Scientists uncover how BRCA2 regulates DNA repair

Cancer Research UK scientists have discovered a ‘molecular switch’ that controls an essential DNA repair process, a study published in Nature¹ reveals today.

Women who carry a faulty BRCA2 gene are more likely to develop breast and ovarian cancer. The reason for this is linked to defects in a process which repairs DNA breaks.

During normal cell growth it is common for breaks to occur in the DNA, and the cell has specialised repair processes that repair these breaks. One such repair process is dependent on a protein called RAD51.

Researchers from Cancer Research UK’s London Research Institute took a closer look at the relationship between RAD51 and BRCA2 protein, which is the product of the normal BRCA2 gene.

They found that a ‘molecular switch’ on the BRCA2 protein controls interactions between BRCA2 and RAD51, which are necessary for normal levels of repair.

The new work shows that mutations in the BRCA2 protein affect this switch, and this can have severe effects on the efficiency of DNA repair and in some cases lead to cancer.

Women with a faulty BRCA2 gene lack the ability to repair damaged DNA by this repair process.

Dr Steve West, lead researcher, says: “This work helps us understand how the BRCA2 gene controls the processes that repair broken chromosomes. We now know that a specific region on the BRCA2 protein acts as a molecular switch to modify interactions with RAD51. This interaction controls the efficiency of RAD51- dependent DNA repair. So, BRCA2 proteins missing this region are unable to interact with RAD51 properly, and this can result in cancer predisposition.”

Dr Lesley Walker, Director of Cancer Information at Cancer Research UK, says: “This work shows how important the structure of the BRCA2 protein is in the DNA repair process. The interaction between RAD51 and the BRCA2 protein act as a ‘pathfinder’ to guide the RAD51 to the damaged areas of DNA. When a specific region is missing from the BRCA2 protein, it’s a bit like having a car breakdown abroad, and a map and a mechanic available in the UK. You have the expertise and tools to fix the problem, but no way of getting there.”

ENDS

1. Nature434 (7033) pp.598-604