Affinage

BRCC3

Lys-63-specific deubiquitinase BRCC36 · UniProt P46736

Length
316 aa
Mass
36.1 kDa
Annotated
2026-06-09
58 papers in source corpus 33 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BRCC3 (BRCC36) is a K63-linked polyubiquitin chain-specific deubiquitinase that uses a JAMM/MPN+ zinc metalloprotease mechanism rather than an active-site cysteine, and it cleaves K63 chains exclusively, sparing K6-, K11-, K29-, K48-, and alpha-linked chains (PMID:19214193). Its activity is partitioned between two scaffold-defined multisubunit complexes that share the common subunits BRE and NBA1/MERIT40: the nuclear BRCA1-A complex, organized by the ABRAXAS scaffold together with RAP80, BRCA1/BARD1, and BRCC45, and the cytoplasmic BRISC complex, organized by the ABRO1/KIAA0157 scaffold (PMID:18077395, PMID:20656690, PMID:21282113). BRCC3 is catalytically inert as a homodimer and is allosterically switched to an active conformation by heterodimerization with the pseudo-DUB scaffolds, with a higher-order 'super-dimer' assembly required for full activity and for engaging targeting subunits such as SHMT2 and RAP80; the adaptor subunits diversify substrate targeting, with ABRAXAS providing a high-affinity BRCA1 site and SHMT2 acting as an inhibitory adaptor on BRISC (PMID:26344097, PMID:31253574). In the DNA damage response, the BRCA1-A complex is recruited to double-strand breaks through RAP80 UIM binding to RNF8/Ubc13-generated K63 chains, and BRCC3 hydrolase activity counterbalances RNF8 ligase activity to set steady-state ubiquitin levels, limit DSB end resection, and control BRCA1 focus formation and phosphorylation (PMID:18077395, PMID:19202061, PMID:16707425, PMID:27288411). Through the cytoplasmic BRISC complex, BRCC3 controls inflammatory and immune signaling by deubiquitinating NLRP3 to license inflammasome activation and by acting on IFNAR1 and STAT1 to sustain type I interferon antiviral responses (PMID:23246432, PMID:33857816, PMID:32673428, PMID:31576005). BRCC3 additionally deubiquitinates and stabilizes a broad set of cell-cycle and signaling substrates including tankyrase 1, ALK2, HMGCR, beta-catenin, and ZEB1, linking it to telomere cohesion, BMP/TGF-beta signaling, vascular calcification, and tumor cell behavior (PMID:27993934, PMID:38557054, PMID:38178583, PMID:39227917, PMID:38449391).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2006 Medium

    Established that BRCC36 is required for the BRCA1 DNA-damage response, the first cellular function assigned to the protein.

    Evidence siRNA knockdown in breast cancer lines with BRCA1/gamma-H2AX foci, phosphorylation, and apoptosis readouts

    PMID:16707425

    Open questions at the time
    • Did not define BRCC36 enzymatic activity or substrate
    • Mechanism of BRCA1 regulation not resolved at molecular level
  2. 2007 High

    Defined BRCC36 as a subunit of the BRCA1-A complex and mapped how the complex is recruited to DSBs, placing BRCC36 downstream of RNF8/Ubc13 K63 ubiquitin marks.

    Evidence Co-IP, coiled-coil domain mapping, and RNAi of RNF8/Ubc13 with foci assays

    PMID:18077395

    Open questions at the time
    • Catalytic role of BRCC36 within the complex not demonstrated
    • Did not establish linkage specificity of any DUB activity
  3. 2009 High

    Identified BRCC36 as the catalytic K63-specific JAMM/MPN+ DUB of the BRISC complex and showed it opposes RNF8-driven ubiquitination at DSBs, unifying its enzymatic identity with its DDR role.

    Evidence Multistep biochemical fractionation with linkage-specific DUB assays; catalytic-mutant epistasis with RNF8 depletion and IR sensitivity

    PMID:19202061 PMID:19214193

    Open questions at the time
    • Structural basis of activation not known
    • Full substrate repertoire at chromatin undefined
  4. 2010 High

    Showed BRCC36 partitions into two scaffold-defined complexes (nuclear ABRAXAS, cytoplasmic KIAA0157/ABRO1) in dynamic balance, explaining how one DUB serves distinct compartments.

    Evidence Co-IP, subcellular fractionation, siRNA, and in vitro DUB assay on K63-diUb-H2A substrate

    PMID:20656690

    Open questions at the time
    • Mechanism of complex switching not defined
    • How scaffolds regulate activity unresolved
  5. 2011 High

    Established BRE and NBA1/MERIT40 as shared subunits whose interaction maintains integrity of both complexes and is required for IR resistance and BRCA1 recruitment.

    Evidence Reciprocal Co-IP, domain mapping, clonogenic survival, and immunofluorescence

    PMID:21282113

    Open questions at the time
    • Did not address cytoplasmic BRISC function
    • Contribution of these subunits to catalysis unknown
  6. 2011 Medium

    Demonstrated an in vivo developmental requirement by showing BRCC3 loss causes angiogenesis defects rescuable by endothelial expression.

