Molecule Information

General Information of the Molecule (ID: Mol04375)

• Name: Lys-63-specific deubiquitinase BRCC36 (BRCC3) ,Homo sapiens
• Synonyms: BRCA1-A complex subunit BRCC36; BRCA1/BRCA2-containing complex subunit 3; BRCA1/BRCA2-containing complex subunit 36; BRISC complex subunit BRCC36
• Molecule Type: Protein
• Gene Name: BRCC3
• Gene ID: 79184
• Sequence:
  MAVQVVQAVQAVHLESDAFLVCLNHALSTEKEEVMGLCIGELNDDTRSDSKFAYTGTEMR
  TVAEKVDAVRIVHIHSVIILRRSDKRKDRVEISPEQLSAASTEAERLAELTGRPMRVVG
  W YHSHPHITVWPSHVDVRTQAMYQMMDQGFVGLIFSCFIEDKNTKTGRVLYTCFQSIQA
  QK SSESLHGPRDFWSSSQHISIEGQKEEERYERIEIPIHIVPHVTIGKVCLESAVELPK
  ILC QEEQDAYRRIHSLTHLDSVTKIHNGSVFTKNLCSQMSAVSGPLLQWLEDRLEQNQQ
  HLQE LQQEKEELMQELSSLE
• Function: Metalloprotease that specifically cleaves 'Lys-63'-linkedpolyubiquitin chains . Does not have activity toward 'Lys-48'-linked polyubiquitin chains . Component of the BRCA1-A complex, acomplex that specifically recognizes 'Lys-63'-linked ubiquitinatedhistones H2A and H2AX at DNA lesions sites, leading to target theBRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks . Inthe BRCA1-A complex, it specifically removes 'Lys-63'-linked ubiquitinon histones H2A and H2AX, antagonizing the RNF8-dependentubiquitination at double-strand breaks .Catalytic subunit of the BRISC complex, a multiprotein complex thatspecifically cleaves 'Lys-63'-linked ubiquitin in various substrates.Mediates the specific 'Lys-63'-specific deubiquitination associatedwith the COP9 signalosome complex , via the interaction of theBRISC complex with the CSN complex . The BRISC complexis required for normal mitotic spindle assembly and microtubuleattachment to kinetochores via its role in deubiquitinating NUMA1. Plays a role in interferon signaling via its role inthe deubiquitination of the interferon receptor IFNAR1;deubiquitination increases IFNAR1 activity by enhancing its stabilityand cell surface expression . Acts asa regulator of the NLRP3 inflammasome by mediating deubiquitination ofNLRP3, leading to NLRP3 inflammasome assembly . Down-regulates the response to bacterial lipopolysaccharide via itsrole in IFNAR1 deubiquitination . DeubiquitinatesHDAC1 and PWWP2B leading to their stabilization .{ECO:0000250|UniProtKB:P46737, ECO:0000269|PubMed:14636569,ECO:0000269|PubMed:16707425, ECO:0000269|PubMed:17525341,ECO:0000269|PubMed:19202061, ECO:0000269|PubMed:19214193,ECO:0000269|PubMed:19261746, ECO:0000269|PubMed:19261748,ECO:0000269|PubMed:19261749, ECO:0000269|PubMed:20656690,ECO:0000269|PubMed:24075985, ECO:0000269|PubMed:26195665,ECO:0000269|PubMed:26344097}.
• Uniprot ID: BRCC3_HUMAN
• Ensembl ID: ENSG0000018551516
• HGNC ID: HGNC:24185

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Lenalidomide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Multiple myeloma [ICD-11: 2A83.0] [1]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Sensitive Drug: Lenalidomide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK 293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: RPMI 8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_7353
• In Vitro Model: LP1 cells; Blood; Homo sapiens (Human); CVCL_E2V5
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); N.A.
• In Vitro Model: ARH-77 cells; Peripheral blood; Homo sapiens (Human); CVCL_1072
• In Vivo Model: BALB/c male nude mice model; Mus musculus
• Experiment for Molecule Alteration: qPCR; Protein degradation assay; Proteasome inhibition assay; Western blot assay; Proximity-labeling assay; MS analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In this study, we used the proximity labeling technique TurboID and quantitative proteomics to identify Lys-63-specific deubiquitinase BRCC36 as a CRBN-interacting protein. Biochemical experiments demonstrated that BRCC36 in the BRISC complex protects CRBN from lysosomal degradation by specifically cleaving the K63-linked polyubiquitin chain on CRBN. Further studies found that a small-molecule compound SHIN1, which binds to BRISC complex subunit SHMT2, can upregulate CRBN by elevating BRCC36. The combination of SHIN1 and Len can further increase the sensitivity of MM cells to IMiDs. Therefore, this study provides the basis for the exploration of a possible strategy for the SHIN1 and Len combination treatment for MM.

References

• Ref 1: Lys-63-specific deubiquitinase BRCC36 enhances the sensitivity of multiple myeloma cells to lenalidomide by inhibiting lysosomal degradation of cereblon. Cell Mol Life Sci. 2024 Aug 13;81(1):349.