PITTSBURGH, July 28, 2015 - By studying the yeast used in beer- and bread-making, researchers at the University of Pittsburgh School of Medicine have uncovered the mechanism by which ancient proteins repair DNA damage and how their dysfunction could lead to the development of tumors. The findings, published online today in Nature Communications, could lead to new ways to tailor cancer therapies.
In humans, protein mutations called RAD51 paralogues have been associated with breast and ovarian tumors, said senior investigator Kara Bernstein, Ph.D., assistant professor of microbiology and molecular genetics at Pitt School of Medicine and the University of Pittsburgh Cancer Institute, partner with UPMC CancerCenter.
"These are proteins that have been present throughout evolution in many species, but very little has been known about what they do," she said. "Our study shows for the first time the mechanism of how they are involved in the repair of damaged DNA."
Because RAD51 paralogues are too difficult to work with in animal cells, the research team instead explored their function in yeast. They found the proteins interact with other proteins called the Shu complex to repair breaks in DNA strands, which can be caused by environmental toxins, radiation and other naturally occurring exposures.
Shu complex works synergistically with additional RAD51 paralogues to search for homologous, or complementary, DNA regions with double-strand breaks, in which both poles of the twisting DNA ladder have been broken, the researchers found. Pieces of the genetic code can be lost in such areas; the paralogues and complex repair the damage by filling in the missing pieces in a process called homologous recombination.
"Now that we understand what the proteins do, we can perhaps tailor therapies for patients who have cancer and mutations in these repair genes," Dr. Bernstein said.
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The team included Stephen K. Godin, Faiz F. Kabbinavar, and Andrew P. Van Demark, Ph.D., of Pitt; and William A. Gaines, Ph.D., Timsi Rao, Ph.D., and Patrick Sung, Ph.D., of Yale University. The project was funded by National Institutes of Health grants ES015252, ES007061, CA168635, GM088413 and GM101808.
About the University of Pittsburgh School of Medicine
As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support.
Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region's economy. For more information about the School of Medicine, see http://www.medschool.pitt.edu.
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Journal
Nature Communications