Protein pair shown 'mending' DNA

The protein BRCA2 is like a double edged sword. It is known to be involved in DNA repair, while at the same time, mutations in the gene that encodes BRCA2 are well known for raising the risk of breast cancer, as well as other types of cancer.

Researchers had previously lacked enough understanding of the protein’s exact shape and mechanism to make it viable for therapeutic use.

“It’s our first view of how the protein looks and how it works

ICL’s Xiaodong Zhang

Now, however, scientists at Imperial College London (ICL) and the Cancer Research UK London Research Institute have purified the BRCA2 protein and used electron microscopy to reveal its structure and how it interacts with other proteins and DNA.

The study was led by Xiaodong Zhang from the Department of Medicine at Imperial College London and Stephen West at the London Research Institute.

According to national statistics, around one in 1000 people in the UK have a mutation in the BRCA2 gene. The lifetime risk of breast cancer for women with BRCA2 mutations is 40 to 85%, depending on the mutation, compared with around 12% for the general population.

Mutations can also raise the risk of other cancers, such as ovarian, prostate and pancreatic cancer, the researchers said.

“This study improves our understanding of a fundamental cause of cancer,” said Zhang.

“It’s our first view of how the protein looks and how it works, and it gives us a platform to design new experiments to probe its mechanism in greater detail.”

Zhang said that if researchers had a more detailed mechanistic understanding of BRCA2 and why certain mutations cause the dysfunction of BRCA2, they could develop ways to rectify these defects in BRCA2’s function, hence reduce the risk of cancer.

“We can also think about how to make the repair process less effective in cancer cells, so that they die,” Zhang said.

Interestingly, the researchers also discovered that the BRCA2 protein works in a pair alongside another protein called RAD51. Researchers claim this is unusual because BRCA2 is considered one of the largest proteins in a cell.

According to researchers, BRCA2 helps RAD51 molecules to assemble on strands of broken DNA and form filaments. The RAD51 filaments then search for matching strands of DNA in order to repair the break.

A full account of the study has been published in the journal Nature Structural and Molecular Biology.