BRCA1-dependent and independent functions of BARD1

Irminger-Finger, Irmgard; Leung, Wai Choi

doi:10.1016/s1357-2725(01)00161-3

Cited by 27 publications

(26 citation statements)

References 16 publications

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“…Consistent with such functional diversity, Ͼ30 protein partners for BRCA1 have been reported and BRCA1 has been found as a component in at least four distinct macromolecular complexes (1,(5)(6)(7)(8)(9). The best characterized BRCA1 interaction involves the complex formed with BARD1 (10,11), a protein that also interacts with CstF-50, an mRNA polyadenylation factor (12,13). In vivo, BRCA1 and BARD1 colocalize in nuclear dots during S-phase of the cell cycle and in nuclear foci that form in response to DNA damage (14,15).…”

mentioning

confidence: 80%

Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex

Brzović

Keeffe

Nishikawa

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

324

341

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BRCA1 is a breast and ovarian cancer tumor suppressor protein that associates with BARD1 to form a RING͞RING heterodimer. The BRCA1͞BARD1 RING complex functions as an ubiquitin (Ub) ligase with activity substantially greater than individual BRCA1 or BARD1 subunits. By using NMR spectroscopy and site-directed mutagenesis, we have mapped the binding site on the BRCA1͞BARD1 heterodimer for the Ub-conjugating enzyme UbcH5c. The results demonstrate that UbcH5c binds only to the BRCA1 RING domain and not the BARD1 RING. The binding interface is formed by the first and second Zn 2؉ -loops and central ␣-helix of the BRCA1 RING domain, a region disrupted by cancer-predisposing mutations. Unexpectedly, a second Ub-conjugating enzyme, UbcH7, also interacts with the BRCA1͞BARD1 complex with similar affinity, although it is not active in Ub-ligase activity assays. Thus, binding alone is not sufficient for BRCA1-dependent Ub-ligase activity.

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mentioning

confidence: 80%

Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex

Brzović

Keeffe

Nishikawa

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

324

341

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“…Another candidate is a protein termed BRCA1-associated RING domain (BARD1). BARD1 interacts with the breast cancer susceptibility protein BRCA1 (26) and the BRCA1/BARD1 complex functions as an E3 ubiquitin ligase (5). BARD1 has also been shown to associate both with p53 and with a Bcl-3 complex (14,27).…”

Section: Discussionmentioning

confidence: 99%

p53 Represses Cyclin D1 Transcription through Down Regulation of Bcl-3 and Inducing Increased Association of the p52 NF-κB Subunit with Histone Deacetylase 1

Rocha

Martin

Meek

et al. 2003

Molecular and Cellular Biology

222

195

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The p53 and NF-B transcription factor families are important, multifunctional regulators of the cellular response to stress. Here we have investigated the regulatory mechanisms controlling p53-dependent cell cycle arrest and cross talk with NF-B. Upon induction of p53 in H1299 or U-2 OS cells, we observed specific repression of cyclin D1 promoter activity, correlating with a decrease in cyclin D1 protein and mRNA levels. This repression was dependent on the proximal NF-B binding site of the cyclin D1 promoter, which has been shown to bind the p52 NF-B subunit. p53 inhibited the expression of Bcl-3 protein, a member of the IB family that functions as a transcriptional coactivator for p52 NF-B and also reduced p52/Bcl-3 complex levels. Concomitant with this, p53 induced a significant increase in the association of p52 and histone deacetylase 1 (HDAC1). Importantly, p53-mediated suppression of the cyclin D1 promoter was reversed by coexpression of Bcl-3 and inhibition of p52 or deacetylase activity. p53 therefore induces a transcriptional switch in which p52/Bcl-3 activator complexes are replaced by p52/HDAC1 repressor complexes, resulting in active repression of cyclin D1 transcription. These results reveal a unique mechanism by which p53 regulates NF-B function and cell cycle progression.

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“…The ankyrin repeat is one of the most frequently observed amino acid motifs in protein databases and mediates protein-protein interactions participating in a diverse set of cellular functions [Mosavi et al, 2004]. Several functions have been ascribed to BARD1 in which BARD1 interacts with BRCA1 or acts independently of BRCA1 [Irminger-Finger and Leung, 2002;Irminger-Finger and Jefford, 2006].…”

Section: Introductionmentioning

confidence: 99%

Cancer predisposing missense and protein truncatingBARD1mutations in non-BRCA1orBRCA2breast cancer families

et al. 2010

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Fifteen years ago BRCA1 and BRCA2 were reported as high penetrant breast cancer predisposing genes. However, mutations in these genes are found in only a fraction of high risk families. BARD1 is a candidate breast cancer gene, but only a limited number of missense mutations with rather unclear pathogenic consequences have been reported. We screened 196 high risk breast cancer families for the occurrence of BARD1 variants. All genetic variants were analyzed using clinical information as well as IN SILICO predictive tools, including protein modeling. We found three candidate pathogenic mutations in seven families including a first case of a protein truncating mutation (p.Glu652fs) removing the entire second BRCT domain of BARD1. In conclusion, we provide evidence for an increased breast cancer risk associated to specific BARD1 germline mutations. However, these BARD1 mutations occur in a minority of hereditary breast cancer families.

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BRCA1-dependent and independent functions of BARD1

Cited by 27 publications

References 16 publications

Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex

Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex

p53 Represses Cyclin D1 Transcription through Down Regulation of Bcl-3 and Inducing Increased Association of the p52 NF-κB Subunit with Histone Deacetylase 1

Cancer predisposing missense and protein truncatingBARD1mutations in non-BRCA1orBRCA2breast cancer families

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