Affinage

USP42

Ubiquitin carboxyl-terminal hydrolase 42 · UniProt Q9H9J4

Length
1324 aa
Mass
145.4 kDa
Annotated
2026-04-28
13 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP42 is a deubiquitinating enzyme that stabilizes multiple nuclear and cytoplasmic substrates—including p53, histone H2B, ZNRF3, TRIM21, and PPARγ—thereby linking ubiquitin homeostasis to transcription, mRNA splicing, DNA repair, and Wnt signalling. USP42 deubiquitinates p53 to enable rapid p53-dependent transcription and cell-cycle arrest during stress, and deubiquitinates H2B at promoters to support basal and induced transcription in concert with RNA Polymerase II (PMID:22085928, PMID:25336640). Its intrinsically disordered C-terminal domain drives liquid–liquid phase separation and localization to SC35-positive nuclear speckles, where USP42 organizes spliceosome components such as PLRG1 and facilitates homologous recombination by promoting DHX9-dependent R-loop resolution and BRCA1 recruitment to double-strand breaks (PMID:33731873, PMID:32541651). At the plasma membrane, USP42 deubiquitinates ZNRF3 to stall R-spondin–LGR4–ZNRF3 complex formation, thereby suppressing Wnt signalling by accelerating turnover of LRP6 and Frizzled receptors (PMID:33786993).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2006 Medium

    Establishing that USP42 possesses intrinsic deubiquitinating activity resolved the basic question of whether the predicted catalytic domain is functional.

    Evidence In vitro and in vivo DUB assays with mouse Usp42

    PMID:16904385

    Open questions at the time
    • No physiological substrate identified
    • Human ortholog activity not directly tested in this study
    • Catalytic mechanism and specificity for ubiquitin chain types undetermined
  2. 2011 High

    Identifying p53 as a direct substrate answered how USP42 participates in the DNA damage response and showed it controls the kinetics of p53 activation rather than steady-state levels.

    Evidence Reciprocal Co-IP, in vivo deubiquitination assay, siRNA knockdown with p53-dependent transcription and cell-cycle arrest readouts in human cells

    PMID:22085928

    Open questions at the time
    • Ubiquitin chain-type specificity on p53 not defined
    • Relationship to other p53-directed DUBs (e.g. USP7) not addressed
    • In vivo relevance in animal models not tested
  3. 2014 High

    Demonstrating that USP42 deubiquitinates H2B at gene promoters and co-localizes with RNA Pol II established a second nuclear function—direct regulation of transcription via chromatin modification.

    Evidence Co-IP/pulldown with H2B, in vitro and in vivo DUB assay, ChIP at promoters, transcription reporter assays upon USP42 depletion

    PMID:25336640

    Open questions at the time
    • Genome-wide distribution of USP42-dependent H2B deubiquitylation unknown
    • Relationship between p53 stabilization and H2B deubiquitylation functions not dissected
    • Structural basis for H2B recognition undetermined
  4. 2020 High

    Showing that USP42 promotes homologous recombination by facilitating BRCA1 recruitment and DHX9-dependent R-loop resolution at DSBs revealed a DNA repair function mechanistically linked to its nuclear speckle localization.

    Evidence siRNA screen, Co-IP with DHX9, HR reporter assay, BRCA1 recruitment assay, DRIP-based R-loop detection

    PMID:32541651

    Open questions at the time
    • Whether DHX9 is a direct deubiquitination substrate of USP42 not determined
    • Mechanism by which USP42 promotes BRCA1 accumulation (direct or indirect) unclear
    • Contribution relative to other speckle-associated repair factors not defined
  5. 2021 High

    Two contemporaneous studies expanded USP42's functional repertoire: phase separation in nuclear speckles organizes splicing, while deubiquitination of ZNRF3 suppresses Wnt signalling at the plasma membrane—demonstrating USP42 operates in distinct subcellular compartments with different substrates.

    Evidence Phase separation assays, domain mutagenesis, splicing analysis upon depletion (nuclear speckle study); Co-IP with ZNRF3, DUB assay, Wnt reporter, intestinal organoid experiments (Wnt study)

    PMID:33731873 PMID:33786993

    Open questions at the time
    • Whether enzymatic activity is required for the splicing-regulatory role versus the structural/scaffolding role not fully separated
    • How USP42 partitions between nuclear speckles and the membrane-associated ZNRF3 pathway is unknown
    • In vivo consequences of USP42 loss on intestinal Wnt signalling in knockout animals not reported
  6. 2022 Medium

    Identification of TRIM21 as a USP42 substrate during viral infection, with a TRIM21–USP42 positive feedback loop, connected USP42 to innate antiviral immunity.

