Affinage

USP51

Ubiquitin carboxyl-terminal hydrolase 51 · UniProt Q70EK9

Length
711 aa
Mass
79.8 kDa
Annotated
2026-06-11
16 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP51 is a deubiquitinase that controls protein stability across DNA repair, transcription, and a broad spectrum of cancer-associated processes by removing ubiquitin from chromatin and multiple non-histone substrates (PMID:27083998, PMID:29119051). In the DNA damage response, USP51 directly binds the H2A-H2B dimer and deubiquitylates histone H2A at K13/K15, acting downstream of RNF168 to regulate the dynamic assembly and disassembly of 53BP1 and BRCA1 foci (PMID:27083998); biochemically it processes H2AK13ub, H2AK15ub, H2AK119ub, and H2BK120ub on reconstituted nucleosomes, with site discrimination governed by steric accessibility of the isopeptide bond (PMID:30192049). Beyond chromatin, USP51 functions as a stabilizing DUB for an array of substrates: it deubiquitinates and stabilizes the EMT transcription factor ZEB1, an activity that requires CDK4/6-mediated phosphorylation of USP51 and drives breast and lung cancer metastasis through a CDK4/6-USP51-ZEB1 axis (PMID:29119051, PMID:32296027, PMID:35058607). USP51 also assembles into the VHL/CUL2/ELOB/ELOC/RBX1 complex via direct binding to Elongin C, where it deubiquitinates and stabilizes HIF1A to activate hypoxia-induced transcription, a step gated by SENP1-mediated deSUMOylation of ELOC (PMID:37816999). Through stabilization of additional substrates—PD-L1, TWIST1, GPX4, GRP78, FAT4, and NEK8—USP51 promotes chemoresistance, cancer stemness, ferroptosis resistance, and Hippo and WNT/β-catenin pathway modulation (PMID:37386737, PMID:31217854, PMID:37422632, PMID:39151312, PMID:40487653, PMID:41475333).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2016 High

    Established USP51 as a chromatin-acting deubiquitinase that targets histone H2A and modulates DNA damage signaling, defining its first molecular function and pathway position.

    Evidence In vitro deubiquitylation and H2A-H2B binding assays with chromatin fractionation and 53BP1/BRCA1/RNF168 foci epistasis after DNA damage

    PMID:27083998

    Open questions at the time
    • Site selectivity for H2AK13/K15 in cells not explained biochemically
    • Recruitment mechanism to damaged chromatin unresolved
  2. 2018 High

    Defined the intrinsic substrate range of USP51 on defined nucleosomal substrates, showing the in vivo site selectivity is not an intrinsic enzymatic property but is set by structural accessibility.

    Evidence Total chemical synthesis of ubiquitylated histones, nucleosome reconstitution, in vitro DUB assays, and molecular dynamics simulation

    PMID:30192049

    Open questions at the time
    • What confers in-cell site selectivity (cofactors, recruitment) remains unknown
    • No structural model of the USP51-nucleosome complex
  3. 2017 Medium

    Extended USP51 function beyond chromatin by identifying ZEB1 as a stabilized substrate, linking the DUB to EMT control in breast cancer.

    Evidence Deubiquitinase library screen, Co-IP, ubiquitination assays, and cell invasion assays in mesenchymal breast cancer cells

    PMID:29119051

    Open questions at the time
    • Direct deubiquitination not reconstituted in vitro
    • Ubiquitin chain type on ZEB1 not defined
  4. 2020 Medium

    Showed that USP51 activity toward ZEB1 is switched on by CDK4/6 phosphorylation, establishing an upstream regulatory kinase axis driving metastasis.

    Evidence In vitro phosphorylation, Co-IP, ubiquitination assays, in vivo metastasis models, and tissue correlation

    PMID:32296027

    Open questions at the time
    • Phosphosite(s) on USP51 not mapped to catalytic mechanism
    • Single lab
  5. 2022 Medium

    Replicated the CDK4/6-USP51-ZEB1 axis in lung adenocarcinoma, generalizing the mechanism across cancer types.

    Evidence Phosphorylation and ubiquitination assays, Co-IP, invasion assays, and clinical tissue correlation

    PMID:35058607

    Open questions at the time
    • Mechanistic detail beyond prior breast cancer work limited
    • Single lab
  6. 2019 Medium

    Placed USP51 within a tumor-suppressive context by stabilizing FAT4 to modulate Hippo signaling, indicating context-dependent functional outputs.