    Evidence Zebrafish morpholino knockdown with tissue-specific rescue and vascular imaging

    PMID:21596366

    Open questions at the time
    • Molecular substrate driving angiogenesis phenotype not identified
    • Relationship to DUB activity not tested
  7. 2012 High

    Identified NLRP3 as a BRISC substrate and BRCC3 as a positive regulator of inflammasome activation, opening its inflammatory signaling role.

    Evidence Pharmacological DUB inhibition, siRNA, ubiquitination and caspase-1/IL-1beta assays

    PMID:23246432

    Open questions at the time
    • Specific ubiquitin chains on NLRP3 not fully mapped
    • Cellular triggers coupling BRISC to NLRP3 not defined here
  8. 2015 High

    Resolved the structural basis of activation, showing BRCC36 is inactive as a homodimer, activated by heterodimerization with the pseudo-DUB KIAA0157, and requires a super-dimer for full activity and targeting-subunit binding.

    Evidence X-ray crystallography, DUB assays, interface mutagenesis, SEC/AUC, and pulldowns

    PMID:26344097

    Open questions at the time
    • Did not capture substrate-bound state
    • Regulation of homodimer-to-heterodimer transition in cells unclear
  9. 2016 High

    Refined the DDR role by showing BRCC36 catalytic activity limits DSB end resection and BRCA1-A accumulation independently of complex integrity, and identified tankyrase 1 as a cell-cycle-regulated BRISC substrate at telomeres.

    Evidence RNAi/CRISPR catalytic inactivation with resection assays; Co-IP, cell-cycle-staged ubiquitination, and telomere FISH

    PMID:27288411 PMID:27993934

    Open questions at the time
    • How catalytic activity selectively limits resection mechanistically unclear
    • Crosstalk between RNF8 and BRISC at telomeres not fully resolved
  10. 2019 High

    Provided high-resolution structures of both complexes, revealing ABRAXAS sequesters BRCA1 away from DSBs and SHMT2 acts as an inhibitory adaptor on BRISC, explaining adaptor-driven functional diversification.

    Evidence Cryo-EM and X-ray crystallography with in vitro DUB and binding assays and mutagenesis

    PMID:31253574

    Open questions at the time
    • In vivo control of SHMT2 inhibition not defined
    • Substrate engagement geometry not captured
  11. 2019 Medium

    Linked BRCC3 DUB function to leukemia by showing t(8;21) AML mutations abrogate its activity on IFNAR1 and inflammasome function, with loss promoting self-renewal.

    Evidence CRISPR inactivation, IFNAR1 DUB activity assays, colony-forming and cytokine readouts

    PMID:31576005

    Open questions at the time
    • Causal role in leukemogenesis vs. correlation not fully established
    • Substrate hierarchy in AML cells unresolved
  12. 2020 Medium

    Showed BRCC36 is stabilized by ABRO1 competing with the E3 ligase WWP2, and maintains STAT1 noncatalytically via USP13, expanding regulation of and by BRCC36 in antiviral immunity.

    Evidence Competition Co-IP, ubiquitination and degradation assays; STAT1 stability and viral challenge in BRCC36-deficient mice

    PMID:32673428 PMID:33107021

    Open questions at the time
    • Noncatalytic scaffolding role mechanistically distinct from DUB activity, not structurally defined
    • In vivo relevance of WWP2 axis incomplete
  13. 2021 Medium

    Expanded the substrate and disease landscape by linking BRCC36 to FLT3-ITD K63-ubiquitination in AML and to ICP0-driven degradation of BRCC36 during HSV-1 infection.

    Evidence Proximity labeling, K63-ubiquitination and site mutagenesis, STAT5 readouts; viral infection Co-IP with IFNAR1 readout

    PMID:33857816 PMID:38288901

    Open questions at the time
    • Whether BRCC36 cleaves vs. reads FLT3-ITD ubiquitin not fully resolved
    • Generality of viral targeting of BRCC36 unknown
  14. 2023 High

    Connected BRCC3-NLRP3 deubiquitination to a defined upstream pathway (TET2 loss -> JNK1) in clonal-hematopoiesis-accelerated atherosclerosis, with pharmacological and genetic inhibition reversing disease.

    Evidence Isogenic TET2-deficient macrophages, NLRP3 ubiquitylation assays, Tet2 CH mouse model, ABRO1 hematopoietic KO, holomycin inhibition

    PMID:37781816

    Open questions at the time
    • Direct molecular link from JNK1 to BRCC3 activity not fully defined
    • Human therapeutic translation untested
  15. 2024 Medium

    Broadened the catalytic substrate repertoire and disease links by identifying ALK2, HMGCR, beta-catenin, ZEB1, CRBN, and MET as BRCC3 substrates across vascular, metabolic, and cancer contexts.

