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Breast cancer susceptibility genes play role in DNA repair

PHILADELPHIA A study led by scientists at The Wistar Institute defines a functional role for the tumor suppressor proteins BRCA1 and BRCA2 in breast cancer. The findings, presented in November issue of the journal Molecular Cell, also identify a number of novel proteins that work alongside BRCA1 and BRCA2 and might also play a part in breast cancer. These proteins offer an important set of new targets for possible anti-cancer drugs.

The link between the BRCA1 and BRCA2 genes and hereditary breast cancer was first identified in the early 1990s, but the biological function of the BRCA1 and BRCA2 proteins has remained elusive. The Wistar researchers demonstrated how the two proteins combine with others to form a complex called BRCC (BRCA1- and BRCA2-containing complex) and defined the role of the complex in regulating DNA repair. The researchers also discovered two new proteins that are part of BRCC and linked one of them, BRCC36, to sporadic breast cancers.

"We know that BRCA1 and BRCA2 are normally tumor suppressor genes that, when mutated, can lead to cancer, but they only account for a fifth of all hereditary breast cancers and about five percent of breast cancers overall" Ramin Shiekhattar, Ph.D., an associate professor at The Wistar Institute and senior author on the study. "The BRCC36 gene and the other genes that factor into the creation of the BRCC complex are good candidates for additional breast cancer susceptibility genes."

Shiekhattar and his colleagues determined that the BRCC protein complex acts as one large regulatory enzyme. They discovered that one target of BRCC is a protein familiar to cancer researchers called p53, a potential cancer-promoter if left unregulated. BRCC attaches a chemical tag, a ubiquitin group, to p53. The ubiquitin tag signals the cell's digestive machinery to destroy the marked protein.

Following treatment of cells with DNA-damaging radiation, BRCC interacted with p53 and, to a lesser degree, a
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Contact: Franklin Hoke
hoke@wistar.upenn.edu
215-898-3716
The Wistar Institute
20-Nov-2003


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