BRCA2, a key tumor suppressor that helps repair and protect DNA during replication, is often mutated in cancer cells. Normally, BRCA2 interacts with another protein, RAD51, to suppress genomic instability by fixing damage at DNA breaks or by protecting DNA at stalled replication forks, which can occur during DNA replication.
By examining the protein structure of a specific region of BRCA2, known as the C-terminal end, researchers led by Katharina Schlacher, Ph.D., and John Tainer, Ph.D., uncovered a new function for BRCA2 that challenges the current understanding. The researchers discovered that BRCA2 C-terminal end acts as a clamp to reshape RAD51 so it can bind to DNA structure at replication forks, which differs from their interactions at DNA breaks and suggests that BRCA2 regulates two separate genome stability pathways. Restoring either of these pathways in BRCA-defective cancer cells can cause resistance to cancer therapy, therefore these findings suggest that both pathways need to be targeted in order to overcome resistance.