    Evidence Co-IP, K63-specific ubiquitination and site mutagenesis assays, catalytic-mutant controls, reporter assays, and mouse models

    PMID:38178583 PMID:38449391 PMID:38470543 PMID:38557054 PMID:39136771 PMID:39227917

    Open questions at the time
    • Many substrates rest on single-lab Co-IP without structural validation
    • Whether targeting occurs via BRISC, BRCA1-A, or other assemblies not always defined
  16. 2024 High

    Demonstrated selective pharmacological control of BRISC, providing proof-of-concept that BRCC36 can be inhibited within one complex without affecting the other.

    Evidence Cryo-EM of molecular-glue-stabilized autoinhibited BRISC dimer, DUB and IFNAR1 ubiquitylation assays, inhibitor-resistant mutant validation (preprint)

    Open questions at the time
    • Peer review pending
    • Selectivity and efficacy in vivo not yet established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BRCC3 substrate selection is governed across its many reported targets — which assembly, adaptor, and targeting subunit route each substrate to the catalytic core in vivo — remains unresolved.
  • No unifying substrate-recruitment model linking the diverse reported substrates
  • Most newer substrates rest on single-lab Co-IP without reciprocal or structural validation
  • Catalytic vs. noncatalytic scaffolding contributions not systematically separated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 9 GO:0140096 catalytic activity, acting on a protein 3 GO:0016787 hydrolase activity 2
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3 GO:0005829 cytosol 3
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 4 R-HSA-73894 DNA Repair 4 R-HSA-8953854 Metabolism of RNA 3
Partners
ABRAXASABRO1BRCA1BREMERIT40RAP80SHMT2USP13
Complex memberships
BRCA1-A complexBRISC complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 BRCC36 (BRCC3) is the catalytic subunit of the BRISC complex and exhibits K63-linked polyubiquitin chain-specific deubiquitinating (DUB) activity; it lacks an active-site cysteine and instead uses a JAMM/MPN+ zinc metalloprotease mechanism. The K63-specific DUB activity is intrinsic to the BRISC complex and does not cleave K6, K11, K29, K48, or alpha-linked chains. Biochemical fractionation through seven chromatographic steps; fluorometric DUB assays with linkage-specific ubiquitin substrates; NEM/ubiquitin-aldehyde insensitivity tests The EMBO journal High 19214193
2007 BRCC36 (BRCC3) is a component of the BRCA1-A complex (also containing BRCA1/BARD1, ABRAXAS/CCDC98, RAP80, BRCC45/BRE, MERIT40). BRCC36 associates with ABRAXAS via coiled-coil domains on each protein, and RAP80 contains an Abraxas-interacting region (AIR) required for association of RAP80 with ABRAXAS, BRCA1, and BRCC36. The entire complex is recruited to DNA double-strand break (DSB) foci through RAP80 UIM-domain binding to RNF8/Ubc13-generated K63-linked polyubiquitin chains. Co-immunoprecipitation; domain mapping; RNAi knockdown of RNF8/Ubc13 with immunofluorescence foci assays Proceedings of the National Academy of Sciences of the United States of America High 18077395
2009 The RAP80-BRCC36 complex opposes RNF8-Ubc13-dependent ubiquitination at DSBs. BRCC36 knockdown or expression of a DUB-inactive BRCC36 mutant rescued 53BP1 recruitment and γ-H2AX ubiquitination following RNF8 depletion, demonstrating that BRCC36 hydrolase activity counterbalances RNF8 ubiquitin ligase activity to set steady-state ubiquitin levels at DSBs. siRNA knockdown; DUB-inactive mutant expression; immunofluorescence; ionizing radiation sensitivity assays Proceedings of the National Academy of Sciences of the United States of America High 19202061
2010 BRCC36 exists in two distinct subcellular complexes determined by two scaffold proteins: nuclear ABRAXAS/CCDC98 (within the BRCA1-A complex) and cytoplasmic KIAA0157 (ABRO1, within BRISC). ABRAXAS and KIAA0157 each regulate BRCC36 DUB activity. Reduction of KIAA0157 increases the BRCA1-A complex in the nucleus, indicating the two complexes are in dynamic balance. BRCC36 reduces K63-linked ubiquitin chains at chromatin and deubiquitinates diubiquitinated histone H2A. Co-immunoprecipitation; subcellular fractionation; siRNA knockdown; in vitro DUB assays with K63-linked diubiquitin-H2A substrate The Journal of biological chemistry High 20656690
2011 Both the nuclear BRCA1-A (ABRAXAS-containing) and cytoplasmic BRISC (ABRO1-containing) complexes share the common subunits BRE and NBA1/MERIT40. NBA1 and BRE interact through a C-terminal conserved motif of NBA1 and the C-terminal UEV domain of BRE; this interaction is essential for maintaining the integrity of both complexes and for cellular resistance to ionizing radiation and BRCA1 recruitment to DSBs. Co-immunoprecipitation; domain deletion/mutation mapping; siRNA knockdown; clonogenic survival assays; immunofluorescence The Journal of biological chemistry High 21282113
