BRCA2 was already known to be a tumor suppressor -- a protective protein that prevents the development of cancer -- but exactly how the protein does its job was not understood. Now MSKCC scientists have been able to map out the structure of the protein, showing that it interacts directly with DNA and helps to repair genetic damage. An inability to correct genetic damage leads to unstable chromosomes and often to cancer.
"If BRCA2 is altered or missing, it leads to a dangerous accumulation of genetic errors," said the study's senior author Nikola P. Pavletich, PhD, head of MSKCC's Laboratory of Structural Biology of Oncogenes and Tumor Suppressors and an investigator in the Howard Hughes Medical Institute. "By studying the normal function of BRCA2, we can understand how changes in the protein contribute to the development of cancer."
BRCA2 is an unusually large molecule, which has made it difficult for researchers to study. But Dr. Pavletich's team, including first author Haijuan Yang, found a way around that problem and was able to crystallize the protein. Those crystals were then bombarded with high-energy X-rays, a process called X-ray crystallography, and the diffraction patterns created by the X-rays were used to calculate the three-dimensional picture of the protein. This picture revealed that BRCA2 is similar in structure to other proteins known to bind DNA. The researchers then took the work a step further, showing that BRCA2 does indeed bind to DNA in special regions that are commonly found around broken DNA strands.
Researchers showed that BRCA2 participates in the repair of "double-strand" breaks: These breaks are a particularly lethal type of damage because if both strands of the DNA double helix break at the same time, cells can permanently lose genetic information. The structure revealed that BRCA2 binds the broken strands and enables the recovery of lost information via a process called homologous recombination -- in which the missing DNA is copied from another part of the cell.
"We are now a step closer to understanding this particular type of inherited breast and ovarian cancers," Dr. Pavletich said.
Mutations in the BRCA2 gene have been implicated in hereditary breast and ovarian cancers since 1995. The other gene commonly linked to hereditary breast and ovarian cancers is called BRCA1.
Researchers from the University of Texas Health Science Center in San Antonio also contributed to the study, which was funded by the National Institutes of Health, the Howard Hughes Medical Institute, the Dewitt Wallace Foundation, the Samuel and May Rudin Foundation, and the Arthur and Rochelle Belfer Foundation.
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