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Breast cancer gene repairs damaged DNA

In a new study, scientists have pinpointed the role of the breast cancer susceptibility gene BRCA2 in DNA repair by looking at its protein structure. This breast cancer gene has been known for some time to suppress tumors by helping to repair damaged DNA.

The findings have implications for the use of mammograms in breast cancer screening for individuals with BRCA2 mutations. Radiation during mammograms can cause breaks in chromosomes that individuals with mutations in BRCA2 might not be able to repair, says Phang-Lang Chen of the University of Texas Health Science Center at San Antonio, who is a member of the research team.

"We want to be very careful [during mammograms] with those people that carry BRCA2 mutations because they may not be able to repair breaks in double-strand DNA," Chen says.

The BRCA2 protein binds to damaged DNA and uses the intact member of a chromosome pair to repair breaks. Unrepaired DNA leads to mutations in the BRCA2 gene that can stop proteins from doing their job. Thus, the still-damaged DNA leads to unchecked growth of cells and cancer.

Mutations mapped onto the mouse BRCA2 structures.

Mutations in BRCA2 are often found in individuals with inherited forms of breast cancer. Researchers have suspected that this gene is involved in DNA repair based on previous studies. Yet, even after the sequence of BRCA2 became available, its specific function has not been clear.

To learn more about the protein and gene itself, Nikola Pavletich of Memorial Sloan-Kettering Cancer Center in New York and colleagues analyzed the structure of the BRCA2 protein.

The researchers also mapped the location of the most frequent mutations to the protein structure. The mutations are evenly distributed across the protein, but the binding sites contain the most frequently mutated regions. Identifying where a mutation occurs may someday help doctors diagnose those at a higher risk for cancer.

The study "demonstrates the power of structural analyses to illuminate the function of proteins, and marks an important milestone in BRCA2 research," write John H. Wilson and Stephen J. Elledge of Baylor College of Medicine, Houston, Texas in a Perspective that accompanies the findings published in Science.

The BRCA2 protein has been conserved during evolution and is found not only in humans, but also in rats and mice. We used the protein found in mice for the study, yet the results can be translated to humans, says Chen.

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Yang, H. et al. BRCA2 function in DNA-binding and recombination from a BRCA2-DSS1-ssDNA structure. Science 297, 1837-1848 (September 13, 2002).
Wilson, J.H. & S.J. Elledge. Cancer: BRCA2 enters the fray. Science 297, 1822-1823 (September 13, 2002).

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