Germline mutations in the BRCA2 gene cause increased susceptibility to breast and ovarian cancers, so much work is being done to understand the cellular role of BRCA2. It is known to interact with — and modulate the function of — RAD51, a protein involved in recombinational DNA repair. But what does this interaction mean at a functional level?

Reporting in Nature, Tom Blundell, Ashok Venkitaraman and colleagues now reveal the structural basis for the BRCA2-dependent regulation of RAD51. They describe the 1.7-Å crystal structure of a complex between BRC repeat 4 (BRC4) of BRCA2 and the RecA-homology domain of RAD51, and show that the BRC repeat mimics a conserved motif found in RAD51, so enabling BRCA2 to control the activity of RAD51.

When mammalian cells are exposed to DNA damage, RAD51 oligomerizes on damaged DNA ends to form a nucleoprotein filament that is essential for subsequent steps in recombinational DNA repair. To work out how this happens, the authors compared the BRC4–RAD51 structure with that of the bacterial RAD51 homologue, RecA, which also forms a helical filament. They discovered that a conserved sequence motif in BRC4 structurally mimics a seven-amino-acid sequence that is found at the interface between subunits in the RecA filament. They then used this information to show that RAD51 oligomerizes through a similar motif. This motif is conserved in RecA-like molecules from bacteria to humans, highlighting a common structural mechanism for the formation of such nucleoprotein filaments.

BRCA2 binds to RAD51 through six of its eight so-called BRC repeats (BRC1–8). From the structure of the BRC4–RAD51 complex, the authors show that these BRC repeats mimic the structure of the natural RAD51 motif that forms the interface between RAD51 subunits in the nucleoprotein filament. So BRCA2 copies a structure in RAD51 to control the oligomerization state of RAD51.

Does this study tell us anything about BRCA2's role in cancer? The authors show that several point mutations in BRCA2, which have previously been linked to cancer, impair the ability of BRCA2 to bind RAD51. RAD51 would therefore be unable to repair damaged DNA, which could explain the development of cancer. The importance of this interaction also means that the BRCA2–RAD51 interface could be a target for the development of small-molecule inhibitors as potential anti-cancer drugs.