    Evidence Co-IP, USP51 knockdown/overexpression, FAT4 protein measurement, and Hippo pathway readouts in endometrial cancer cells

    PMID:31217854

    Open questions at the time
    • Direct deubiquitination of FAT4 not biochemically demonstrated
    • Reconciliation with oncogenic roles elsewhere not addressed
  7. 2019 Low

    Linked AMPK signaling to USP51-dependent stabilization of pro-apoptotic Bim, implicating USP51 in apoptosis sensitization.

    Evidence siRNA depletion of USP51 and Bim, AMPK activation, apoptosis assays, and xenograft

    PMID:31817696

    Open questions at the time
    • No direct biochemical demonstration of USP51-Bim deubiquitination
    • Causal link is indirect
  8. 2023 Medium

    Defined USP51 as a functional subunit of the VHL/CUL2 complex that deubiquitinates HIF1A, with its incorporation controlled by SENP1-driven deSUMOylation of ELOC.

    Evidence Co-IP, ubiquitination/deubiquitination and SUMOylation assays, SENP1 manipulation, and functional readouts

    PMID:37816999

    Open questions at the time
    • No in vitro reconstitution of the USP51-VHL complex
    • Stoichiometry within the CUL2 ligase unresolved
  9. 2023 Medium

    Identified PD-L1 as a USP51 substrate, connecting the DUB to immune-checkpoint protein stability and NF-κB-driven chemoresistance.

    Evidence Co-IP, pulldown, Ub-AMC DUB activity assay, cellular thermal shift, and SPR in NSCLC cells

    PMID:37386737

    Open questions at the time
    • In vivo relevance of PD-L1-ITGB1 axis incompletely defined
    • Single lab
  10. 2023 Medium

    Showed USP51 stabilizes TWIST1 to maintain cancer stem cell properties, expanding its role in stemness control.

    Evidence Cycloheximide chase, polyubiquitination assays, TWIST1 rescue, sphere formation, and xenograft in NSCLC

    PMID:37422632

    Open questions at the time
    • Direct in vitro deubiquitination not shown
    • Ubiquitin linkage type unspecified
  11. 2024 Medium

    Connected USP51 to ferroptosis regulation by stabilizing GPX4, defining a redox-survival function exploitable by berbamine.

    Evidence Ubiquitination/deubiquitination and rescue assays, ferroptosis markers, and xenograft in esophageal squamous cell carcinoma

    PMID:39151312

    Open questions at the time
    • Whether USP51 directly binds GPX4 not fully established
    • Single lab
  12. 2025 Medium

    Demonstrated USP51 stabilization of GRP78 promotes cell-surface GRP78 and ABCB1-mediated drug efflux, providing a mechanism for chemoresistance.

    Evidence Co-IP, ubiquitination/deubiquitination assays, surface GRP78 localization, doxorubicin accumulation, and xenograft in TNBC

    PMID:40487653

    Open questions at the time
    • Mechanism coupling GRP78 deubiquitination to surface trafficking unclear
    • Single lab
  13. 2025 Medium

    Added NEK8 as a USP51 substrate driving WNT/β-catenin-dependent colorectal cancer proliferation, broadening the oncogenic substrate set.

    Evidence Co-IP, co-IF, ubiquitination assays, functional rescue, and subcutaneous tumor formation

