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  • Review Article
  • Published:

Is there more to BARD1 than BRCA1?

Nature Reviews Cancer volume 6, pages 382–391 (2006)Cite this article

Key Points

  • BRCA1-associated ring domain 1 (BARD1) is the main binding partner of BRCA1 and is essential for the tumour-suppressor functions of BRCA1.

  • The BARD1–BRCA1 heterodimer has ubiquitin ligase activity that targets proteins involved in cell-cycle regulation and DNA repair for degradation.

  • BARD1 has a BRCA1-independent function in mediating p53-dependent apoptosis. It binds to p53, facilitating its phosphorylation and stabilization.

  • BARD1 is expressed in most proliferative tissues, including that of the breast, ovary and uterus. It is transcriptionally upregulated in response to DNA damage, hypoxia and hormone signalling. Its translation is activated by cell-cycle-dependent phosphorylation.

  • BARD1 is mutated or truncated in breast, ovarian and uterine tumour samples.

  • Depletion of BARD1 leads to early embryonic lethality in mice, and genomic instability in vitro and in vivo; phenotypes that are also observed for BRCA1 or BRCA2 deficiencies.

Abstract

It has been over a decade since mutations in BRCA1 and BRCA2 were found to be associated with a small number of familial breast cancer cases. BRCA1 is a large protein that interacts with many other proteins that have diverse functions, so it has been a challenge to determine how defects in its function could lead to cancer. One particular protein, BARD1, seems to be an important regulator of the tumour-suppressor function of BRCA1, as well as acting as a tumour suppressor itself. BARD1 is indispensable for cell viability, so loss-of-function mutations are rare, but mutations and truncations that alter its function might be involved in the pathogenesis of breast cancer.

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Figure 1: BARD1 protein.
Figure 2: Protein interactions and functional domains of BARD1.
Figure 3: Hypothetical model of BARD1 pathways and functions.

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Acknowledgements

I am grateful to G.J. Laurent and W.C. Leung for discussions, comments and critiques. This work was supported by a grant from the Swiss National Science Foundation (SNSF) to I.I.-F.

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Authors and Affiliations

  1. Department of Geriatrics and Department of Gynecology and Obstetrics, Biology of Aging Laboratory, Geneva University and University Hospitals, 30, Bloulevard de la Cluse, Geneva, CH-1211, Switzerland

    Irmgard Irminger-Finger & Charles Edward Jefford

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Correspondence to Irmgard Irminger-Finger.

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Biomolecular Interaction Network Database BIND

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Gene Expression Omnibus (GEO) database

Human Gene Mutations Database BIOBASE

Search Tool for the Retrieval of Interacting Genes/Proteins STRING

Simple Modular Architecture Research Tool (SMART)

Glossary

RING-finger domain

The RING-finger domain, first identified in the RING (really interesting new gene) protein, describes a specific cysteine-rich class of Zn2+-binding Zinc-finger motifs. RING-finger domains are found as DNA-binding domains and as protein-interaction domains. Recently, ubiquitin ligase activity has been attributed to many RING-finger proteins.

Loss of heterozygosity

(LOH). In cells that carry a mutated allele of a tumour-suppressor gene, the gene becomes fully inactivated when the cell loses a large part of the chromosome carrying the wild-type allele. Regions with a high frequency of LOH are believed to harbour tumour-suppressor genes.

Clear cell adenocarcinoma

Like most ovarian cancers, the clear cell carcinoma has a surface epithelial origin. Clear cell carcinomas are characterized by large epithelial cells with abundant clear cytoplasm. Clear cell carcinomas are dedifferentiated, highly aggressive tumours, and the 5-year survival rate is less than 50%.

Ubiquitin ligase (E3)

Proteins targeted for degradation by the proteasome are selected by having covalently linked ubiquitin chains. This ubiquitylation requires a ubiquitin-conjugating enzyme and a ubiquitin-protein ligase. The importance of E3s is highlighted by the number of normal cellular processes they regulate and the number of diseases that are associated with their loss of function or inappropriate targeting.

Nuclear dots

The term nuclear dots describes the local accumulation of proteins within the nucleus, as detected by immunostaining.

Oestrus, dioestrus and postoestrus

Oestrus specifies the time of ovulation in mammals, which can be stimulated by different factors. Dioestrus and postoestrus indicate the time before and after ovulation, respectively.

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Irminger-Finger, I., Jefford, C. Is there more to BARD1 than BRCA1?. Nat Rev Cancer 6, 382–391 (2006). https://doi.org/10.1038/nrc1878

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