Discovery gives insight into the way cells protect their most precious possession: their own genetic material
(Toronto – August 19, 2010) In a groundbreaking study, Mount Sinai Hospital researchers including Drs. Daniel Durocher, Anne-Claude Gingras and Frank Sicheri have uncovered a protein called OTUB1 that helps block accumulation of DNA damage in the cell—a discovery that may lead to the development of strategies to improve some cancer therapies.
Lead author Dr. Durocher, Lunenfeld Senior Investigator and the Thomas Kierans Research Chair in Mechanisms of Cancer Development, as well as colleagues at Mount Sinai Hospital and the Keio University in Japan, have revealed pivotal new information on how cells regulate their genetic material. In addition, the discovery improves understanding of familial breast and ovarian cancer, as the research shows that OTUB1 inhibits the action of BRCA1, a DNA repair protein often mutated in these cancers.
“In recent years, we have been very good at finding proteins necessary for DNA repair,” said Dr. Durocher. “What we did not appreciate was that gatekeepers existed to inhibit the capacity of the cell to repair DNA. The obvious question now is: Can we enhance the ability of the cell to repair DNA by blocking OTUB1?”
The findings were reported as a full article in the August 19 issue of the prestigious international journal Nature.
The researchers identified OTUB1 using a technique termed RNA interference (or RNAi), an approach that helps scientists determine the functions of proteins and genes. In effect, RNAi provides researchers with a highly selective tool to inhibit the function of any given gene. After exposing cells to radiation, Dr. Durocher and his team used RNAi to discover that OTUB1 inhibits a cell’s DNA repair mechanisms, through its role in a process known as ubiquination.
Ubiquitins are small regulatory proteins in cells. The addition of many ubiquitins onto a target protein can act as a ‘mayday’ signal at the site of DNA damage, attracting repair mechanisms to fix the damage. Dr. Durocher’s team found that OTUB1 mutes the mayday signal by preventing the addition of ubiquitin units.
“Perhaps the biggest surprise was that OTUB1 works by an entirely new and elegant mechanism,” said Dr. Durocher. “Mutations in genes that repair our DNA can lead to cancer, infertility and immune deficiency. Therefore, inhibiting the proteins that block DNA repair could lead to new types of therapeutics for these diseases.”
For example, Dr. Durocher explained that by inhibiting OTUB1, healthy cells may be better able to withstand cancer treatment with radiation and certain chemotherapy medications such as doxorubicin. As well, inhibiting OTUB1 may lead to treatments for genetic immunodeficiency disorders such as RIDDLE syndrome, in which cells lose their ability to repair DNA damage.
Dr. Durocher, recently named one of Canada’s Top 40 Under 40, has made a series of high-impact discoveries through his investigations into how normal cells become cancerous and how healthy cells detect and repair damage to their DNA, and his present discovery builds on earlier research in this area. In 2007, he and his team discovered that a gene known as RNF8 helps guide BRCA1. By guiding BRCA1 to the damaged DNA, RNF8 helps ensure that the necessary repairs can be made.
Last year, Dr. Durocher discovered that a gene known as RNF168 is mutated in RIDDLE syndrome. In the present study, Dr. Durocher and his colleagues found that OTUB1 directly inhibits UBC13, a protein that helps repair DNA damage, and interferes with its effect on the RNF168 pathway (in effect inhibiting a cell’s response to DNA damage).
“Furthermore, reducing the levels of OTUB1 bolsters the cell’s DNA repair mechanisms, meaning that blocking OTUB1 could actually help prevent DNA damage,” said Dr. Durocher.
The study was supported by the Canadian Institutes of Health Research.