    Evidence Co-IP, DUB assay, miR-590-3p manipulation, siRNA knockdown in human microglial cells during JEV infection

    PMID:35779335

    Open questions at the time
    • Feedback loop mechanism (TRIM21 stabilizing USP42 independent of its RING domain) lacks detailed mechanistic explanation
    • Single pathogen system; generalizability to other viral infections untested
    • In vivo confirmation in animal infection models absent
  7. 2025 Medium

    Three recent studies broadened USP42's substrate repertoire and disease contexts: stabilization of PPARγ promotes liver regeneration, loss of USP42 impairs DNA repair in prostate cancer, and USP42 depletion activates JNK/p38-mediated apoptosis in breast cancer.

    Evidence Co-IP and DUB assays for PPARγ in hepatocytes with in vivo liver injury model; γ-H2AX/RNA-seq in prostate cancer cells with AR modulation; siRNA with pharmacological JNK/p38 inhibitor rescue and xenograft in breast cancer cells

    PMID:40091484 PMID:40718793 PMID:41120683

    Open questions at the time
    • AR-driven transcriptional regulation of USP42 lacks direct ChIP evidence
    • Whether anti-apoptotic effect is direct (specific substrate) or indirect (general proteostasis) is unresolved
    • PPARγ stabilization finding from single lab; independent replication needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for USP42's substrate recognition, its ubiquitin chain-type selectivity, how nucleocytoplasmic partitioning determines substrate access, and whether its phase-separation and catalytic functions are independently regulated.
  • No crystal or cryo-EM structure of USP42 or any substrate complex
  • Ubiquitin linkage specificity (K48, K63, etc.) systematically untested
  • No genetic knockout mouse model characterizing organismal phenotype

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 6 GO:0140096 catalytic activity, acting on a protein 6 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-162582 Signal Transduction 2 R-HSA-4839726 Chromatin organization 1 R-HSA-5357801 Programmed Cell Death 1 R-HSA-73894 DNA Repair 1 R-HSA-8953854 Metabolism of RNA 1
Partners
DHX9H2BC1PLRG1PPARGTP53TRIM21ZNRF3

