Scientists at the University of California Los Angeles (UCLA) recently produced the clearest-ever image of telomerase, an enzyme involved in cancer and aging. This knowledge could inform development of anti-cancer and anti-aging therapies. The research was enabled in part by an award from the UCLA Clinical and Translational Science Institute (CTSI), an NCATS Clinical and Translational Science Award (CTSA) Program hub.
The telomerase enzyme works to keep cells alive and healthy by renewing telomeres, the caps of DNA at the ends of chromosomes that protect the chromosomes from damage. Telomeres shorten every time a cell divides, eventually prompting the cell to stop dividing or die. In some cells, telomerase slows this process. Drugs that enhance telomerase activity could be used to treat various aging-related conditions. Conversely, most cancers involve abnormally elevated levels of telomerase activity, so drugs that block telomerase potentially could treat cancer.
The research was published in the Oct. 30, 2015, issue of the journal Science. Senior author Juli Feigon, Ph.D., a professor of chemistry and biochemistry at UCLA, applied for the CTSI award to fund the imaging of telomerase using a special, high-powered microscopy technique called cryo-electron microscopy (cryo-EM) in collaboration with Hong Zhou, Ph.D., a UCLA professor of microbiology, immunology and molecular genetics. “We had very limited funds for cryo-EM research, so the CTSI award greatly facilitated the project and allowed us to obtain the first-ever cryo-EM structure of telomerase,” said Feigon.
CTSI staff issue the peer-reviewed awards to investigators on a competitive basis to be used as credit at any of UCLA’s core facilities, which house shared research resources for university scientists. Applicants must demonstrate the translational relevance of their research.
Feigon’s team, in collaboration with Kathleen Collins, Ph.D., a professor of biochemistry at the University of California, Berkeley, used a one-celled organism called Tetrahymena, which contains telomerase that is much easier to access than human telomerase. The work uncovered that Tetrahymena telomerase structure is much more similar to human telomerase, and thus a better model for it, than previously thought. In addition to more clearly visualizing the enzyme’s structure, the team was able to gain insight into how telomerase interacts with telomeres.
“Basic science discoveries such as this one are an important first step in the translational process,” said Steven M. Dubinett, M.D., director of the UCLA CTSI. “The CTSI awards program provides an avenue for investigators to quickly access resources they need to answer important translational science questions.”
The group used several other modes of high-powered imaging to confirm their findings. Feigon said her team’s discovery has underscored the power of this multi-modal approach, called integrative structural biology. It is a platform that other researchers can use to more effectively study and visualize other important molecules. The study’s findings also could offer critical information for the future development of telomerase-targeting therapies for cancer and aging-related conditions.
Feigon’s research is not yet complete: She and her team are continuing to study the telomerase images and are working to obtain even higher-resolution pictures to gain further insights into the enzyme’s structure and function.
Posted June 2016
In addition to CTSA Program funding for cryo-EM, the research was supported by the National Institute of General Medical Sciences and the National Science Foundation.