Medical Pike

Telomere research seeks ways to make cancer cells fray and die off
Princeton scientist makes progress

August 6, 2000. Telomeres, structures found at the ends of chromosomes, are like caps wound around the ends of shoe laces to stop them fraying. They consist of specialized repeated sequences of DNA (TTAGGG in humans) that serve to maintain the integrity of the chromosome.

Telomeres normally are biodegradable. They protect chromosomes only for a span determined by the number of times cells divide. Then they unravel, exposing the aging chromosomes to damage. By this point the telomeres are acting as a fuse or "clock" for cellular death.

Cells normally divide only 60 to 100 times in the course of their lifespan. Each time a cell divides, telomeres shorten, eventually exposing the genetic material. Cell division halts and the cells enter a state known as senescence or aging then die.

In major types of cancer including prostate cancer, an enzyme called telomerase resets the cellular clock by restoring telomere length. This allows cancer cells to immortalize, or replicate indefinitely.

Now, a Princeton scientist has discovered a protein that halts the growth of telomeres. Virginia Zakian and her team have found a naturally occurring protein, called Pif1p, which acts directly on the chromosome ends (the telomeres), to keep the lengthening process in check.

Researchers have been studying telomerase with great intensity for the past 15 years because it appears to play a central role in the way cells age or become cancerous. Studies have shown that telomerase is present in 90 percent of cancer types, but is absent from most healthy cells.

In prostate cancer and some other cancers, it has been found, telomerase levels match clinical outcome for the patient. Cancer researchers and biotech companies are looking for ways to detect and measure telomerase in tumors and interfere with its action. Another goal is to find ways to use telomerase to extend the lifespan of normal cells and halt degenerative diseases.

Zakian's research suggests that mimicking or enhancing the action of Pif1p may be a good way to counter telomerase. In 1994, Zakian and collaborator Vincent Schulz reported that Pif1p keeps telomeres from lengthening. It remained unclear, however, how Pif1p accomplished that feat. There are many natural substances that could inhibit telomere lengthening in indirect ways, Zakian said.

The new paper, published in Science (Aug 4), shows that Pif1p acts on the telomerase pathway itself and interacts directly with telomeric DNA, a potentially attractive feature for drug developers.

One interesting aspect of Pif1p is that it is a special type of enzyme, a helicase, that unwinds the double strands of DNA. Zakian's research team created a small mutation in the gene that encodes Pif1p so that the protein is produced normally yet lacks this unwinding ability.

When telomerase-rich cells carried this mutated gene, Pif1p no longer worked and telomere lengthening progressed unchecked. Zakian believes that Pif1p may work by unzipping a temporary bond that forms between telomerase and the chromosome as telomeres are synthesized.

The experiments were done in baker's yeast cells, but Zakian said that telomere regulation has been so important throughout evolution that human cells employ many of the same mechanisms.

"These are very lowly organisms. This is what we use to bake bread," she said. "However, as we show in this paper, humans have a protein very similar to yeast Pif1p. It would be quite gratifying if it turned out that it also functions in a similar way in humans and could give us insights into human cancer."

Links

Ann N Y Acad Sci 1999;886:1-11 Telomerase. A target for anticancer therapy. Lichtsteiner SP; Anticancer Res 2000 May-Jun;20(3B):1905-12

Genetic alterations in human prostate cancer: a review of current literature. Ozen M, Pathak S Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.