Immortalizing agent

October 21, 1994

"Immortalizing agent" of tumor cells found in yeast

Researchers at the University of Chicago Medical Center have isolated the gene for a component of the elusive molecular machinery that plays a key role in making cancer cells immortal, offering scientists a tantalizing target for new anticancer drugs of greater effectiveness and lower toxicity. The finding is reported in today's issue of the journal Science.

The suspected immortalizing agent is an enzyme called telomerase (tee-LOW-mer-ace) that adds DNA to the endcaps, or telomeres, of the cell's chromosomes. Normally these vital end caps protect the loose ends of chromosomes from being chewed up or joined together, but are themselves whittled down every time the cell divides. Scientists think that normal cells, which apparently lack the telomerase enzyme, stop dividing and die off appropriately after 50 to 100 divisions when their telomeres are worn to the nub.

"At the beginning of life, our cells have very long telomeres, which grow shorter from then on," says Daniel Gottschling, PhD, associate professor of molecular genetics and cell biology, one of two authors on the Science paper. "The lack of telomerase results in the telomeres shrinking, which provides a way for the cells to mark time and age every time they divide."

Telomerase is believed to play a role in the normal development of progenitor cells. In cancerous cells, telomerase somehow becomes reactivated, and the telomeres begin growing again.

Telomerase would be a prime target for anticancer drugs. While most chemotherapy drugs kill all rapidly dividing cells in the body, causing serious side effects which limit their use, a drug that inhibits telomerase would only affect those cells that are immortal and malignant.

Telomerase activity has been observed in cells made immortal in the laboratory and in human cancer cells. It was discovered 10 years ago in single-cell pond organisms that have many tiny chromosomes, and thus many telomeres. But a component gene identified in this organism did not lead to the rest of the genes that define telomerase.

Gottschling and his graduate student Miriam Singer devised a way to hunt for mutations in genes that must somehow be involved with telomere function in yeast. Since telomeres normally silence genes located near them, the researchers looked for mutations that would restore the expression of marker genes placed near two telomeres.

Using that genetic trick, Singer discovered 10 new genes, but one stood out because mutations in it caused all telomeres to grow shorter. The researchers then demonstrated that this gene, called TLC1, encodes an essential RNA component of the telomerase enzyme. Gottschling now hopes that this yeast gene will lead him to all the other cogs in the telomerase machinery.

"Yeast is a very powerful research tool. If you find one component of a system like telomerase, you can pick out all the others by genetic manipulations," he said. "Now we will be able to figure out who all the other key players are, and how the whole process is controlled. This will provide a sound rationale for new drug design."

Because the vital genetic housekeeping functions are nearly the same in all cells, telomere maintenance in yeast and humans is very similar. "If you want to understand something in humans, it's great to have a model organism," Gottschling said.

The research reported today was funded by the National Institutes of Health and the Pew Charitable Trust.