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Targeting Enzymes That Immortalize Cancer Cells

  [ 21 votes ]   [ Discuss This Article ] • September 4, 2002

By Robert Sanders, Media Relations

Berkeley — Discovery of a clever trick that cancer cells use to make themselves immortal may lead to a way to stop their unchecked growth, according to scientists at the University of California, Berkeley.

In a paper published this week in the journal Nature Cell Biology, UC Berkeley molecular biologists describe a significant difference between the way normal and cancerous cells handle an enzyme called telomerase, which is critical to unrestricted cell growth. The enzyme maintains the telomeres that cap the ends of each chromosome, keeping them long enough so that DNA replication and cell division go without a hitch.

When a cell's telomeres get too short and are not properly tied up, division stops.

Post-doctoral fellow Judy M. Y. Wong and associate professor Kathleen Collins discovered that telomerase is walled off from the chromosomes of normal cells until needed, and is then released into the DNA-rich area of the nucleus to touch up the telomeres, which shorten somewhat with each cell division. The enzyme is then shuttled back to its compartment, called the nucleolus, to await the next round of division.

At top, the nucleus of a normal cultured fibroblast cell at rest, stained with green fluorescent protein to show the location of telomerase sequestered in the nucleoli of the cell. Below, the nucleus of a cell transformed into a cancer cell by the virus SV40 has telomerase everywhere in the nucleus except the nucleoli.

Cancer cells, on the other hand, have found a way to mobilize telomerase continually so they can quickly double and redouble while keeping the telomeres intact. Some cancer cell lines in use today have been growing for almost half a century, their telomeres kept long and healthy by the readily available telomerase.

"Normal somatic cells keep most of the telomerase away from the DNA, whereas cancer cells let all of it go," said Collins, a member of the Department of Molecular & Cell Biology and part of the campus's Health Sciences Initiative. "This should help the transformed (cancer) cells use telomerase much more efficiently."

Though Wong and Collins have yet to discover how cancer cells mobilize telomerase, finding a way to round them up again could stop the unbridled growth of cancer cells. They now are searching for the proteins and signals involved in telomerase shuttling around the cell nucleus.

An alternative approach taken by most telomerase researchers and a number of biotech firms is to search for ways to turn off telomerase to stop cancerous growth.

The UC Berkeley researchers also see a potential medical benefit in boosting telomerase in patients receiving chemotherapy, or in people with HIV who experience continual, rapid turnover of immune cells, which exhausts the limited number of divisions allotted to immune cells.

"Activation of telomerase, perhaps by gene therapy, could have a lot of benefit for these people," Collins said. "Combining telomerase activation with chemotherapy is an approach we would like to try."

One group of people who could benefit from more telomerase are those with a rare, predominantly inherited disease called dyskeratosis congenita (DKC). In 1999, Collins and her colleagues reported that some cases of DKC are caused by a shortage of telomerase. Because at each cell division the telomeres get shorter, cells that continually renew themselves, such as blood, skin and other epithelial cells, reach the end of their growth capacity quicker without telomerase to refresh their telomeres.

As a result, those with DKC develop skin lesions and anemia, are prone to life-threatening infections, and frequently die from bone marrow failure. Those who survive into their twenties or thirties often die of cancer.

Telomeres were recognized as chromosome end caps in the early 20th century, but it wasn't until 1982 that research at UC Berkeley proved that they protected the chromosome ends from improper rearrangements and generally unhealthy habits. That work by UC Berkeley professor Elizabeth Blackburn, now at UC San Francisco, showed that telomeres, which are comprised of the same short sequence of base pairs repeated over and over, are there to protect valuable DNA from a flaw in the DNA replication process. The machinery that reads and duplicates DNA can't go all the way to the end of the chromosome, so a few base pairs — the building blocks of DNA — are lost from the ends each round. During a single cell division, human chromosomes may lose 50-250 base pairs from each end, out of a starting total of 4-15,000 base pairs per telomere.

In most mammalian cells, part of the length of telomeres are expendable, giving cells a fixed life span — they divide perhaps 35 to 50 times, and that's it. After that, they just sit around or die a natural death. The Blackburn lab's discovery of telomerase in 1984 provided the answer to how some cells keep dividing indefinitely. In yeast, for example, telomerase is always around, replacing lost telomere tips and allowing yeast to divide forever.

Though in most human cells telomerase production is turned off, the enzyme is turned on in cells that turn over frequently — blood cells, skin cells and others that line surfaces (epithelial cells), and cancer cells. The enzyme refreshes the telomere ends and allows more cell divisions.

Collins got interested in telomerase once it was found to be not merely protein, but a complex of protein and RNA — a ribonucleoprotein. Initially, the RNA was thought to be merely a template that the protein used it to make the DNA that it subsequently added to the chromosome end. Collins and her graduate students at UC Berkeley have shown in many experiments over the past few years that the RNA is much more than a template.

"The RNA is not just specialized as an internal template, the non-template region of RNA is critical for catalysis," she said. "People used to think that functional RNA was just a relic of an ancestral 'RNA World' left over in the evolution to protein-based enzymes, but recently there has been a recognition that RNA plays an important role in ribonucleoprotein enzymes with recently evolved roles: a modern-day 'RNP World.'"

Most of the ribonucleoprotein in cells is in the form of the ribosome, an ancient complex that translates RNA into protein. Like telomerase, it is built in the nucleus, inside a haven called the nucleolus.

In searching for where telomerase hangs out in the nucleus, Wong noticed that telomerase is not always in the same place, at least in cultured human fibroblasts. During most of the cell cycle, telomerase is attached to the outer region of the nucleolus, based on localization studies of the telomerase reverse transcriptase protein tagged with green fluorescent protein. But just before cell division, when one would expect telomerase to be active at the telomeres, it suddenly appears throughout the nucleus.

Looking at cancer cells, however, Wong and Collins found that telomerase was everywhere throughout the cells' entire cell cycle — it was never sequestered in the nucleolus. When Wong and graduate student Leonard Kusdra infected a normal cell with simian virus 40 — a standard way to induce cancer — telomerase was all over the resulting transformed cell.

Finally, when Wong irradiated a normal cell and a transformed, cancerous cell to induce chromosome breaks, she found that telomerase was taken up and sequestered into the nucleolus.

These results explain one puzzle of telomerase: If it can add telomeric repeat units to chromosome ends, why doesn't it also add repeats to the ends of breaks that occur frequently in DNA? This would interfere with the ability of the cell to repair breaks, and quickly lead to genomic instability and death.

Based on this new research, cells evidently sweep up telomerase when DNA damage occurs to prevent such interference.

Collins and her laboratory colleagues continue to explore the activity of telomerase and other RNA enzymes, concentrating on how they're assembled and how they're regulated.

The work was supported by grants from the American Cancer Society and the National Institutes of Health.

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