    PMID:41475333

    Open questions at the time
    • Direct in vitro deubiquitination not reconstituted
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How USP51 substrate selection and site specificity are governed in cells across such a broad substrate repertoire, and how its phosphorylation and complex incorporation are coordinated, remains unresolved.
  • No structural model of USP51 bound to any substrate
  • No unifying determinant of in-cell substrate/site selectivity
  • Reconciliation of tumor-suppressive (FAT4, Bim) versus oncogenic substrate roles unaddressed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016787 hydrolase activity 3 GO:0042393 histone binding 2
Localization
GO:0005634 nucleus 2 GO:0005694 chromosome 1
Pathway
R-HSA-392499 Metabolism of proteins 7 R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-73894 DNA Repair 1
Partners
ELOCFAT4GPX4HIF1ANEK8PD-L1TWIST1ZEB1
Complex memberships
VHL/CUL2/ELOB/ELOC/RBX1 ubiquitin ligase complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 USP51 directly binds H2A-H2B and deubiquitylates histone H2A at K13 and K15 (H2AK13,15ub) in vitro. In cells, USP51 is recruited to chromatin after DNA damage and regulates dynamic assembly/disassembly of 53BP1 and BRCA1 foci. USP51 overexpression suppresses 53BP1 and BRCA1 but not RNF168 foci, placing USP51 downstream of RNF168 in the DNA damage response pathway. In vitro deubiquitylation assay, direct binding assay (H2A-H2B pulldown), chromatin fractionation, epistasis via foci analysis (RNF168/53BP1/BRCA1), USP51 depletion/overexpression Genes & development High 27083998
2018 USP51 deubiquitylates H2AK13Ub, H2AK15Ub, and H2AK119Ub in vitro on reconstituted nucleosomes without site selectivity (in contrast to in vivo observations). USP51 can also deubiquitylate H2BK120Ub but not H2BK34Ub in vitro. Molecular dynamics simulations suggest steric hindrance of the isopeptide bond affects USP51 catalytic activity on certain sites. Total chemical protein synthesis of ubiquitylated histones, nucleosome reconstitution, in vitro deubiquitylation assay, molecular dynamics simulation Chembiochem High 30192049
2017 USP51 binds, deubiquitinates, and stabilizes the transcription factor ZEB1, identified by screening a human deubiquitinase library. Depletion of USP51 in mesenchymal-like breast cancer cells leads to downregulation of ZEB1 protein, upregulation of E-cadherin, downregulation of mesenchymal markers, and inhibition of cell invasion. Deubiquitinase library screen, co-immunoprecipitation, ubiquitination assay, USP51 depletion/overexpression, cell invasion assay American journal of cancer research Medium 29119051
2020 CDK4/6 phosphorylates and activates USP51, which is necessary for USP51 to deubiquitinate and stabilize ZEB1, thereby promoting breast cancer metastasis. This establishes a CDK4/6-USP51-ZEB1 signaling axis. In vitro phosphorylation assay, co-immunoprecipitation, ubiquitination assay, USP51 depletion/overexpression, in vivo tumor metastasis models, tissue correlation analysis Signal transduction and targeted therapy Medium 32296027
2023 USP51 directly binds Elongin C (ELOC) and forms a functional complex with the VHL E3 ligase (USP51/VHL/CUL2/ELOB/ELOC/RBX1). Within this complex, USP51 deubiquitinates HIF1A and stabilizes it, activating hypoxia-induced gene transcription. SUMOylation of ELOC at K32 inhibits its binding to USP51; SENP1-mediated deSUMOylation of ELOC promotes USP51-ELOC binding and facilitates HIF1A stabilization. Co-immunoprecipitation, ubiquitination/deubiquitination assay, SUMOylation assay, SENP1 manipulation, USP51 depletion/overexpression, functional readouts (proliferation, migration, stemness) Cell death and differentiation Medium 37816999
2023 USP51 deubiquitinates and stabilizes PD-L1 protein in NSCLC cells. PD-L1, stabilized by USP51, directly binds ITGB1 at the cell membrane and activates NF-κB signaling to promote chemoresistance. Co-immunoprecipitation, pulldown assay, protein deubiquitination assay, Ub-AMC-based DUB activity assay, cellular thermal shift assay, surface plasmon resonance (SPR), USP51 depletion/overexpression Cancer communications Medium 37386737
2019 USP51 directly binds FAT4 (confirmed by co-immunoprecipitation). USP51 stabilizes FAT4 protein; ablation of USP51 decreases FAT4 protein levels while overexpression increases them. USP51-FAT4 interaction is required for FAT4's tumor-suppressive function via the Hippo pathway in endometrial cancer cells. Co-immunoprecipitation, USP51 shRNA knockdown/overexpression, FAT4 protein level measurement, Hippo pathway activity assay (LATS1/2 phosphorylation, YAP localization) American journal of translational research Medium 31217854
2023 USP51 deubiquitinates TWIST1, attenuating its polyubiquitination and stabilizing the TWIST1 protein, thereby maintaining cancer stem cell properties in NSCLC cells. Re-expression of TWIST1 rescued the inhibitory effects of USP51 knockdown on cell stemness. Cycloheximide chase assay, polyubiquitination assay, USP51 overexpression/knockdown, TWIST1 rescue experiment, colony/sphere formation assays, in vivo xenograft Journal of translational medicine Medium 37422632
2024 USP51 deubiquitinates GPX4, stabilizing it and protecting it from proteasomal degradation. Reduction of USP51 by berbamine leads to increased ubiquitination and degradation of GPX4, triggering ferroptosis in esophageal squamous cell carcinoma cells. USP51 overexpression rescues GPX4 from BBM-induced downregulation. Ubiquitination/deubiquitination assay, USP51 overexpression rescue experiment, cell death assay (ferroptosis markers: Fe, ROS, MDA), in vivo xenograft Biomedicine & pharmacotherapy Medium 39151312
2019 AMPK activation by hispidulin upregulates USP51 expression, which in turn stabilizes the pro-apoptotic protein Bim at the post-translational level, sensitizing cancer cells to TRAIL-induced apoptosis. Depletion of Bim blocks this effect. USP51 expression analysis, siRNA depletion of Bim and USP51, AMPK activation, apoptosis assay, in vivo xenograft Cancers Low 31817696
2022 CDK4/6 phosphorylates and activates USP51 in lung adenocarcinoma, leading to deubiquitination and stabilization of ZEB1, thereby promoting tumor metastasis. p-USP51 and ZEB1 levels are positively correlated in human lung adenocarcinoma samples. Phosphorylation assay, co-immunoprecipitation, ubiquitination assay, USP51 depletion/overexpression, in vitro invasion assays, clinical tissue correlation Cancer gene therapy Medium 35058607
2025 USP51 deubiquitinates and stabilizes GRP78. This stabilization increases GRP78 cell-surface localization, which enhances ABCB1 efflux pump activity and reduces doxorubicin accumulation in triple-negative breast cancer cells, conferring chemoresistance. Co-immunoprecipitation, ubiquitination/deubiquitination assay, USP51 overexpression, cell surface GRP78 localization assay, doxorubicin accumulation assay, in vivo xenograft Acta pharmaceutica Sinica B Medium 40487653
2025 USP51 directly interacts with NEK8, reduces its ubiquitination level, and stabilizes NEK8 protein. NEK8 stabilization by USP51 promotes colorectal cancer cell proliferation and invasion through activation of the WNT/β-catenin pathway. Co-immunoprecipitation, co-immunofluorescence, ubiquitination assay, functional rescue experiments, USP51/NEK8 knockdown, WNT/β-catenin pathway readout (β-catenin protein levels), subcutaneous tumor formation Pathology, research and practice Medium 41475333
2025 CDK4/6 kinase activity and USP51 cooperate to enhance ZEB1 protein stability via deubiquitination, promoting cell migration in a mesenchymal breast cancer model. Suppression of USP51 or CDK4/6 attenuates ZEB1 stability and cell migration. Ubiquitin-proteasome pathway analysis, CDK4/6 and USP51 inhibition/knockdown, ZEB1 protein stability assay, cell migration assay Scientific reports Low 40877392

