The findings, published online in Oncogene, focus on the gene BRCA1, which is mutated in a majority of families who have hereditary breast and/or ovarian cancers, according to senior author Ronit I. Yarden, PhD, assistant professor in the Department of Human Science at the School of Nursing & Health Studies.
“There is a debate in the scientific community about whether BRCA1 enzymatic activity is important in tumor suppressor function,” Yarden said. “My lab thinks it is.”
Previous research by other investigators, according to Yarden, has shown that BRCA1 is an ubiquitin E3 ligase enzyme. When added to other proteins, ubiquitin has the ability to mark them for degradation and recycling.
Her laboratory worked to discover which proteins BRCA1 is targeting with ubiquitin and how that activity might help attenuate cell division in response to DNA damage – a function that is important for maintaining genomic integrity and suppressing tumor growth.
“Cells have surveillance mechanisms and check points that govern cell division,” she said. “In order to conduct DNA repair in a timely fashion, a cell must be stopped for awhile 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 said. “This work shows that BRCA1 enzymatic function is essential for maintaining genomic integrity and may explain BRCA1 role in tumor suppression.”
“We identified a novel function,” she said. “Although different substrates for BRCA1 were previously identified by other investigators, those didn’t explain directly BRCA1′s role in maintenance of genomic integrity. Our new targets are the first to directly link this ubiquitination function of BRCA1 to halting cell division that is important for maintenance of genomic integrity and stability, an important activity of tumor suppression.”
Shabana Shabbeer, PhD, a post-doctoral fellow in Yarden’s laboratory at Georgetown, and Dorit Omer, a former graduate student in Yarden’s previous laboratory 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, and human science major Alexandra Pietraszkiewicz; Dana Berneman, Osnat Weitzman, Sally Metsuyanim, and Moshe Z. Papa – all of Sheba Medical Center; and Alla Shainskaya, PhD, of the Weizmann Institute of Science in Israel.
This study was supported by a Research Career Development Award from the Israel Cancer Research Fund and through funding from the Ministry of Health in Israel, the Israel Cancer Association, and Georgetown University. The authors report having no personal financial interests related to the study.