One of the genes associated with breast cancer and ovarian cancer is BRCA2. Mutations in BRCA2 can result in early onset breast and ovarian cancer. It was the second breast cancer susceptibility gene discovered – after BRCA1. It was found from positional cloning through women with inherited breast cancer.
Cell lines with mutations in BRCA2 are genetically unstable and can accumulate large chromosomal rearrangements. Double-stranded breaks (DSB) in DNA can occur due to exposure to DNA damaging substances such as UV light or as a consequence of regular metabolic activity.
BRCA2 is known to be involved in DNA repair through a process called ‘homology-directed repair’ – sometimes called ‘homologous recombination’. In homology-directed repair, the repair involves the use of DNA that is similiar in sequence to the DNA that needs to be repaired.
The Rad51 protein is also involved in homology-directed repair. It binds to damaged DNA to begin the repair process. Some mutations in Rad51 have also been associated with breast cancer.
The BRCA2 protein is 3418 amino acids in length. Its central region of around 1000 amino acids contains a series of 8 repeated motifs called BRC repeats. This region binds to Rad51. The C-terminal end binds to single-stranded DNA (ssDNA) and has some similarity to a protein called RPA (replication protein A) which also binds to single stranded DNA.
In a paper published in June in PNAS Maria Jasin‘s group constructed fusion proteins composed of one or more of the BRC repeats and the large subunit of the RPA protein. What they found was that in cell lines containing a mutant form of BRCA2 they were able to restore homology-directed repair when both transiently and stably expressing these fusion proteins in the cells.
Cells with a mutant form of BRCA2 are especially sensitive to DNA damage. Cells transfected with the fusion proteins were resistant to this damage presumably because they were able to restore the DNA repair activity of the cell.
The authors concluded that the primary role of BRCA2 is to bring Rad51 to ssDNA to maintain the genetic integrity of cells.
BRCA1 is also known to interact with RAD51 and be involved with homology-directed repair of DNA.
Further research into the roles of BRCA2, BRCA1 and Rad51 in DNA repair is critical to the understanding and development of future prevention and/or treatment of breast and other cancers.
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