2012 BRCC3 (BRCC36) deubiquitinates NLRP3 and acts as a critical positive regulator of NLRP3 inflammasome activation. NLRP3 is a substrate of the cytosolic BRISC complex containing BRCC3. Pharmacological and siRNA-mediated inhibition of BRCC3 DUB activity suppresses NLRP3 inflammasome activation. Pharmacological DUB inhibition; siRNA knockdown; ubiquitination assays; caspase-1 and IL-1β activity assays Molecular cell High 23246432
2006 BRCC36 (BRCC3) regulates BRCA1 activation in response to DNA damage: knockdown of BRCC36 disrupts ionizing radiation-induced BRCA1 phosphorylation and prevents formation of BRCA1 nuclear foci at DSBs, sensitizing breast cancer cells to IR-induced apoptosis. BRCC36 regulates ubiquitin E3 ligase activity of the BRCC complex. siRNA knockdown in MCF-7, ZR-75-1, T47D cells; immunoblot; immunofluorescence of BRCA1 and γ-H2AX foci; apoptosis assays Cancer research Medium 16707425
2011 Loss of BRCC3 function in zebrafish (brcc3 morphants) causes angiogenesis defects that are rescued by endothelium-specific expression of brcc3, establishing BRCC3 as an essential regulator of angiogenesis in vivo. Morpholino knockdown in zebrafish; rescue by endothelium-specific BRCC3 expression; vascular imaging American journal of human genetics Medium 21596366
2015 Structural characterization of the BRCC36-KIAA0157 (ABRO1) heterodimer reveals BRCC36 is activated by contacts with the pseudo-DUB KIAA0157 (MPN− domain). An inactive BRCC36 homodimer exists; heterodimerization with KIAA0157 switches BRCC36 to an active conformation. Furthermore, a higher-order dimer-of-heterodimers ('super-dimer') assembly is required for full DUB activity and for interactions with targeting proteins SHMT2 and RAP80. X-ray crystallography; in vitro DUB activity assays; mutagenesis of interface residues; size-exclusion chromatography/analytical ultracentrifugation; pulldown assays Molecular cell High 26344097
2016 BRCC36 DUB activity within the BRCA1-A complex limits DSB end resection and DNA repair. Inactivation of BRCC36 DUB (via RNAi or CRISPR editing) attenuated BRCA1-A complex accumulation at DSBs and led to unrestrained DSB end resection and hyperactive DNA repair, while the structural integrity of the complex was maintained. RNAi; CRISPR/Cas9 genome editing; catalytic mutant expression; end resection assays; BRCA1-A foci quantification The Journal of biological chemistry High 27288411
2016 The BRISC complex (ABRO1/BRCC36) removes K63-linked ubiquitin chains from tankyrase 1 in G1 phase, while RNF8 adds K63-linked ubiquitin chains in late S/G2. This ubiquitination/deubiquitination cycle controls tankyrase 1 stabilization, telomere association, and resolution of sister telomere cohesion in a cell cycle-regulated manner. Co-immunoprecipitation; ubiquitination assays; cell cycle synchronization; telomere FISH; siRNA knockdown of ABRO1/BRCC36 The EMBO journal High 27993934
2019 Crystal/cryo-EM structures of the BRCA1-A and BRISC complexes reveal: (1) In BRCA1-A, ABRAXAS integrates RAP80 and provides a high-affinity BRCA1-binding site that sequesters BRCA1 away from DSBs. (2) In BRISC, ABRO1 binds the metabolic enzyme SHMT2α, which in this context prevents BRCC36 from binding and cleaving ubiquitin chains (inhibitory regulation). Different adaptor subunits thus confer diversified targeting and regulatory functions on the same BRCC36 catalytic subunit. Cryo-EM and X-ray crystallography; in vitro DUB activity assays; binding assays; mutagenesis Molecular cell High 31253574
2018 SHMT2 acts as a regulatory adaptor in the BRISC complex: SHMT2 and BRCC36 (via BRISC) regulate HIV-1 Tat K63-ubiquitylation. Knockdown of SHMT1/2 or BRCC36 strongly increased K63-Ub-dependent autophagic destruction of Tat; point mutation of multiple lysines in Tat or knockdown of BRCC36/SHMT1,2 prevented JIB-04-induced Tat destruction. Proximity proteomics (DiffPOP); mass spectrometry; siRNA knockdown; Tat ubiquitination assays; autophagy flux assays; site-directed mutagenesis of Tat lysines PLoS pathogens Medium 29791506
2019 Vitamin D receptor (VDR) physically binds NLRP3 and blocks the association of NLRP3 with BRCC3, thereby preventing BRCC3-mediated deubiquitination and subsequent NLRP3 activation. VDR thus acts as a negative regulator of NLRP3 by competing with BRCC3 for NLRP3 binding. Co-immunoprecipitation; ubiquitination assays; VDR knockout mice; IL-1β/caspase-1 activation assays Frontiers in immunology Medium 31866999
