HGNC Approved Gene Symbol: BARD1
Cytogenetic location: 2q35 Genomic coordinates (GRCh38): 2:214,725,646-214,809,683 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q35 | {Breast cancer, susceptibility to} | 114480 | Autosomal dominant; Somatic mutation | 3 |
In an effort to understand the function of BRCA1 (113705), Wu et al. (1996) used a yeast 2-hybrid system to identify proteins that associate with BRCA1 in vivo. This analysis led to the identification of a novel protein that interacts with the N-terminal region of BRCA1. Wu et al. (1996) designated this protein BARD1 (BRCA1-associated RING domain-1). In addition to its ability to bind BRCA1 in vivo and in vitro, BARD1 shares homology with the 2 most conserved regions of BRCA1: the N-terminal RING motif and the C-terminal BRCT domain. The RING motif is a cysteine-rich sequence found in a variety of proteins that regulate cell growth, including the products of tumor suppressor genes and dominant protooncogenes. The BARD1 protein also contains 3 tandem ankyrin repeats. Wu et al. (1996) demonstrated that the BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. They proposed that BARD1 itself may be the target of oncogenic mutations in breast or ovarian cancer.
By Western and immunofluorescence analyses in synchronized T24 bladder cancer cells, Jin et al. (1997) studied the expression patterns of the BARD1 and BRCA1 proteins. They found that the steady state levels of BARD1, unlike those of BRCA1, remain relatively constant during cell cycle progression. However, immunostaining revealed that BARD1 resides within BRCA1 nuclear dots during S phase of the cell cycle, but not during the G1 phase. Nevertheless, BARD1 polypeptides are found exclusively in the nuclear fractions of both G1- and S-phase cells. Therefore, progression to S phase is accompanied by the aggregation of nuclear BARD1 polypeptides into BRCA1 nuclear dots. This cell cycle-dependent colocalization of BARD1 and BRCA1 indicates a role for BARD1 in BRCA1-mediated tumor suppression.
Kleiman and Manley (1999) demonstrated that the 50-kD subunit of cleavage stimulation factor (CSTF1; 600369) interacts in vitro and in intact cells with BARD1. The BARD1-CSTF1 interaction inhibited polyadenylation in vitro. BARD1, like CSTF1, interacts with RNA polymerase-2. BARD1, BRCA1, and CSTF1 were shown to associate in vivo. Kleiman and Manley (1999) demonstrated that BARD1 inhibits pre-mRNA 3-prime cleavage in vitro and that the same region of BARD1 required for binding of CSTF1 is necessary for inhibiting 3-prime pre-mRNA cleavage. Kleiman and Manley (1999) concluded that their results suggested a model in which BARD1, as part of the RNA polymerase-2 holoenzyme, senses sites of DNA damage and repair, and the inhibitory interaction with CSTF1 ensures that nascent RNAs are not erroneously polyadenylated at such sites.
Irminger-Finger et al. (2001) suggested that BARD1 is a mediator of apoptosis because (1) cell death in vivo (ischemic stroke) and in vitro was accompanied by increased levels of BARD1 protein and mRNA; (2) overexpression of BARD1 induced cell death with all features of apoptosis; and (3) BARD1-repressed cells were defective for the apoptotic response to genotoxic stress. The proapoptotic activity of BARD1 involved binding to and elevation of p53 (191170). BRCA1 was not required for induction of apoptosis by BARD1 but partially counteracted it. A tumor-associated mutation of BARD1 (glu564 to his) was defective in apoptosis induction, suggesting a role for BARD1 in tumor suppression by mediating the signaling from proapoptotic stress toward induction of apoptosis.
Dong et al. (2003) isolated a holoenzyme complex containing BRCA1, BRCA2 (600185), BARD1, 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 (610497) and BRCC3 (300617) 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 the BRCC is a ubiquitin E3 ligase that enhances cellular survival following DNA damage.
Joukov et al. (2006) found that the heterodimeric tumor suppressor complex BRCA1/BARD1 was required for mitotic spindle-pole assembly and for accumulation of TPX2 (605917), a major spindle organizer, on spindle poles in both HeLa cells and Xenopus egg extracts. This BRCA1/BARD1 function was centrosome independent, operated downstream of Ran GTPase (601179), and depended upon BRCA1/BARD1 E3 ubiquitin ligase activity. Joukov et al. (2006) concluded that BRCA1/BARD1 function in mitotic spindle assembly likely contributes to its role in chromosome stability control and tumor suppression.
By examining purified wildtype and mutant BRCA1 (113705)-BARD1, Zhao et al. (2017) showed that both BRCA1 and BARD1 bind DNA and interact with RAD51, and that BRCA1-BARD1 enhances the recombinase activity of RAD51. Mechanistically, BRCA1-BARD1 promotes the assembly of the synaptic complex, an essential intermediate in RAD51-mediated DNA joint formation. Zhao et al. (2017) provided evidence that BRCA1 and BARD1 are indispensable for RAD51 stimulation. Notably, BRCA1-BARD1 mutants with weakened RAD51 interactions showed compromised DNA joint formation and impaired mediation of homologous recombination and DNA repair in cells.
