Alternative titles; symbols
HGNC Approved Gene Symbol: BRCC3
Cytogenetic location: Xq28 Genomic coordinates (GRCh38) : X:155,071,508-155,123,077 (from NCBI)
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).
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.
Cryoelectron Microscopy
Walden et al. (2019) presented the cryoelectron microscopy structure of the human BRISC (BRCC36 isopeptidase complex)-SHMT2 (138450) complex at a resolution of 3.8 angstroms. BRISC is a U-shaped dimer of 4 subunits, and SHMT2 sterically blocks the BRCC36 active site and inhibits deubiquitylase activity. Only the inactive SHMT2 dimer, and not the active PLP-bound tetramer, binds and inhibits BRISC. Mutations in BRISC that disrupt SHMT2 binding impair type I interferon signaling in response to inflammatory stimuli. Intracellular levels of PLP (pyridoxal-5-prime-phosphate) regulate the interaction between BRISC and SHMT2, as well as inflammatory cytokine responses. Walden et al. (2019) concluded that their data revealed a mechanism in which metabolites regulate deubiquitylase activity and inflammatory signaling.
By somatic cell hybrid analysis, Kenwrick et al. (1992) mapped the BRCC3 gene to chromosome Xq28.
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 reminiscent of chromosome breakage syndromes.
Dong, Y., Hakimi, M.-A., Chen, X., Kumaraswamy, E., Cooch, N. S., Godwin, A. K., Shiekhattar, R. Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Molec. Cell 12: 1087-1099, 2003. [PubMed: 14636569] [Full Text: https://doi.org/10.1016/s1097-2765(03)00424-6]
Kenwrick, S., Levinson, B., Taylor, S., Shapiro, A., Gitschier, J. Isolation and sequence of two genes associated with a CpG island 5-prime of the factor VIII gene. Hum. Molec. Genet. 1: 179-186, 1992. [PubMed: 1303175] [Full Text: https://doi.org/10.1093/hmg/1.3.179]
Miskinyte, S., Butler, M. G., Herve, D., Sarret, C., Nicolino, M., Petralia, J. D., Bergametti, F., Arnould, M., Pham, V. N., Gore, A. V., Spengos, K., Gazal, S., Woimant, F., Steinberg, G. K., Weinstein, B. M., Tournier-Lasserve, E. Loss of BRCC3 deubiquitinating enzyme leads to abnormal angiogenesis and is associated with syndromic moyamoya. Am. J. Hum. Genet. 88: 718-728, 2011. [PubMed: 21596366] [Full Text: https://doi.org/10.1016/j.ajhg.2011.04.017]
Okamoto, K., Bartocci, C., Ouzounov, I., Diedrich, J. K., Yates, J. R, III, Denchi, E. L. A two-step mechanism for TRF2-mediated chromosome-end protection. Nature 494: 502-505, 2013. [PubMed: 23389450] [Full Text: https://doi.org/10.1038/nature11873]
Walden, M., Tian, L., Ross, R. L., Sykora, U. M., Byrne, D. P., Hesketh, E. L., Masandi, S. K., Cassel, J., George, R., Ault, J. R., El Oualid, F., Pawlowski, K., Salvino, J. M., Eyers, P. A., Ranson, N. A., Del Galdo, F., Greenberg, R. A., Zeqiraj, E. Metabolic control of BRISC-SHMT2 assembly regulates immune signalling. Nature 570: 194-199, 2019. [PubMed: 31142841] [Full Text: https://doi.org/10.1038/s41586-019-1232-1]