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 USP42 forms a direct complex with p53, deubiquitinates p53, and controls the level of p53 ubiquitination during the early phase of the stress response, enabling rapid activation of p53-dependent transcription and p53-dependent cell-cycle arrest. Co-immunoprecipitation, deubiquitination assay, loss-of-function (siRNA knockdown) with p53 transcription and cell-cycle arrest readouts The EMBO journal High 22085928
2014 USP42 co-localizes with RNA Polymerase II in nuclear foci, directly binds histone H2B, and deubiquitylates H2B; depletion of USP42 increases H2B ubiquitylation at model promoters and decreases basal and induced transcription from multiple promoters. Co-localization imaging, Co-immunoprecipitation/pulldown, in vitro/in vivo deubiquitylation assay, ChIP, reporter transcription assays with USP42 depletion The Journal of biological chemistry High 25336640
2006 Mouse Usp42 protein contains conserved catalytic domains (Cys, Asp, His, Asn/Asp) characteristic of deubiquitinating enzymes and can cleave ubiquitin from ubiquitinated substrates both in vitro and in vivo. In vitro and in vivo deubiquitinating enzyme assay Gene expression patterns : GEP Medium 16904385
2021 USP42 localizes to SC35-positive nuclear speckles via its intrinsically disordered C-terminal domain (in a positively charged residue- and enzymatic activity-dependent manner), undergoes liquid-liquid phase separation, directs integration of the spliceosome component PLRG1 into nuclear speckles, and its depletion disrupts SC35 foci conformation and deregulates multiple mRNA splicing events. Subcellular localization imaging, phase separation assays, domain deletion/mutagenesis, siRNA knockdown with RNA splicing readout, Co-immunoprecipitation Cell death and differentiation High 33731873
2021 USP42 binds to the Dishevelled interacting region (DIR) of ZNRF3, deubiquitinates ZNRF3, stalls the R-spondin-LGR4-ZNRF3 ternary complex, thereby preventing R-spondin-dependent membrane clearance of ZNRF3/RNF43 and inhibiting Wnt signalling; USP42 consequently increases turnover of LRP6 and Frizzled receptors. Co-immunoprecipitation, deubiquitination assay, cell-surface receptor turnover assays, Wnt reporter assays, small intestinal organoid experiments, siRNA knockdown EMBO reports High 33786993
2020 USP42 localizes to nuclear speckles, promotes homologous recombination by facilitating BRCA1 recruitment to DSB sites and DNA-end resection; it interacts with the DNA-RNA helicase DHX9 and is required for efficient resolution of DSB-induced R-loops. siRNA screen, Co-immunoprecipitation, immunofluorescence localization, HR reporter assay, BRCA1 recruitment/resection assay, R-loop detection (DRIP assay) Oncogenesis High 32541651
2022 USP42 stabilizes TRIM21 by deubiquitinating it; increased USP42 (driven by suppression of miR-590-3p during JEV infection) maintains elevated levels of both TRIM21 and OAS1 in human microglial cells; TRIM21 in turn increases USP42 levels in a positive feedback loop independently of its RING domain. miRNA overexpression/inhibition, Co-immunoprecipitation, deubiquitination assay, siRNA knockdown, in vitro and in vivo experiments Virology Medium 35779335
2025 USP42 interacts with, deubiquitinates, and stabilizes PPARγ in hepatocytes; FGF2 signalling induces USP42 expression and enhances the USP42-PPARγ interaction, leading to increased PPARγ-target gene expression, protection from oxidative injury, and promotion of liver regeneration. Co-immunoprecipitation, deubiquitination assay, protein stability assay, siRNA/overexpression, PPARγ target gene expression analysis, in vivo CCl4 liver injury model Advanced science Medium 40091484
2025 USP42 knockdown in prostate cancer cells induces significant defects in DNA damage repair, and the androgen receptor (AR) positively regulates USP42 mRNA and protein expression. siRNA knockdown, γ-H2AX detection (DNA damage marker), RNA-seq/proteomics, AR modulation experiments, in vivo xenograft model Frontiers in molecular biosciences Low 40718793
2025 USP42 knockdown in breast cancer cells activates the JNK/p38 MAPK pathway, upregulates caspase-3 and Bax, downregulates Bcl-2, and increases apoptosis; JNK and p38 inhibitors rescue the apoptotic phenotype caused by USP42 silencing, placing USP42 upstream of the JNK/p38 pathway as a suppressor of apoptosis. siRNA knockdown, flow cytometry (apoptosis), Western blot (apoptotic and signaling proteins), pharmacological rescue with JNK/p38 inhibitors, in vivo xenograft Scientific reports Medium 41120683

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Regulation of p53 stability and function by the deubiquitinating enzyme USP42. The EMBO journal 93 22085928
2006 A novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquitin-specific protease gene USP42. Leukemia 62 16357831
2021 USP42 drives nuclear speckle mRNA splicing via directing dynamic phase separation to promote tumorigenesis. Cell death and differentiation 54 33731873
2021 USP42 protects ZNRF3/RNF43 from R-spondin-dependent clearance and inhibits Wnt signalling. EMBO reports 43 33786993
2014 Ubiquitin-specific peptidase 42 (USP42) functions to deubiquitylate histones and regulate transcriptional activity. The Journal of biological chemistry 38 25336640
2020 USP42 enhances homologous recombination repair by promoting R-loop resolution with a DNA-RNA helicase DHX9. Oncogenesis 32 32541651
2006 The expression of Usp42 during embryogenesis and spermatogenesis in mouse. Gene expression patterns : GEP 27 16904385
2022 Japanese Encephalitis Virus infection increases USP42 to stabilize TRIM21 and OAS1 for neuroinflammatory and anti-viral response in human microglia. Virology 12 35779335
2014 5'RUNX1-3'USP42 chimeric gene in acute myeloid leukemia can occur through an insertion mechanism rather than translocation and may be mediated by genomic segmental duplications. Molecular cytogenetics 10 25298786
2025 FGF2 Mediated USP42-PPARγ Axis Activation Ameliorates Liver Oxidative Damage and Promotes Regeneration. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 5 40091484
2024 Investigating USP42 Mutation as Underlying Cause of Familial Non-Medullary Thyroid Carcinoma. International journal of molecular sciences 2 38338801
2025 Targeting USP42 induces DNA damage and inhibits cell growth in prostate cancer. Frontiers in molecular biosciences 0 40718793
2025 Deubiquitinating enzyme USP42 promotes breast cancer progression by inhibiting JNK/p38-mediated apoptosis. Scientific reports 0 41120683