Daza-Martin et al. (2019) showed that BRCA1 in complex with BARD1, and not the canonical BRCA1-PALB2 (610355) interaction, is required for fork protection. BRCA1-BARD1 is regulated by a conformational change mediated by the phosphorylation-directed prolyl isomerase PIN1 (601052). PIN1 activity enhances BRCA1-BARD1 interaction with RAD51, thereby increasing the presence of RAD51 at stalled replication structures. Daza-Martin et al. (2019) identified genetic variants of BRCA1-BARD1 in patients with cancer that exhibit poor protection of nascent strands but retain homologous recombination proficiency, thus defining domains of BRCA1-BARD1 that are required for fork protection and associated with cancer development.
By PCR analysis of human monochromosomal hybrid cell line DNA, Wu et al. (1996) mapped the BARD1 gene to chromosome 2q. By FISH, Thai et al. (1998) regionalized the gene to 2q34-q35.
To investigate whether aberrations in the BARD1 gene predispose to hereditary breast and/or ovarian cancer, Karppinen et al. (2004) analyzed the index cases of 126 Finnish cancer families. A cys557-to-ser substitution (C557S; 601593.0001) was seen at elevated frequency in the cancer family patients compared to healthy controls (5.6% vs 1.4%, p = 0.005). The highest prevalence of C557S was found among a subgroup of 94 patients with breast cancer (114480) whose family history did not include ovarian cancer (7.4% vs 1.4%, p = 0.001). Karppinen et al. (2004) concluded that C557S may be a commonly occurring and mainly breast cancer-predisposing allele.
In transient colony and apoptosis assays, Sauer and Andrulis (2005) demonstrated a correlation between loss of growth suppression and loss of apoptosis, respectively, with several putative disease-causing variants of BARD1 including C557S (601593.0001). There was no loss of function with the putative benign polymorphisms P24S, E153K, R658C, and I738V.
For a discussion of a possible association between variation in the BARD1 gene and aggressive high-risk neuroblastoma, see 256700.
McCarthy et al. (2003) determined that Bard1-null mouse embryos died between embryonic day 7.5 and embryonic day 8.5 due to severely impaired cell proliferation and not to increased apoptosis. In Bard1 -/-; p53 -/- double mutant embryos, the developmental defects were partly ameliorated, and lethality was delayed until embryonic day 9.5. Mitotic spreads of cells from double mutant embryos showed increased chromosomal aneuploidy over that shown by p53-null cells alone, suggesting a role for Bard1 in maintaining genomic stability. McCarthy et al. (2003) also developed Bard1 -/-; Brca1 -/- double mutant embryos. Embryos that carried at least 1 wildtype allele of both Bard1 and Brca1 were normal and had 20 to 25 somites, while each embryo that was null for either Bard1 or Brca1 exhibited the characteristic phenotype of severe growth retardation and degeneration. Embryos with double mutant Bard1 -/-; Brca1 -/- genotype were phenotypically indistinguishable from either single Bard1 or single Brca1 homozygous mutants. The similarity of phenotypes indicated to McCarthy et al. (2003) that the developmental functions of Brca1 and Bard1 are mediated by the Brca1/Bard1 heterodimer.
Shakya et al. (2008) found that conditional inactivation of Bard1 in mouse mammary epithelial cells induced basal-like mammary carcinomas with a frequency, latency, and histopathology indistinguishable from those developed in conditional Brca1-mutant mice and in double conditional Bard1/Brca1-mutant mice. Reminiscent of human breast carcinomas due to BRCA1 mutation, the mouse tumors were triple negative for estrogen receptor (see 133430) and progesterone receptor (PGR; 607311) expression and Her2/neu (ERBB2; 164870) amplification. They also expressed basal cytokeratins Ck5 (KRT5; 148040) and Ck14 (KRT14; 148066), had elevated frequency of p53 lesions, and displayed high levels of chromosomal instability. Shakya et al. (2008) concluded that the tumor suppressor activities of both BARD1 and BRCA1 are mediated through the BRCA1/BARD1 heterodimer.
In 7 of 126 (5.6%) index cases from Finnish families with breast and/or ovarian cancer, Karppinen et al. (2004) identified a cys557-to-ser substitution (C557S) in the BARD1 gene at elevated frequency compared to healthy controls (5.6% vs 1.4%, p = 0.005). The highest prevalence of C557S was found among a subgroup of 94 patients with breast cancer (114480) whose family history did not include ovarian cancer (7.4% vs 1.4%, p = 0.001). The C557S mutation is located in a region of BARD1 needed for induction of apoptosis and possibly also transcriptional regulation. Karppinen et al. (2004) concluded that C557S may be a commonly occurring and mainly breast cancer-predisposing allele.
