferroptosis assays, mouse chemoresistance models Nature communications Medium 41387682
2026 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. Co-immunoprecipitation, ubiquitination assay, catalytic mutant analysis, proteasome inhibitor experiments, computational CA9-expression surrogate analysis Molecular oncology Medium 42125859
2008 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. Cell line-based promoter reporter assays, serial deletion and site-directed mutagenesis of YY1 binding sites and CSE1 BMC molecular biology Medium 19068137

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 JTV1 co-activates FBP to induce USP29 transcription and stabilize p53 in response to oxidative stress. The EMBO journal 117 21285945
2021 Extracellular vesicles derived from melatonin-preconditioned mesenchymal stem cells containing USP29 repair traumatic spinal cord injury by stabilizing NRF2. Journal of pineal research 113 34562326
2020 USP29 maintains the stability of cGAS and promotes cellular antiviral responses and autoimmunity. Cell research 72 32457395
2014 USP29 controls the stability of checkpoint adaptor Claspin by deubiquitination. Oncogene 63 24632611
2020 Deubiquitinase USP29 promotes gastric cancer cell migration by cooperating with phosphatase SCP1 to stabilize Snail protein. Oncogene 59 32973332
2021 USP29-mediated HIF1α stabilization is associated with Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis. Oncogenesis 51 34272356
2023 Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 43 36782089
2001 Imprinting and evolution of two Kruppel-type zinc-finger genes, ZIM3 and ZNF264, located in the PEG3/USP29 imprinted domain. Genomics 39 11543637
2020 USP29 enhances chemotherapy-induced stemness in non-small cell lung cancer via stabilizing Snail1 in response to oxidative stress. Cell death & disease 38 32968046
2021 USP29 coordinates MYC and HIF1α stabilization to promote tumor metabolism and progression. Oncogene 35 34601505
2022 The Deubiquitinase USP29 Promotes SARS-CoV-2 Virulence by Preventing Proteasome Degradation of ORF9b. mBio 29 35638730
2023 Promotive role of USP29-mediated deubiquitination in malignant proliferation of colorectal cancer cells via the KIAA1429/SOX8 axis. Biomolecules & biomedicine 18 36373629
2008 Two evolutionarily conserved sequence elements for Peg3/Usp29 transcription. BMC molecular biology 15 19068137
2024 USP29 alleviates the progression of MASLD by stabilizing ACSL5 through K48 deubiquitination. Clinical and molecular hepatology 13 39355870
2024 USP29 activation mediated by FUBP1 promotes AURKB stability and oncogenic functions in gastric cancer. Cancer cell international 11 38233848
2019 The deubiquitinating gene Usp29 is dispensable for fertility in male mice. Science China. Life sciences 9 30919279
2019 Deubiquitinase USP29 Governs MYBBP1A in the Brains of Parkinson's Disease Patients. Journal of clinical medicine 9 31878357
2022 USP29 Deubiquitinates SETD8 and Regulates DNA Damage-Induced H4K20 Monomethylation and 53BP1 Focus Formation. Cells 8 36010569
2023 Identification of USP29 as a key regulator of nucleotide biosynthesis in neuroblastoma through integrative analysis of multi-omics data. Cancer biology & therapy 3 37463886
2022 Deubiquitinase USP29 correlates RORγt expression and its association with thymoma myasthenia gravis. American journal of translational research 3 36628242
2016 Transcriptional Truncation of the Long Coding Imprinted Gene Usp29. PloS one 3 27327533
2025 USP29 and SMURF1 orchestrate FSP1-mediated ferroptosis suppression to facilitate chemoresistance in gastric cancer. Nature communications 2 41387682
2024 The emerging role of USP29 in cancer and other diseases. Cell biochemistry and function 2 38269503
2025 ELAVL1-mediated USP29 mRNA degradation activates TAK1 driving M1 microglial polarization and neural stem cell differentiation dysregulation in spinal cord injury. Cell death discovery 1 40634288
2026 USP29-regulated noncanonical stabilization of the hypoxia-inducible factor-α in aggressive prostate cancer. Molecular oncology 0 42125859

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