FIRST PICTURES OF BRCA2 PROTEIN SHOW HOW IT WORKS TO REPAIR DNA
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. The
results are published today in Nature Structural and Molecular Biology.
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, prostate
and pancreatic cancer.
The BRCA1 and BRCA2 genes encode proteins 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 correct most of this damage, but unrepaired damage can lead to
cancer.
The study was led by Professor Xiaodong Zhang from the
Department of Medicine at 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 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 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.
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