BRCA2

Did You Know?

• The BRCA2 gene was discovered in 1994 by a multi-institutional team led by researchers at The Institute of Cancer Research, London.
• In 1996, Kenneth Offit and his group at Memorial Sloan Kettering Cancer Center identified the most common BRCA2 mutation among individuals of Ashkenazi Jewish ancestry.

Clinical significance

Variations in BRCA2 increase the risk for breast cancer as part of hereditary breast–ovarian cancer syndrome. Hundreds of mutations have been identified, most often small insertions or deletions that produce an abnormal, nonfunctional protein. The defective protein cannot repair DNA damage, leading to error-prone translesion synthesis and accumulation of mutations that may drive uncontrolled cell division and tumor formation. Individuals with two mutated copies develop Fanconi anemia, characterized by extremely low BRCA2 protein levels, and are prone to leukemias, solid tumors of the head, neck, skin, and reproductive organs, and bone marrow suppression. Women with inherited defective BRCA1 or BRCA2 face such high risks for breast and ovarian cancer that many choose prophylactic surgery. The tissue specificity of these cancers may be explained by factors such as exposure to carcinogens, chronic inflammation, or infectious agents in target tissues, combined with the innate genomic deficit that impairs normal responses. This model suggests options beyond prophylactic surgery.

Meiosis

In Arabidopsis thaliana, loss of the BRCA2 homolog AtBRCA2 causes severe defects in male meiosis and female gametocyte development. AtBRCA2 is required for proper localization of the synaptonemal complex protein AtZYP1 and the recombinases AtRAD51 and AtDMC1, and for proper meiotic synapsis, indicating a role in meiotic recombination. Homologs of BRCA2 are essential for meiosis in Ustilago maydis, Caenorhabditis elegans, and Drosophila melanogaster. Mice producing truncated BRCA2 are viable but sterile; BRCA2 mutant rats show growth inhibition and sterility due to failure of homologous chromosome synapsis. Human DMC1 interacts directly with BRC repeats in BRCA2, which stimulate joint molecule formation by promoting single-stranded DNA interaction with DMC1. This process pairs homologous DNA during synapsis, a central step in homologous recombination. Thus BRCA2 plays a key role in recombinational repair of DNA damages during meiotic recombination.

Domain architecture

BRCA2 contains 39-amino-acid repeats critical for binding RAD51 and resistance to methyl methanesulphonate. The helical domain has a four-helix cluster core and two beta-hairpins, with a 50-amino-acid segment of four short helices meandering around the core. Alpha 9 and alpha 10 pack with the OB1 domain via van der Waals contacts and hydrogen bonds; this domain binds the DSS1 protein. The OB1 domain adopts an OB fold with a shallow groove for weak single-strand DNA binding and also binds DSS1. The OB3 domain has a pronounced groove for strong ssDNA binding. The Tower domain consists of two long antiparallel alpha-helices supporting a three-helix bundle with a helix-turn-helix motif similar to DNA-binding domains of bacterial recombinases and eukaryotic transcription factors. This domain is essential for BRCA2 tumor suppressor function and appropriate DNA binding; its conformation is allosterically controlled by DSS1, which interacts with the helical, OB1, and OB2 domains.

Patents, enforcement, litigation, and controversy

A patent application for isolated BRCA1 and cancer-promoting mutations was filed in 1994 by the University of Utah, NIEHS, and Myriad Genetics. The first BRCA2 patent was filed in the US in 1995 by Myriad and other institutions. Myriad, as exclusive licensee, enforced these patents against clinical diagnostic labs, leading to controversy over high prices and inability to obtain second opinions. This culminated in the lawsuit Association for Molecular Pathology v. Myriad Genetics. In June 2013, the US Supreme Court unanimously ruled that naturally occurring DNA segments are not patent eligible merely because they have been isolated, invalidating Myriad's BRCA1 and BRCA2 patents, but held that manipulated genes not found in nature could still be patentable. The Federal Court of Australia upheld a Myriad BRCA1 patent in February 2013, but that decision was under appeal with consideration of the US ruling.