BARD1

BRCA1-associated RING domain protein 1 is a is_associated_with::protein that in humans is encoded by the BARD1 is_associated_with::gene. The human BARD1 protein is 777 is_associated_with::amino acids long and contains a is_associated_with::RING finger domain (residues 46-90), three is_associated_with::ankyrin repeats (residues 420-5250), and two tandem is_associated_with::BRCT domains (residues 568-777).

Function
Most, if not all, is_associated_with::BRCA1 heterodimerizes with BARD1 is_associated_with::in vivo. BARD1 and is_associated_with::BRCA1 form a heterodimer via their is_associated_with::N-terminal is_associated_with::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 is_associated_with::tumor suppressor genes and dominant is_associated_with::protooncogenes, and developmentally important genes such as the is_associated_with::polycomb group of genes. The BARD1 protein also contains three tandem is_associated_with::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 is_associated_with::uterine cancers, suggesting the mutations disable BARD1's is_associated_with::tumor suppressor function. Three is_associated_with::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.

BARD1 is vital in the rapid relocation of BRCA1 to DNA damage sites. BARD1 tandem BRCA1 C-terminus (BRCT) motifs fold into a binding pocket with a key is_associated_with::lysine residue (K619), and bind to poly(ADP-ribose) (PAR), which targets the BRCA1/BARD1 heterodimer to damaged DNA sites. Double stranded breaks (DSB) in DNA trigger poly(ADPribose) polymerase 1 (PARP1) to catalyze the formation of poly(ADPribose) (PAR) so that PAR can then bind to an array of DNA response proteins, including the BRCA1/BARD1 heterodimer, and target them to DNA damage sites. When the BRCA1/BARD1 heterodimer is transported to the damaged DNA site, it acts as an E3 is_associated_with::ubiquitin ligase. The BRCA1/BARD1 heterodimer ubiquitinates RNA polymerase II, preventing the transcription of the damaged DNA, and restoring genetic stability.

Interactions
BARD1 has been shown to interact with:


 * AURKB,
 * is_associated_with::BCL3,
 * is_associated_with::BRCA1,
 * is_associated_with::BRCA2,
 * is_associated_with::BRCC3,
 * BRE,
 * is_associated_with::CSTF1,
 * is_associated_with::CSTF2,
 * EWSR1,
 * is_associated_with::FANCD2,
 * is_associated_with::H2AFX,
 * is_associated_with::NPM1,
 * is_associated_with::P53,
 * is_associated_with::RAD51,
 * is_associated_with::TACC1, and
 * is_associated_with::UBE2D1.

Implication in Cancer Treatments
If a cancer cell's capacity to repair DNA damage were incapacitated, cancer treatments would be more effective. Inhibiting cancer cells' BRCA1/BARD1 heterodimer from relocating to DNA damage sites would target these cells for apoptosis rather than repair. One inhibition possibility is the BARD1 BRCT key lysine residue (K619). Inhibiting this lysine residue's ability to bind poly(ADP-ribose) would prevent the BRCA1/BARD1 heterodimer from localizing to DNA damage sites and subsequently prevent DNA damage repair. This would make cancer therapies such as chemotherapy and radiation vastly more effective.