BRCC3

This gene encodes a subunit of the BRCA1-BRCA2-containing complex (BRCC), which is an E3 ubiquitin ligase. This complex plays a role in the DNA damage response, where it is responsible for the stable accumulation of BRCA1 at DNA break sites. The component encoded by this gene can specifically cleave Lys 63-linked polyubiquitin chains, and it regulates the abundance of these polyubiquitin chains in chromatin. The loss of this gene results in abnormal angiogenesis and is associated with syndromic moyamoya, a cerebrovascular angiopathy. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 5. [provided by RefSeq, Jun 2011]

BRCA1/BRCA2-Containing Complex Subunit 3

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. 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). 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:26344097, PubMed:26195665).
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).
Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985).

Cell cycle Source: UniProtKB-KW
Cell division Source: UniProtKB-KW
Double-strand break repair Source: UniProtKB
Double-strand break repair via nonhomologous end joining Source: Reactome
Histone H2A K63-linked deubiquitination Source: UniProtKB
Positive regulation of DNA repair Source: UniProtKB
Protein deubiquitination Source: Reactome
Protein K63-linked deubiquitination Source: UniProtKB
Response to ionizing radiation Source: UniProtKB
Response to X-ray Source: MGI
Signal transduction involved in G2 DNA damage checkpoint Source: UniProtKB

Cytoplasm; Nucleus; 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).

A chromosomal aberration involving BRCC3 is a cause of pro-lymphocytic T-cell leukemia (T-PLL). Translocation t(X;14)(q28;q11) with TCRA.