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.”
- Nature434 (7033) pp.598-604
Researchers have found that a specific site on the BRCA2 protein, called S3291, gets modified by the addition of phosphate groups. This phosphorylation blocks interactions between BRCA2 and RAD51, impeding the repair mechanism. The extent of S3291 phosphorylation varies depending on the stage of the cell cycle. It is lowest when cells are replicating their DNA, so that BRCA2 and RAD51 can interact, and DNA damage that occurs at this time can be repaired.
Faults in the breast cancer genes BRCA1 and BRCA2 increase cancer risk because they are both genes that normally protect cells from cancerous changes. So a BRCA gene fault doesn’t mean a person has cancer, or that they’ll definitely get cancer. But it does mean that breast cancer is more likely because breast cells are one step further along the road than if you didn’t have the gene fault.
Information on breast and ovarian cancer is available on Cancer Research UK’s patient information website, CancerHelp UK.