2020 ABRO1 stabilizes BRCC3 protein by competing with the HECT-type E3 ubiquitin ligase WWP2 for binding to BRCC3, thereby preventing WWP2-mediated K48-linked ubiquitination and proteasomal degradation of BRCC3. WWP2 overexpression in macrophages inhibits NLRP3 inflammasome activation by reducing BRCC3 levels. Co-immunoprecipitation; ubiquitination assays; cycloheximide chase; siRNA/lentiviral overexpression; caspase-1 and IL-1β assays FEBS letters Medium 33107021
2021 BRCC36 (BRCC3) specifically associates with FLT3-ITD (but not wild-type FLT3 or FLT3-TKD) through K63-linked polyubiquitination at K609 of the ITD mutant. BRCC36 knockdown decreases STAT5 phosphorylation and cell proliferation in FLT3-ITD AML cells. Proximity labeling (TurboID); K63-ubiquitination assays; site-directed mutagenesis (K609R); siRNA knockdown; phospho-STAT5 immunoblot; cell proliferation assays Cancer science Medium 38288901
2021 HSV-1-encoded ICP0 induces K48-linked polyubiquitination and proteasomal degradation of BRCC36, leading to downmodulation of IFN-I receptor IFNAR1 and suppression of the host type I interferon antiviral response. Co-immunoprecipitation; ubiquitination assays; viral infection time-courses; immunoblot; IFNAR1 surface level measurement Molecular immunology Medium 33857816
2020 BRCC36 maintains STAT1 protein stability noncatalytically by recruiting USP13 to form a complex that antagonizes Smurf1-mediated STAT1 degradation. BRCC36 deficiency causes rapid STAT1 downregulation during viral infection, impairing antiviral immunity in vivo. Co-immunoprecipitation; STAT1 stability assays; viral challenge in BRCC36-deficient mice; USP13/Smurf1 epistasis experiments European journal of immunology Medium 32673428
2023 In TET2-deficient macrophages, increased JNK1 signaling (due to hypermethylation and decreased expression of the phosphatase DUSP10) promotes BRCC3-mediated NLRP3 deubiquitylation and inflammasome activation, accelerating atherosclerosis. The BRCC3 inhibitor holomycin or hematopoietic deficiency of ABRO1 (essential BRISC scaffolding protein) reversed accelerated atherosclerosis and NETosis in Tet2 CH mice. Cholesterol-loaded TET2-deficient macrophages (murine and human ESC-derived isogenic); JNK1 phosphorylation assays; NLRP3 ubiquitylation assays; Tet2 CH mouse atherosclerosis model; ABRO1 hematopoietic KO; holomycin pharmacological inhibition Circulation High 37781816
2019 BRCC3 mutations in AML with t(8;21) abrogate its DUB activity on IFNAR1, resulting in impaired interferon response, and also diminish inflammasome activity. BRCC3 inactivation by CRISPR/Cas9 in t(8;21) AML cell lines improved proliferation and, combined with AML1-ETO, induced unlimited self-renewal of mouse hematopoietic progenitors. CRISPR/Cas9 inactivation; DUB activity assays on IFNAR1 substrate; interferon response assays; colony-forming assays; cytokine profiling Leukemia Medium 31576005
2024 BRCC36 deubiquitinates HMGCR in a DUB-activity-dependent manner, stabilizing HMGCR and suppressing ferroptosis while promoting pyroptosis in hepatocellular carcinoma cells. Co-immunoprecipitation; ubiquitination assays; DUB-inactive mutant; cell death assays (ferroptosis/pyroptosis markers); in vivo xenograft model with thiolutin (BRCC36 inhibitor) Advanced science Medium 38178583
2024 BRCC3 deubiquitinates ALK2 at Lys-472 and Lys-475 (K63-linked), activating receptor-regulated Smad1/5/9 and transcriptional activation of BMP-regulated PPARγ, p53, and Id1. BRCC3 also attenuates TGF-β signaling by downregulating TGF-β expression and inhibiting Smad3 phosphorylation. Smooth muscle cell-specific BRCC3 transgenic mice are protected from experimental pulmonary hypertension, while Brcc3−/− mice show increased susceptibility. Bioinformatic ubiquitination site prediction; site-directed mutagenesis (K472/475R ALK2); Co-immunoprecipitation; ubiquitination assays; SM22α-BRCC3-Tg and Brcc3−/− mouse models; pulmonary hemodynamics Circulation High 38557054
2022 BRCC36 binds β-catenin and inhibits its phosphorylation; BRCC36 overexpression reduces phosphorylated β-catenin levels in the nucleus and calcium deposition in VSMCs, negatively regulating the Wnt/β-catenin pathway to prevent vascular calcification. Co-immunoprecipitation; immunofluorescence; Alizarin red staining; calcium content assays; overexpression/knockdown in VSMCs and CKD mouse model Experimental cell research Medium 35149088
2024 BRCC36 inhibits the Wnt/β-catenin pathway by specifically decreasing K63-linked ubiquitination of β-catenin, attenuating osteogenic differentiation of VSMCs and vascular calcification. This was confirmed by TOPFlash luciferase reporter assay and rescue experiments. Co-immunoprecipitation; K63-specific ubiquitination assays; TOPFlash luciferase reporter; VSMC-specific overexpression/knockdown; CKD mouse model Journal of translational medicine Medium 39227917
