Scientists have taken pictures of the BRCA2 protein for the
first time, showing how it works to repair damaged DNA.
Mutations in the gene that encodes BRCA2 are well known for
raising the risk of breast cancer and other cancers. Although the
protein was known to be involved in DNA repair, its shape and
mechanism have been unclear, making it 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.
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 per cent, depending on the mutation, compared
with around 12 per cent for the general population. Many women who
test positive for BRCA1 and BRCA2 mutations choose to undergo
surgery to reduce their risk of breast cancer. Mutations can also
raise the risk of other cancers, such as ovarian cancer, prostate
cancer and pancreatic cancer.
The BRCA1 and BRCA2 genes encode proteins that are involved in
DNA repair. The DNA in our cells undergoes damage thousands of
times a day, caused by toxic chemicals, metabolic by-products and
ultraviolet radiation. Repair mechanisms fix most of this damage,
but unrepaired damage can lead to cancer.
The study was led by Professor Xiaodong Zhang from Imperial
College London and Dr Stephen West at the London Research
Institute.
"This study improves our understanding of a fundamental cause of
cancer," said Professor Zhang, a Wellcome Trust Senior
Investigator. "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. We can also think about how to make the repair process
less effective in cancer cells."
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.
The paper, Structure and Mechanism of Action of the BRCA2 Breast Cancer Tumor
Suppressor, is published in Nature Structural and
Molecular Biology.