A University of Alberta biochemist has recreated the three-dimensional structure of a critical portion of the BRCA1 protein, which if mutated, causes hereditary breast cancer.
Using ultra-sensitive x-ray crystallography, Biochemistry assistant professor Mark Glover has uncovered the three dimensional structure of an important part of the breast cancer-associated protein, BRCA1. Mutations in BRCA1 cause about half of all hereditary breast cancers.
The structure may give clinicians the ability to formulate genetic screening programs to identify women at risk for the deadly disease. The finely detailed images, will give researchers new clues on how the crucial protein effectively prevents cells from becoming cancerous. It is a first step towards developing strategies to counteract the effects of the defective gene.
The protein is enormous in size and scope, with a chain of some 1,863 amino acids that comprises a complex, three-dimensional structure. Scientists have been focusing their investigations on the two ends of the protein, the C terminus and the N terminus. The focus of Dr. Glover's work has been the C-terminus, which consists of a pair of related structures, called BRCT repeats. BRCT repeats not only occur in BRCA1, but are a hallmark of a large family of proteins which play a role in the repair of DNA damage.
Researchers know that the ends of the complex protein are particularly susceptible to mutations implicated in breast and ovarian cancers. A team of researchers lead by University of Washington professor Rachel Klevit, using nuclear magnetic resonance imaging techniques, has been focusing its investigations on the N terminus.
Since the U of A work was published this month in Nature Structural Biology--the flagship journal for structural biologists--Dr. Glover has been fielding calls from clinicians around the world, who are interested in the implications the work may have for designing screening programs for breast cancer.
"They're very interested in our work," says Dr. Glover, who is now working much more closely with the clinicians. "This could help clinicians identify high-risk patients sooner and detect the disease much earlier."
Researchers at the University of Alberta have a particularly long and successful history of pioneering x-ray crystallography techniques. Mapping three-dimensional structures is crucial to researchers' understanding of the biological functions of proteins.
Dr. Glover's work was funded by the Canadian Institutes of Health Research, the Alberta Heritage Foundation for Medical Research and the Canadian Breast Cancer Research Initiative. Co-researchers include PhD student Scott Williams and technician Ruth Green.
Established in 1993, the Canadian Breast Cancer Research Initiative is Canada's primary agency for the funding of breast cancer research. CBCRI has contributed $71.7 million to support 249 research grants as of March 31, 2001. CBCRI partners include the Avon Flame Foundation, the Canadian Breast Cancer Foundation, the Canadian Breast Cancer Network, the Canadian Cancer Society, the Canadian Institutes of Health Research, Health Canada and the National Cancer Institute of Canada.
In 2001, an estimated 19,500 women in Canada will be diagnosed with breast cancer. An estimated 5,500 women will die from their disease.
The U of A in Edmonton, Alberta is one of Canada's premier teaching and research universities serving more than 30,000 students with 6,000 faculty and staff. It continues to lead the country with the most 3M Teaching Fellows, Canada's only national award recognizing teaching excellence.