2024 BRCC36 in the BRISC complex protects cereblon (CRBN) from lysosomal degradation by specifically cleaving K63-linked polyubiquitin chains on CRBN. SHIN1, which binds SHMT2 (a BRISC subunit), upregulates CRBN by activating BRCC36 in this context. TurboID proximity labeling; quantitative proteomics; Co-immunoprecipitation; K63-specific ubiquitination assays; lysosomal degradation assays; cell viability assays Cellular and molecular life sciences : CMLS Medium 39136771
2023 BRCC3 interacts with TAZ (WWTR1) and the cytoplasmic BRCA1 complex controls TAZ ubiquitination and stability. Loss of BRCC3 or BRCA1 leads to increased TAZ levels and transcriptional activity, linking BRCA1 complex inactivation to TAZ oncogene activation. siRNA screen; Co-immunoprecipitation; ubiquitination assays; TAZ reporter assays; loss-of-function genetic approaches Cells Low 37887275
2019 Cyclin-dependent kinase 5 (Cdk5) increases BRCC3 expression levels in a PD cell model; Cdk5 and BRCC3 physically interact (confirmed by co-immunoprecipitation); inhibition of Cdk5 reduces BRCC3 expression and downstream NLRP3 inflammasome activation. Co-immunoprecipitation; shRNA lentiviral knockdown; pharmacological Cdk5 inhibition; caspase-1 and IL-1β assays Biochemical and biophysical research communications Low 31787240
2022 Cdk5 phosphorylates BRCC3 in vitro; multiple phosphorylation sites were predicted and confirmed by in vitro kinase assay, western blotting, and mass spectrometry using purified His-BRCC3 fusion protein. In vitro kinase assay; mass spectrometry; western blotting with phospho-specific detection; recombinant protein purification Bulletin of experimental biology and medicine Medium 35503584
2022 TRIM14 recruits USP14 and BRCC3 to form a regulatory complex (TRIM14-USP14-BRCC3) that inhibits OPTN-mediated autophagic degradation of the histone demethylase KDM4D, thereby epigenetically promoting inflammatory gene expression. Co-immunoprecipitation; autophagy flux assays; inflammatory gene expression readouts (described in brief communication format) Autophagy Low 35311471
2024 BRCC3 deubiquitinates and stabilizes ZEB1 (an EMT transcription factor) in triple-negative breast cancer cells; BRCC3 physically interacts with ZEB1 and reduces its ubiquitination, increasing ZEB1 protein stability and promoting EMT, proliferation, migration, invasion, and metastasis. Co-immunoprecipitation; ubiquitination assays; protein stability assays (cycloheximide chase implied); siRNA knockdown; in vivo TNBC mouse model Acta biochimica et biophysica Sinica Medium 38449391
2024 BRCC3 promotes NF-κB signaling in dental pulp cells by expediting IκBα phosphorylation and degradation and p65 nuclear translocation; conditional knockout of Brcc3 in mouse dental pulp cells reduces IL-6, immune cell recruitment, and pulp necrosis after pulp exposure. RNA-sequencing; dual luciferase reporter assay; immunofluorescence; western blot; conditional Brcc3 knockout mice; pulpitis histology Biochimica et biophysica acta. Molecular basis of disease Medium 39880291
2024 BRCC3 (BRCC36) deubiquitinates MET receptor in colon adenocarcinoma cells, stabilizing MET protein and promoting migration, invasion, and EMT; overexpression of MET reverses the effects of BRCC3 knockdown. Co-immunoprecipitation; ubiquitination assays; shRNA knockdown; rescue with MET overexpression; migration/invasion assays Genes & genomics Low 38470543
2024 BRCC36 promotes BRCC3 stability by activating the BRCC36-BRG1-mTOR signaling axis in mammary epithelial cells: BRCC36 binds BRG1, inhibits BRG1 protein level and BRG1 binding to the mTOR promoter, thereby suppressing mTOR gene transcription and protein phosphorylation. Methionine decreases BRCC36 protein via ubiquitin-proteasome degradation, thereby relieving suppression of this axis. Co-immunoprecipitation; chromatin immunoprecipitation (BRG1 on mTOR promoter); BRCC36 knockdown/overexpression; MG132/cycloheximide/chloroquine treatment; ubiquitination assays Journal of agricultural and food chemistry Medium 38240727
2024 Molecular glues ('BLUEs') stabilize a 16-subunit BRISC dimer in an autoinhibited conformation, blocking BRCC36 active sites and interactions with the SHMT2 targeting subunit, resulting in selective inhibition of BRISC (K63-linked DUB activity on IFNAR1) without affecting the BRCA1-A complex or other JAMM/MPN DUBs. BLUEs increased IFNAR1 K63-ubiquitylation and decreased IFNAR1 surface levels, reducing interferon-stimulated gene expression. Cryo-EM structural determination; in vitro DUB activity assays; mutagenesis of inhibitor-binding interface; IFNAR1 ubiquitylation assays; ISG expression in cells with WT vs. inhibitor-resistant BRISC bioRxivpreprint High