In transient colony and apoptosis assays, Sauer and Andrulis (2005) demonstrated loss of growth suppression and loss of apoptosis, respectively, with the C557S variant. Sauer and Andrulis (2005) concluded that C557S is a deleterious variant rather than a polymorphism.
Daza-Martin, M., Starowicz, K., Jamshad, M., Tye, S., Ronson, G. E., MacKay, H. L., Chauhan, A. S., Walker, A.K., Stone, H. R., Beesley, J. F. J., Coles, J. L., Garvin, A. J., Stewart, G. S., McCorvie, T. J., Zhang, X., Densham, R. M., Morris, J. R. Isomerization of BRCA1-BARD1 promotes replication fork protection. Nature 571: 521-527, 2019. [PubMed: 31270457] [Full Text: https://doi.org/10.1038/s41586-019-1363-4]
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]
Irminger-Finger, I., Leung, W.-C., Li, J., Dubois-Dauphin, M., Harb, J., Feki, A., Jefford, C. E., Soriano, J. V., Jaconi, M., Montesano, R., Krause, K.-H. Identification of BARD1 as mediator between proapoptotic stress and p53-dependent apoptosis. Molec. Cell 8: 1255-1266, 2001. [PubMed: 11779501] [Full Text: https://doi.org/10.1016/s1097-2765(01)00406-3]
Jin, Y., Xu, X. L., Yang, M.-C. W., Wei, F., Ayi, T.-C., Bowcock, A. M., Baer, R. Cell cycle-dependent colocalization of BARD1 and BRCA1 proteins in discrete nuclear domains. Proc. Nat. Acad. Sci. 94: 12075-12080, 1997. [PubMed: 9342365] [Full Text: https://doi.org/10.1073/pnas.94.22.12075]
Joukov, V., Groen, A. C., Prokhorova, T., Gerson, R., White, E., Rodriguez, A., Walter, J. C., Livingston, D. M. The BRCA1/BARD1 heterodimer modulates Ran-dependent mitotic spindle assembly. Cell 127: 539-552, 2006. [PubMed: 17081976] [Full Text: https://doi.org/10.1016/j.cell.2006.08.053]
Karppinen, S.-M., Heikkinen, K., Rapakko, K., Winqvist, R. Mutation screening of the BARD1 gene: evidence for involvement of the cys557ser allele in hereditary susceptibility to breast cancer. J. Med. Genet. 41: e114, 2004. Note: Electronic Article. [PubMed: 15342711] [Full Text: https://doi.org/10.1136/jmg.2004.020669]
Kleiman, F. E., Manley, J. L. Functional interaction of BRCA1-associated BARD1 with polyadenylation factor CstF-50. Science 285: 1576-1579, 1999. [PubMed: 10477523] [Full Text: https://doi.org/10.1126/science.285.5433.1576]
McCarthy, E. E., Celebi, J. T., Baer, R., Ludwig, T. Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability. Molec. Cell. Biol. 23: 5056-5063, 2003. [PubMed: 12832489] [Full Text: https://doi.org/10.1128/MCB.23.14.5056-5063.2003]
Sauer, M. K., Andrulis, I. L. Identification and characterization of missense alterations in the BRCA1 associated RING domain (BARD1) gene in breast and ovarian cancer. J. Med. Genet. 42: 633-638, 2005. [PubMed: 16061562] [Full Text: https://doi.org/10.1136/jmg.2004.030049]
Shakya, R., Szabolcs, M., McCarthy, E., Ospina, E., Basso, K., Nandula, S., Murty, V., Baer, R., Ludwig, T. The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression. Proc. Nat. Acad. Sci. 105: 7040-7045, 2008. [PubMed: 18443292] [Full Text: https://doi.org/10.1073/pnas.0711032105]
Thai, T. H., Du, F., Tsan, J. T., Jin, Y., Phung, A., Spillman, M. A., Massa, H. F., Muller, C. Y., Ashfaq, R., Mathis, J. M., Miller, D. S., Trask, B. J., Baer, R., Bowcock, A. M. Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers. Hum. Molec. Genet. 7: 195-202, 1998. [PubMed: 9425226] [Full Text: https://doi.org/10.1093/hmg/7.2.195]
Wu, L. C., Wang, Z. W., Tsan, J. T., Spillman, M. A., Phung, A., Xu, X. L., Yang, M.-C. W., Hwang, L.-Y., Bowcock, A. M., Baer, R. Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nature Genet. 14: 430-440, 1996. [PubMed: 8944023] [Full Text: https://doi.org/10.1038/ng1296-430]
Zhao, W., Steinfeld, J. B., Liang, F., Chen, X., Maranon, D. G., Ma, C. J., Kwon, Y., Rao, T., Wang, W., Sheng, C., Song, X., Deng, Y., Jimenez-Sainz, J., Lu, L., Jensen, R. B., Xiong, Y., Kupfer, G. M., Wiese, C., Greene, E. C., Sung, P. BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing. Nature 550: 360-36, 2017. [PubMed: 28976962] [Full Text: https://doi.org/10.1038/nature24060]