BARD1

BRCA1-associated RING domain protein 1 is a protein that in humans is encoded by the BARD1 gene. The human BARD1 protein is 777 amino acids long and contains a RING finger domain (residues 46-90), four ankyrin repeats (residues 420-555), and two tandem BRCT domains (residues 568-777).

Function

Most, if not all, BRCA1 heterodimerizes with BARD1 in vivo. BARD1 and BRCA1 form a heterodimer via their N-terminal RING finger domains. The BARD1-BRCA1 interaction is observed in vivo and in vitro and is essential for BRCA1 stability. BARD1 shares homology with the two 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, and developmentally important genes such as the polycomb group of genes. The BARD1 protein also contains four tandem ankyrin repeats.

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. BARD1 may be the target of oncogenic mutations in breast or ovarian cancer. Mutations in the BARD1 protein that affect its structure appear in many breast, ovarian, and uterine cancers, suggesting the mutations disable BARD1's tumor suppressor function. Three missense mutations, each affecting BARD1's BRCT domain, are known to be implicated in cancers: C645R is associated with breast and ovarian cancers, V695L is associated with breast cancer, and S761N is associated with breast and uterine cancers. BARD1 expression is upregulated by genotoxic stress and involved in apoptosis through binding and stabilizing p53 independently of BRCA1.