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 USP51 deubiquitylates H2AK13,15ub and regulates DNA damage response. Genes & development 80 27083998
2017 USP51 promotes deubiquitination and stabilization of ZEB1. American journal of cancer research 70 29119051
2020 CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism. Signal transduction and targeted therapy 69 32296027
2023 USP51 facilitates colorectal cancer stemness and chemoresistance by forming a positive feed-forward loop with HIF1A. Cell death and differentiation 41 37816999
2023 USP51/PD-L1/ITGB1-deployed juxtacrine interaction plays a cell-intrinsic role in promoting chemoresistant phenotypes in non-small cell lung cancer. Cancer communications (London, England) 37 37386737
2018 Examination of the Deubiquitylation Site Selectivity of USP51 by Using Chemically Synthesized Ubiquitylated Histones. Chembiochem : a European journal of chemical biology 31 30192049
2023 USP51/ZEB1/ACTA2 axis promotes mesenchymal phenotype in gastric cancer and is associated with low cohesion characteristics. Pharmacological research 26 36603607
2019 FAT4-USP51 complex regulates the proliferation and invasion of endometrial cancer via Hippo pathway. American journal of translational research 20 31217854
2024 Berbamine promotes ferroptosis of esophageal squamous cell carcinoma by facilitating USP51-mediated GPX4 ubiquitination and degradation. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 16 39151312
2023 USP51 promotes non-small cell lung carcinoma cell stemness by deubiquitinating TWIST1. Journal of translational medicine 16 37422632
2019 Hispidulin Enhances TRAIL-Mediated Apoptosis via CaMKK/AMPK/USP51 Axis-Mediated Bim Stabilization. Cancers 16 31817696
2022 CDK4/6-USP51 axis regulates lung adenocarcinoma metastasis through ZEB1. Cancer gene therapy 15 35058607
2022 The role of USP51 in attenuating chemosensitivity of lung cancer cells to cisplatin by regulating DNA damage response. Biotechnology and applied biochemistry 14 35856403
2025 USP51/GRP78/ABCB1 axis confers chemoresistance through decreasing doxorubicin accumulation in triple-negative breast cancer cells. Acta pharmaceutica Sinica. B 4 40487653
2025 Regulation of divergent epithelial-to-mesenchymal transition responses via the CDK4/6-USP51 pathway through ZEB1 protein stabilization. Scientific reports 2 40877392
2025 NEK8 stabilization via USP51-mediated deubiquitination promotes colorectal cancer progression. Pathology, research and practice 0 41475333

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