Lys-63-specific deubiquitinase BRCC36 (BRCC3)
The protein contains 316 amino acids for an estimated molecular weight of 36072 Da.
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 (updated: Jan. 31, 2018)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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| Variant | Description |
|---|---|
| dbSNP:rs28997578 |
Biological Process
Cell cycle
Cell division
DNA repair
Double-strand break repair
Double-strand break repair via nonhomologous end joining
G2 DNA damage checkpoint
Histone H2A K63-linked deubiquitination
Positive regulation of DNA repair
Protein deubiquitination
Protein K63-linked deubiquitination
Regulation of catalytic activity
Response to ionizing radiation
Response to X-ray
Signal transduction involved in G2 DNA damage checkpoint
The reference OMIM entry for this protein is 300617
Brca1/brca2-containing complex, subunit 3; brcc3
C6.1a
Brcc36
CLONING
Kenwrick et al., 1992 identified cDNA clones corresponding to the BRCC3 and MTCP1 (300116) genes, which they called C6.1A and C6.1B, respectively. The C6.1A gene was highly conserved between species and expressed abundantly in many human and mouse tissues. Dong et al. (2003) determined that the BRCC3 gene encodes a 316-amino acid protein with a molecular mass of 36 kD. BRCC3 shares sequence homology with the JAMM domain of POH1 (PSMD14; 607173) and COPS5 (604850).GENE FUNCTION
Dong et al. (2003) demonstrated that in human cell lines BRCC3 and BRE (610497) are components of a holoenzyme complex containing BRCA1 (113705), BRCA2 (600185), BARD1 (601593), and RAD51 (179617), which they called the BRCA1- and BRCA2-containing complex (BRCC). The complex showed UBC5 (see UBE2D1; 602961)-dependent ubiquitin E3 ligase activity. Inclusion of BRE and BRCC3 enhanced ubiquitination by the complex, and cancer-associated truncations in BRCA1 reduced the association of BRE and BRCC3 with the complex. RNA interference of BRE and BRCC3 in HeLa cells increased cell sensitivity to ionizing radiation and resulted in a defect in G2/M checkpoint arrest. Dong et al. (2003) concluded that BRCC is a ubiquitin E3 ligase that enhances cellular survival following DNA damage. Okamoto et al. (2013) addressed the molecular properties of TRF2 (602027) that are both necessary and sufficient to protect chromosome ends in mouse embryonic fibroblasts, and stated that their data supported a 2-step mechanism for TRF2-mediated end protection. First, the dimerization domain of TRF2 is required to inhibit ATM (607585) activation, the key initial step involved in the activation of a DNA damage response (DDR). Next, TRF2 independently suppresses the propagation of DNA damage signaling downstream of ATM activation. This novel modulation of the DDR at telomeres occurs at the level of the E3 ubiquitin ligase RNF168 (612688). Inhibition of RNF168 at telomeres involves the deubiquitinating enzyme BRCC3 and the ubiquitin ligase UBR5 (608413), and is sufficient to suppress chromosome end-to-end fusions. Okamoto et al. (2013) concluded that this 2-step mechanism for TRF2-mediated end protection helped to explain the apparent paradox of frequent localization of DDR proteins at functional telomeres without concurrent induction of detrimental DNA repair activities.MAPPING
By somatic cell hybrid analysis, Kenwrick et al. (1992) mapped the BRCC3 gene to chromosome Xq28.MOLECULAR GENETICS
In affected members of 3 unrelated families with an X-linked recessive syndromic form of moyamoya disease (MYMY4; 300845), Miskinyte et al. (2011) identified 3 different deletions on chromosome Xq28. The critical region of overlap was a 3.4-kb region including exon 1 of the MTCP1/MTCP1NB gene (300116) and the first 3 exons of the BRCC3 gene, resulting in loss of BRCC3 and MTCP1NB expression in patient lymphoblastoid cell lines. Morpholino knockdown of Brcc3 in zebrafish resulted in defective angiogenesis that could be rescued by endothelial expression of Brcc3, suggesting that loss of BRCC3 function was responsible for the human disorder. The phenotype is a multisystem disorder characterized by moyamoya disease, short stature, hypergonadotropic hypogonadism, and facial dysmorphism. Other variable features include dilated cardiomyopathy and premature graying of the hair. Miskinyte et al. (2011) noted that some of the features of the disorder were reminisce ... More on the omim web site
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 300617 was added.