UT Southwestern Medical Center researchers have determined the atomic structure of an enzyme that plays an essential role in cell division, the fundamental process that occurs countless times daily in many life forms on Earth. Understanding the structure of this enzyme, separase, could lead to better treatments for cancer, which occurs when cells divide out of control, said Dr. Hongtao Yu, Professor of Pharmacology and a Howard Hughes Medical Institute (HHMI) Investigator at UT Southwestern.
“Chromosomes contain the genetic blueprint for life, and must be precisely duplicated and equally partitioned during each cell division. The cohesin complex forms a molecular ring to encircle the duplicated chromosomes and tether them together until the moment of chromosome separation,” said Dr. Yu, senior author of the study published online in Nature. “In organisms from fungi to humans, separase – an enzyme that breaks down proteins – cleaves and opens the cohesin ring to allow chromosome separation and subsequent partition into the two new daughter cells.”
Despite its central role in cell biology, the atomic structure of separase has eluded scientists since its discovery nearly two decades ago. This situation left a void in the understanding of the enzyme’s mechanism and regulation, the researchers said.
“We determined the atomic structure of separase from a fungus that can grow at high temperatures. The structure reveals how separase recognizes and cleaves the cohesin ring, allowing the chromosomes to separate,” said Dr. Yu, a Michael L. Rosenberg Scholar in Medical Research and member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. “This particular protein is very unstable in species that grow at normal temperature, such as human body temperature, but was more stable in the high-temperature fungus that we studied.”
Because of the enzyme’s role in cell division, chemical inhibitors of separase are expected to block cell proliferation and therefore may have therapeutic value in treating cancer. “The fungal separase that we studied is very similar to human separase. For that reason, we believe our structure will aid in the design of such inhibitors,” he said, “because once you have the shape of the structure, you can computationally look for molecules that will bind to it.”
Study co-authors included Dr. Zhonghui Lin, a research specialist at the HHMI and in the Department of Pharmacology, and Dr. Xuelian “Sue” Luo, Associate Professor of Pharmacology and Biophysics. This study was supported by the Cancer Prevention and Research Institute of Texas (CPRIT), the National Institutes of Health, and the Welch Foundation. The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 45 NCI-designated Comprehensive Cancer Centers in the nation.
The Simmons Comprehensive Cancer Center includes 13 major cancer care programs with a focus on treating the whole patient with innovative treatments, while fostering groundbreaking basic research that has the potential to improve patient care and prevention of cancer worldwide. In addition, the Center’s education and training programs support and develop the next generation of cancer researchers and clinicians.
The Simmons Cancer Center is among only 30 U.S. cancer research centers to be named a National Clinical Trials Network Lead Academic Participating Site, a prestigious new designation by the NCI, and the only cancer center in North Texas to be so designated. The designation and associated funding is designed to bolster the cancer center’s clinical cancer research for adults and to provide patients access to cancer research trials sponsored by the NCI, where promising new drugs often are tested.