BRCA1 is a large protein that interacts with many other proteins of diverse function. BARD1, its major protein binding partner is required for most of the tumor suppressor function of BRCA1 and acts as a tumor suppressor in its own right.
The diverse functions attributed to BARD1 might make it indispensable for cell viability, which might explain why loss-of-function mutations have are rare in BARD1, but dominant negative mutations might occur in cancer. It is therefore important to characterize all essential functions of BARD1.
Phosphorylation of BARD1 by CDK/cyclin complexes suggested a role in mitosis, which would explain lethality and genetic instability phenotype after BARD1 depletion.
Structure
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.
BRCA1/BARD1 RING complex
BRCA1 associates with BARD1 to form a RING/RING heterodimer. The BRCA1/BARD1 RING complex functions as an ubiquitin (Ub) ligase with activity substantially greater than individual BRCA1 or BARD1 subunits.
The BRCA1 tumor suppressor forms a heterodimer with the BARD1 protein, and the resulting complex functions as an E3 ubiquitin ligase that catalyzes the synthesis of polyubiquitin chains.
UbcH5c and UbcH7 also interact with the BRCA1/BARD1 complex with similar affinity. Although the in vivo substrate(s) is not yet known, BRCA1 has been observed to undergo autoubiquitination and is capable of monoubiquitinating histones 2A and 2AX in vitro.
Pathology
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 itself may be the target of oncogenic mutations in breast or ovarian cancer.
References
Lombardi G, Falaschi E, Cristofano CD, Naccarato AG, Sensi E, Aretini P, Roncella M, Bevilacqua G, Caligo MA. Identification of novel alternatively spliced BRCA1-associated RING domain (BARD1) messenger RNAs in human peripheral blood lymphocytes and in sporadic breast cancer tissues. Genes Chromosomes Cancer. 2007 May 11; PMID: 17497650