Telomerase, a powerful enzyme found at the ends of chromosomes, can keep humans healthy, or promote cancer growth. Researchers at the University of Colorado in Boulder used a process called single-molecule imaging to look into the complicated processes that this enzyme uses to attach itself to the ends of chromosomes. This new understanding could help researchers develop better diagnostics and drugs for treating cancer and other diseases.
The findings, which were recently published in the journal Cell, show that telomerase has a small window of opportunity, lasting only minutes, to connect to the telomeres at the ends of chromosomes. The team was surprised to find that telomerase may probe each telomere thousands of times, rarely forming a stable connection, in order to be successful at connecting to the chromosomes. Researchers believe that inhibiting telomerase from attaching to cancer cells is a target for better treatment of the disease.
Telomeres have been studied since the 1970’s for their role in cancer. They are constructed of repetitive nucleotide sequences that sit at the ends of our chromosomes like the ribbon tails on a bow. This extra material protects the ends of the chromosomes from deteriorating, or fusing, with neighboring chromosome ends. Telomeres are consumed during cell division and, over time, will become shorter and provide less cover for the chromosomes they are protecting. The enzyme, telomerase, replenishes telomeres throughout their lifecycles.
Telomerase is the enzyme that keeps cells young. From stem cells to germ cells, telomerase helps cells continue to live and multiply. Too little telomerase produces diseases of bone marrow, lungs and skin. Too much telomerase results in cells that over proliferate and may become “immortal.” As these immortal cells continue to divide and replenish, they build cancerous tumors. Scientists estimate that telomerase activation is a contributor in up to 90 percent of human cancers.
“This discovery changes the way we look at how telomerase recruitment works in general,” says University of Colorado Boulder Distinguished Professor and Nobel laureate Thomas Cech, who is director of CU’s BioFrontiers Institute and the lead author on the study. “It’s exciting to see this in living cells as it happens. Single-molecule imaging freezes the process, allowing us to study it. We are the only ones who have done this type of imaging of telomerase.”
The research team included coauthors, Jens Schmidt (pictured, left), a postdoctoral fellow and staff scientist, Arthur Zaug. They used the CRISPR genome editing and single molecule imaging to track telomerase’s movements in the nuclei of living human cancer cells. CRISPR, or Clustered Regularly Interspaced Short Palindromic Repeats, uses segments of DNA that contain short copies of base sequences. The team used single-molecule imaging, attaching fluorescent protein tags to human cancer cells so that the enzymatic process was visible under a powerful microscope.
“At the end of the day, the goal is to target telomerase as an approach to treat cancer,” say Schmidt. “You can inhibit telomerase across the board, but the challenge is isolating the telomerase in cancer cells from the telomerase participating in the normal processes of healthy cells. This research brings us closer to understanding these processes.”