Source papers

Stage 0 corpus · 58 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Molecular cell 588 23246432
2007 Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage. Proceedings of the National Academy of Sciences of the United States of America 357 18077395
2009 K63-specific deubiquitination by two JAMM/MPN+ complexes: BRISC-associated Brcc36 and proteasomal Poh1. The EMBO journal 194 19214193
2009 The Rap80-BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-dependent ubiquitination events at DNA double strand breaks. Proceedings of the National Academy of Sciences of the United States of America 184 19202061
2010 The Lys63-specific deubiquitinating enzyme BRCC36 is regulated by two scaffold proteins localizing in different subcellular compartments. The Journal of biological chemistry 103 20656690
2017 Mitochondrial DNA oxidation induces imbalanced activity of NLRP3/NLRP6 inflammasomes by activation of caspase-8 and BRCC36 in dry eye. Journal of autoimmunity 97 28238526
2011 Loss of BRCC3 deubiquitinating enzyme leads to abnormal angiogenesis and is associated with syndromic moyamoya. American journal of human genetics 96 21596366
2019 Vitamin D Receptor Inhibits NLRP3 Activation by Impeding Its BRCC3-Mediated Deubiquitination. Frontiers in immunology 95 31866999
2023 BRCC3-Mediated NLRP3 Deubiquitylation Promotes Inflammasome Activation and Atherosclerosis in Tet2 Clonal Hematopoiesis. Circulation 70 37781816
2018 LncRNA ANRIL promotes NLRP3 inflammasome activation in uric acid nephropathy through miR-122-5p/BRCC3 axis. Biochimie 68 30347231
2006 BRCC36 is essential for ionizing radiation-induced BRCA1 phosphorylation and nuclear foci formation. Cancer research 67 16707425
2019 Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation. Molecular cell 65 31253574
2011 NBA1/MERIT40 and BRE interaction is required for the integrity of two distinct deubiquitinating enzyme BRCC36-containing complexes. The Journal of biological chemistry 62 21282113
2015 Higher-Order Assembly of BRCC36-KIAA0157 Is Required for DUB Activity and Biological Function. Molecular cell 53 26344097
2007 Expression of BRCC3, a novel cell cycle regulated molecule, is associated with increased phospho-ERK and cell proliferation. International journal of molecular medicine 44 17143545
2018 SHMT2 and the BRCC36/BRISC deubiquitinase regulate HIV-1 Tat K63-ubiquitylation and destruction by autophagy. PLoS pathogens 43 29791506
2016 The Lys63-deubiquitylating Enzyme BRCC36 Limits DNA Break Processing and Repair. The Journal of biological chemistry 40 27288411
2024 BRCC36 Deubiquitinates HMGCR to Regulate the Interplay Between Ferroptosis and Pyroptosis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 39 38178583
2021 Long noncoding RNA TMPO-AS1/miR-126-5p/BRCC3 axis accelerates gastric cancer progression and angiogenesis via activating PI3K/Akt/mTOR pathway. Journal of gastroenterology and hepatology 39 33295056
2023 miR-369-3p Modulates Intestinal Inflammatory Response via BRCC3/NLRP3 Inflammasome Axis. Cells 34 37681916
2019 Regulation of oxidized LDL-induced inflammatory process through NLRP3 inflammasome activation by the deubiquitinating enzyme BRCC36. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 33 31485755
2016 Cell cycle-regulated ubiquitination of tankyrase 1 by RNF8 and ABRO1/BRCC36 controls the timing of sister telomere resolution. The EMBO journal 33 27993934
2019 The BRCC3 regulated by Cdk5 promotes the activation of neuronal NLRP3 inflammasome in Parkinson's disease models. Biochemical and biophysical research communications 30 31787240
2024 BRCC3 Regulation of ALK2 in Vascular Smooth Muscle Cells: Implication in Pulmonary Hypertension. Circulation 28 38557054
2015 BRCC3 mutations in myeloid neoplasms. Haematologica 25 26001790
2024 BRCC3 mediates inflammation and pyroptosis in cerebral ischemia/reperfusion injury by activating the NLRP6 inflammasome. CNS neuroscience & therapeutics 23 38544474
2016 B7-H3 upregulates BRCC3 expression, antagonizing DNA damage caused by 5-Fu. Oncology reports 23 27175567
2019 Functional characterization of BRCC3 mutations in acute myeloid leukemia with t(8;21)(q22;q22.1). Leukemia 22 31576005
2023 Inhibition of CD82 improves colitis by increasing NLRP3 deubiquitination by BRCC3. Cellular & molecular immunology 20 36600050
2021 BRCC3 Promotes Tumorigenesis of Bladder Cancer by Activating the NF-κB Signaling Pathway Through Targeting TRAF2. Frontiers in cell and developmental biology 20 34604222
