Protein for DNA repair says cheese

UK scientists have taken pictures of the BRCA2 protein, which is involved in DNA repair, for the first time.

The BRCA1 and BRCA2 genes encode proteins involved in repairing our DNA, which undergoes damage thousands of times a day as a result of toxic chemicals, metabolic by-products and ultraviolet radiation. Repair mechanisms correct most of this damage, but unrepaired damage can lead to cancer.

Around one in 1000 people in the UK have a mutation in the gene that encodes BRCA2, which can raise their risk of breast cancer (to 40-85%, depending on the mutations) as well as ovarian, prostate and pancreatic cancer. As the shape and mechanism of BRCA2 has, until now, been unclear, it has been impossible to target with therapies.

Researchers at Imperial College London and the Cancer Research UK London Research Institute purified the protein and used electron microscopy to reveal its structure and how it interacts with other proteins and DNA. The study found that BRCA2 proteins work in pairs - which the researchers found surprising since BRCA2 is one of the largest proteins in the cell.

BRCA2 works in partnership with another protein called RAD51. 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.

The findings showed that each pair of BRCA2 proteins binds two sets of RAD51 that run in opposite directions. This allows it to work on strands of broken DNA that point in either direction. They also show that BRCA2’s job is to help RAD51 form short filaments at multiple sites along the DNA, presumably to increase the efficiency of establishing longer filaments required to search for matching strands.

“This study improves our understanding of a fundamental cause of cancer,” said Professor Xiaodong Zhang from the Department of Medicine at Imperial College London. “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.

“Once we have added more detail to the picture, we can design ways to correct defects in BRCA2 and help cells repair DNA more effectively to prevent cancer. We can also think about how to make the repair process less effective in cancer cells, so that they die.”

The study was funded by the Medical Research Council and the Wellcome Trust. It has been published the journal Nature Structural and Molecular Biology.

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