USP42

USP42 is a deubiquitylating enzyme (DUB) that regulates diverse nuclear and signalling processes by removing ubiquitin from distinct substrate proteins (PMID:16904385). In the stress response it forms a direct complex with p53 and deubiquitinates it, enabling rapid p53-dependent transcription and cell-cycle arrest without affecting basal or fully activated p53 levels (PMID:22085928). Beyond p53, USP42 acts broadly on transcription: it binds and deubiquitinates histone H2B, co-localizes with RNA Polymerase II, and supports both basal and induced transcription from multiple promoters (PMID:25336640). It localizes to SC35-positive nuclear speckles through a positively charged, disordered C-terminal domain that confers liquid-liquid phase separation, and from this compartment it directs PLRG1 integration into speckles and proper mRNA splicing required for cancer cell growth (PMID:33731873); speckle localization also underlies a role in homologous recombination repair, where USP42 facilitates BRCA1 recruitment and DNA-end resection and partners with the helicase DHX9 to resolve double-strand-break-induced R-loops (PMID:32541651). At the plasma membrane USP42 binds the Dishevelled-interacting region of ZNRF3 and deubiquitinates it, stalling the R-spondin–LGR4–ZNRF3 ternary complex to protect ZNRF3/RNF43 and thereby antagonize Wnt signalling in colon cancer cells and intestinal organoids (PMID:33786993). USP42 additionally stabilizes substrates by deubiquitination in context-specific settings, including TRIM21 during viral infection (PMID:35779335) and PPARγ during liver regeneration (PMID:40091484).

1. 2006 Medium

   Establishing whether USP42 was a bona fide enzyme was the first prerequisite; this showed the protein carries the conserved DUB catalytic residues and can cleave ubiquitin from substrates.

   Evidence in vitro and in vivo deubiquitination assays on mouse Usp42

   PMID:16904385

   Open questions at the time

   • No substrate specificity defined
   • No active-site mutagenesis to confirm catalytic residues
   • Single lab
2. 2011 High

   Identifying the first physiological substrate, this work showed USP42 deubiquitinates p53 specifically during the early stress response, defining a role in timing rapid p53-dependent transcription and cell-cycle arrest.

   Evidence Co-IP, deubiquitination assays, and siRNA knockdown with p53 transcriptional and cell-cycle readouts

   PMID:22085928

   Open questions at the time

   • Does not control basal or fully activated p53 levels
   • Mechanism of stress-phase selectivity unclear
3. 2014 High

   Extending USP42 beyond p53, this established a direct chromatin role: it deubiquitinates histone H2B and supports transcription, indicating a p53-independent function in gene expression.

   Evidence Co-IP, deubiquitination assay, ChIP, transcription reporters, and IF co-localization with RNA Pol II

   PMID:25336640

   Open questions at the time

   • Promoter selectivity not defined
   • Link between H2B deubiquitination and Pol II co-localization not fully resolved
4. 2020 High

   This connected USP42 nuclear speckle localization to genome maintenance, showing it promotes homologous recombination via BRCA1 recruitment, end resection, and DHX9-dependent R-loop resolution at double-strand breaks.

   Evidence HR reporter assay, IF for BRCA1/resection markers, Co-IP with DHX9, and R-loop detection

   PMID:32541651

   Open questions at the time

   • Direct DUB substrate at break sites not identified
   • Whether DHX9 is a deubiquitination target unknown
5. 2021 High

   This defined the structural basis of USP42 nuclear compartmentalization, showing its disordered, charged C-terminus drives phase separation into SC35 speckles to direct PLRG1 integration and mRNA splicing.

   Evidence IF co-localization with SC35, phase separation assays, C-terminal mutagenesis, splicing profiling, and growth assays

   PMID:33731873

   Open questions at the time

   • Whether PLRG1 is a deubiquitination substrate not shown
   • Splicing targets not mapped
6. 2021 High

   This placed USP42 in Wnt receptor regulation, showing it binds the ZNRF3 DIR, deubiquitinates ZNRF3, and stalls the R-spondin ternary complex to antagonize paracrine Wnt signalling.

   Evidence Co-IP, deubiquitination assay, Wnt reporters, receptor turnover assays, and intestinal organoids

   PMID:33786993

   Open questions at the time

   • Plasma membrane vs nuclear pools not reconciled
   • Selectivity for ZNRF3 vs RNF43 not fully defined
7. 2022 Medium

   This added a substrate-stabilization role in innate immunity, showing USP42 deubiquitinates and stabilizes TRIM21 in a positive feedback loop during viral infection.

   Evidence Co-IP, deubiquitination assay, knockdown, and Western blot in microglial cells with JEV infection

   PMID:35779335

   Open questions at the time

   • Mechanism of the feedback loop not detailed
   • Single lab, limited mechanistic depth
8. 2025 Medium

   This identified PPARγ as a USP42 substrate in liver regeneration, showing USP42 stabilizes PPARγ to drive proliferative and antioxidative gene programs downstream of FGF2.

   Evidence Co-IP, deubiquitination assay, Western blot, knockdown/overexpression in hepatocytes, and CCl4 injury model

   PMID:40091484

   Open questions at the time

   • Ubiquitin linkage type on PPARγ not defined
   • FGF2-to-USP42 signalling axis not resolved
9. 2025 Medium

   This linked USP42 to androgen signalling and DNA repair in prostate cancer, showing AR drives USP42 expression and USP42 inhibition impairs DNA damage repair and sensitizes cells to olaparib.

   Evidence AR modulation, RNA-seq, proteomics, γ-H2A.X detection, and xenograft model

   PMID:40718793

   Open questions at the time

   • Direct DUB substrate in this DNA repair context not identified
   • Relationship to the HR/BRCA1 mechanism not integrated
10. 2025 Medium

    This positioned USP42 as a suppressor of stress-kinase apoptosis in breast cancer, showing its knockdown activates JNK/p38 and pro-apoptotic effectors with rescue by pathway inhibitors.

    Evidence siRNA knockdown, Western blot, flow cytometry, inhibitor rescue (SP600125/SB203580), and xenograft model

    PMID:41120683

    Open questions at the time

    • Direct substrate upstream of JNK/p38 not identified
    • Whether effect is catalytic-dependent untested

• How USP42's multiple substrate-specific functions are coordinated, and what ubiquitin-linkage selectivity and recruitment mechanisms govern each, remains unresolved.
• No structural model of substrate recognition
• Linkage specificity across substrates undefined
• How nuclear-speckle, chromatin, and membrane pools are partitioned is unknown