> Researchers at the Abramson Family Cancer Research Institute of the University of Pennsylvania and the Dana-Farber Cancer Institute describe 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.
> In this study, the researchers found Rap80 binds to the region of the BRCA1 protein that is necessary for recognizing sites of DNA damage.
> Therefore, Rap80, by interacting with a BRCA1 region that is essential for BRCA tumor suppression, now becomes a candidate to investigate as another breast cancer disease gene in families that do not have BRCA1 and BRCA2 mutations, but have a history of breast and/or ovarian cancer
> These findings are published in this week’s issue of Science

(PHILADELPHIA) – Researchers at the Abramson Family Cancer Research Institute of the University of Pennsylvania and the Dana-Farber Cancer Institute describe in this week’s 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.

BRCA1 and Rap80

BRCA1 and Rap80 are recruited to the same structures at DNA damage sites in human cells treated with ionizing radiation.

Click on thumbnail
to view full-size images

Cancer-causing mutations in the BRCA1 protein cause it to 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 BRCA1’s 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 basis of breast cancers in other families has been largely unknown,” explains Greenberg. “These families aren’t able to make informed choices about screening and treatment, prophylactic or otherwise, the way the BRCA families can.”

Researchers from multiple labs, including Penn and those led by co-senior author David M. Livingston at Dana-Farber, are finding that many of these non-BRCA families have mutations in genes that have a relationship with BRCA1. Many of the genes that encode these proteins are also altered in familial breast cancer.

BRCA1 Damaged DNA Sites

Depletion of Rap80 from human cells (right panel) reduces the ability of BRCA1 to migrate to laser-induced DNA damage sites as compared to control cells (left panel).

Click on thumbnail
to view full-size images

“Thus Rap80, by interacting with a BRCA1 region that is essential for BRCA tumor suppression, now becomes a candidate to investigate as another breast cancer disease gene in families that do not have BRCA1 and BRCA2 mutations, but have a history of breast and/or ovarian cancer,” says Greenberg. “In collaboration with other researchers we are currently looking to see if families that have a history of breast cancer, but lack BRCA1 and BRCA2 mutations, have any gene sequence changes in Rap80.”

This research was funded by the National Cancer Institute and startup funds from the Abramson Family Cancer Research Institute.

Co-authors are Bijan Sobhian, David M. Livingston, Aedín C. Culhane, Lisa Moreau, and Bing, Xia from Dana Farber, and Genze Shao and Dana R. Lilly from Penn.

###

PENN Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honors [Hospital of the University of Pennsylvania; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.