PHILADELPHIA -- Researchers at the Abramson Family Cancer Research Institute of the University of Pennsylvania and the Dana-Farber Cancer Institute describe in this weeks issue of Science a new candidate breast-cancer susceptibility gene. The Rap80 gene is required for the normal DNA-repair function of the well-known breast cancer gene BRCA1.
Cancer-causing mutations in the BRCA1 protein fail to bind to the Rap80 protein. Consequently BRCA1 is unable to identify DNA damage sites in the genome. When BRCA1 fails to fix DNA damage, cancer-causing mutations accumulate, spawning the development of breast and ovarian malignancies.
"With this current discovery, we have made significant new insights into the molecular mechanism by which BRCA1 recognizes sites of DNA damage that breast-cancer-causing mutated forms of BRCA1 cannot recognize," says co-senior author Roger Greenberg MD, PhD, Assistant Professor of Cancer Biology at Penn. "Now we have gained a partial understanding of the molecular basis between cancer-causing BRCA1 failures to fix DNA damage versus normal BRCA1s ability to fix DNA damage."
In this study, the researchers found Rap80 binds to the region of the BRCA1 protein that is necessary for recognizing sites of DNA damage. In the 1990s, investigators discovered that BRCA1 was involved in DNA repair by maintaining the normal number and structure of chromosomes. DNA breaks that aren't repaired can lead to cancer by increasing the rate of mutations, cancer-causing changes in the gene sequence.
More specifically, modification of proteins in the cell nucleus by another protein called ubiquitin that are tightly bound to DNA are responsible for signaling BRCA1 via Rap80 to action. Rap80 binds to specific types of ubiquitin that concentrate at DNA damage sites, enabling BRCA1 to be recruited to sites of damage.
BRCA1 and BRCA2 mutations account for less than 50 percent of inherited breast cancer. "The genetic b
Contact: Karen Kreeger
University of Pennsylvania School of Medicine