2020 ABRO1 stabilizes the deubiquitinase BRCC3 through inhibiting its degradation mediated by the E3 ubiquitin ligase WWP2. FEBS letters 18 33107021
2021 BRCC3 promotes activation of the NLRP6 inflammasome following cerebral ischemia/reperfusion (I/R) injury in rats. Neuroscience letters 16 33979701
2018 Knockdown of BRCC3 exerts an anti‑tumor effect on cervical cancer in vitro. Molecular medicine reports 15 30272359
2021 Inhibition of lncRNA NEAT1 protects endothelial cells against hypoxia/reoxygenation‑induced NLRP3 inflammasome activation by targeting the miR‑204/BRCC3 axis. Molecular medicine reports 14 34850961
2024 BRCC36 associates with FLT3-ITD to regulate its protein stability and intracellular signaling in acute myeloid leukemia. Cancer science 12 38288901
2021 HSV-1-encoded ICP0 degrades the host deubiquitinase BRCC36 to antagonize interferon antiviral response. Molecular immunology 12 33857816
2023 Vitamin D3 attenuates SARS-CoV-2 nucleocapsid protein-caused hyperinflammation by inactivating the NLRP3 inflammasome through the VDR-BRCC3 signaling pathway in vitro and in vivo. MedComm 10 37361896
2022 BRCC36 prevents vascular calcification in chronic kidney disease through the β-catenin signalling pathway. Experimental cell research 10 35149088
2024 The deubiquitinase BRCC3 increases the stability of ZEB1 and promotes the proliferation and metastasis of triple-negative breast cancer cells. Acta biochimica et biophysica Sinica 8 38449391
2024 Deletion of BRCC3 ameliorates airway inflammation in asthma by inhibiting the activation of NLRP3 inflammasome. International immunopharmacology 8 39642564
2024 Lys-63-specific deubiquitinase BRCC36 enhances the sensitivity of multiple myeloma cells to lenalidomide by inhibiting lysosomal degradation of cereblon. Cellular and molecular life sciences : CMLS 7 39136771
2020 BRCC36 functions noncatalytically to promote antiviral response by maintaining STAT1 protein stability. European journal of immunology 7 32673428
2024 BRCC36 regulates β-catenin ubiquitination to alleviate vascular calcification in chronic kidney disease. Journal of translational medicine 6 39227917
2023 UCA1 executes an oncogenic role in pancreatic cancer by regulating miR-582-5p/BRCC3. Frontiers in oncology 6 37564930
2022 BRCC36 promotes intestinal mucosal barrier injury caused by BMP2 after ischemia reperfusion via inhibiting PPARγ signaling. Bioscience, biotechnology, and biochemistry 5 34888627
2022 The TRIM14-USP14-BRCC3 complex epigenetically regulates inflammation through inhibiting OPTN-mediated autophagic degradation of KDM4D. Autophagy 5 35311471
2024 Methionine Promotes Milk Synthesis through the BRCC36-BRG1-mTOR Signaling Axis in Mammary Epithelial Cells. Journal of agricultural and food chemistry 3 38240727
2023 Identification of BRCC3 and BRCA1 as Regulators of TAZ Stability and Activity. Cells 3 37887275
2025 BRCC3 aggravates pulpitis by activating the NF-κB signaling pathway in dental pulp cells. Biochimica et biophysica acta. Molecular basis of disease 2 39880291
2024 BRCC3 -Associated Syndromic Moyamoya Angiopathy Diagnosed Through Clinical RNA Sequencing. Clinical genetics 2 39552268
2025 Complexes Formed by the K63-Specific Deubiquitinating Enzyme BRCC36: New Promising Therapeutic Targets in Human Disease. Biomolecules 1 41463377
2024 Deubiquitinase BRCC3 promotes the migration, invasion and EMT progression of colon adenocarcinoma by stabilizing MET expression. Genes & genomics 1 38470543
2026 Paeonol alleviates pulmonary arterial hypertension by activation of BRCC3. Phytomedicine : international journal of phytotherapy and phytopharmacology 0 41638058
2026 Mechanism of BRCC36 affecting cardiac rupture after acute infarction through the Wnt‑JNK signaling pathway. Molecular medicine reports 0 41891972
2026 Post-transcriptional knockdown of BRCC3 via siRNA-loaded niosomes modulates autophagy and endoplasmic reticulum stress in rotenone-induced Parkinson's Disease model. Journal of drug targeting 0 42090613
2026 Thiolutin ameliorates postoperative cognitive dysfunction induced by intestinal ischemia-reperfusion in aged mice: a potential role for modulation of the BRCC3/NLRP3 axis. Archives of biochemistry and biophysics 0 42214739
2024 Loss of Brcc3 in Zebrafish Embryos Increases Their Susceptibility to DNA Damage Stress. International journal of molecular sciences 0 39596176
2022 Identification and Verification of the Ability of Cdk5 to Phosphorylate Deubiquitinating Enzyme BRCC3 In Vitro. Bulletin of experimental biology and medicine 0 35503584

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