Telomerase, a powerful enzyme that acts at the ends of human chromosomes, can keep us healthy, but it can also promote cancer growth. Now, researchers at the University of Colorado Boulder have used a process called single-molecule imaging to visualize the process that this enzyme uses to attach itself to the ends of chromosomes.
The new understanding could help researchers develop new approaches 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 do its job 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 chromosome end. Researchers believe that inhibiting telomerase from attaching to telomeres in cancer cells is a strategy for treatment of the disease.
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.
Telomeres have been studied since the 1970’s for their role in cancer. They are constructed of repetitive DNA 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 from 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.
“This discovery changes the way we look at how telomerase recruitment works,” said CU 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 isolates the process, allowing us to study its dynamics.”
The research team included co-authors Jens Schmidt, a Damon Runyon Cancer Research Foundation postdoctoral fellow, and Staff Scientist Arthur Zaug. They used 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, allowed the team to attach fluorescent protein tags to telomerase and telomeres in human cancer cells so that the search 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,” said 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.”