BRCC3
Function
Metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains (PubMed:19214193, PubMed:20656690, PubMed:24075985, PubMed:26344097). Does not have activity toward 'Lys-48'-linked polyubiquitin chains (PubMed:19214193, PubMed:20656690, PubMed:24075985, PubMed:26344097). Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs) (PubMed:14636569, PubMed:16707425, PubMed:17525341, PubMed:19202061, PubMed:19261746, PubMed:19261748, PubMed:19261749). In the BRCA1-A complex, it specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX, antagonizing the RNF8-dependent ubiquitination at double-strand breaks (DSBs) (PubMed:20656690). Catalytic subunit of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:20656690, PubMed:24075985, PubMed:26195665, PubMed:26344097). Mediates the specific 'Lys-63'-specific deubiquitination associated with the COP9 signalosome complex (CSN), via the interaction of the BRISC complex with the CSN complex (PubMed:19214193). The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). Plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985, PubMed:26344097). Acts as a regulator of the NLRP3 inflammasome by mediating deubiquitination of NLRP3, leading to NLRP3 inflammasome assembly (By similarity). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985). Deubiquitinates HDAC1 and PWWP2B leading to their stabilization (By similarity).
Involvement in disease
A chromosomal aberration involving BRCC3 is a cause of pro-lymphocytic T-cell leukemia (T-PLL). Translocation t(X;14)(q28;q11) with TCRA.
Sequence Similarities
Belongs to the peptidase M67A family. BRCC36 subfamily.
Tissue Specificity
Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Aberrantly expressed in the vast majority of breast tumors.
Cellular localization
- Nucleus
- Cytoplasm
- Cytoplasm
- Cytoskeleton
- Spindle pole
- Localizes at sites of DNA damage at double-strand breaks (DSBs) (PubMed:20656690, PubMed:26344097). Interaction with ABRAXAS2 retains BRCC3 in the cytoplasm (PubMed:20656690).
Alternative names
BRCC36, C6.1A, CXorf53, BRCC3, Lys-63-specific deubiquitinase BRCC36, BRCA1-A complex subunit BRCC36, BRCA1/BRCA2-containing complex subunit 3, BRCA1/BRCA2-containing complex subunit 36, BRISC complex subunit BRCC36