Study Uncovers Possible Tumor Suppression Mechanism

DECEMBER 17, 2012 - A new study by Georgetown University Medical Center researchers has revealed how a well-known tumor suppressor gene may stop cancer cell growth.

The findings, published online today in Oncogene, one of the world’s leading cancer journals, focus on the gene BRCA1.

The gene is mutated in a majority of families with hereditary breast and/or ovarian cancers, says senior author Ronit I. Yarden, PhD, assistant professor in the Department of Human Science at the School of Nursing & Health Studies.

Targeting Proteins

“There is a debate in the scientific community about whether BRCA1 enzymatic activity is important in tumor suppressor function,” says Yarden, a geneticist. “My lab thinks it is.”

The professor says previous research by other investigators has shown that BRCA1 is a type of enzyme called ubiquitin ligase. When added to certain proteins, ubiquitin has the ability to mark them for degradation.

Her laboratory worked to discover which proteins BRCA1 is targeting with ubiquitin and how that activity might help reduce cell division in response to DNA damage – a function important in suppressing tumor growth.

Surveillance Methods

“Cells have surveillance mechanisms and check points that govern cell division,” she says. “In order to conduct DNA repair in a timely fashion, a cell must be stopped for a while and then repaired. Once DNA is fixed, division can then begin again.”

Yarden’s lab discovered that BRCA1 targets two specific proteins – cyclin B and Cdc25c – which are the “keeper genes” that regulate the G2/M checkpoint – the last checkpoint a cell has to go through before it divides.

“The paper shows that in response to DNA damage, BRCA1 is responsible for tagging these two proteins to stop the cells from dividing so repair can occur,” Yarden says. “This work shows that BRCA1 enzymatic function is essential for maintaining genomic integrity and may explain the role of BRCA1 in tumor suppression.”

Georgetown and Israeli Authors

Shabana Shabbeer, PhD, a post-doctoral fellow in Yarden’s lab at Georgetown, and Dorit Omer, a former graduate student in Yarden’s former lab at Sheba Medical Center in Israel, are lead authors of the manuscript.

Co-authors include two undergraduate students from NHS – international health major Alexandra Alpaugh (NHS’13) and human science major Alexandra Pietraszkiewicz (NHS’14).

Other researchers include those from Sheba Medical Center and the Weizmann Institute of Science in Israel.

A Research Career Development Award from the Israel Cancer Research Fund, the Ministry of Health in Israel, the Israel Cancer Association and Georgetown University funded Yarden’s research.