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March 15, 2000

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Scientists Clarify Much-Sought Enzyme, Pave Road To Cancer Therapy

Scientists worldwide have eagerly eyed the enzyme telomerase as an ideal target for anti-cancer therapy. Active in cancer cells, which need it to divide, telomerase has sparked keen research. Biotech companies have pumped millions into finding a telomerase inhibitor.

Now a team of researchers at Johns Hopkins has taken a key step toward such anti-telomerase cancer therapy. In a report in the March issue of Cell, they describe the fundamental shape of the telomerase molecule in mammals and other vertebrates. Knowing this structure, they say, helps them pinpoint the enzyme's vulnerable spots. "This puts us far closer to finding a way to inhibit it," says molecular biologist Carol Greider, Ph.D., who led the team.

After cloning the gene for the "business end" of the telomerase molecule in 32 different animals -- from shrew to elephant -- the researchers compared the structure of the resulting enzyme. They found four common areas highly involved with the enzyme's working, regardless of animal type.

"By taking this comparative or phylogenetic approach, we learned what shape nature thought best for telomerase to work," says Greider. That shape is basically the same from animal to animal, even though parts of the enzyme differ in length and chemical makeup. It emphasizes how important the particular structure must be for telomerase to function.

Telomerase's role in cells is to maintain highly specialized bits of DNA at the ends of chromosomes. These areas, called telomeres, act as caps, protecting chromosome ends either from being degraded or from abnormally sticking to other chromosomes. Without telomeres, one scientist wrote in an earlier Cell article, the resulting chromosome instability would "wreak havoc on the genome."

Scientists have found that normal and cancer cells differ greatly with respect to telomerase. Normal cells shut down production of telomerase early on, in embryo development. In cancer cells, however, the enzyme continues to be widely active, says Greider. The exact reason for telomerase's continued activity in cancer cells isn't clear, says Greider. Some have speculated, she says, that whatever sparks cancer's continuous cell division somehow also resurrects programs in cells usually turned on in the making of "immortal" cells such as stem cells. Those programs likely involve telomerase. "But whatever is going on in the cancer cells to activate telomerase," Greider explains, "our recent experiments have shown that inhibiting it leads to cancer cell death. We hope this new information on basic structure will prompt a flurry of approaches to inhibit the enzyme."

Knowing the basic or secondary structure of a molecule is a bit like knowing the bellows of an accordion is corrugated. You see the general possibilities of how it can work. The next step is learning how that shape can vary how the bellows could expand, contract or twist. This is Greider's next goal: to find telomerase's "tertiary" structure. Then, she says, "we should be able to explain precisely how it works."

The study was funded by a National Institutes of Health grant.

Other researchers on the study are Jiunn-Liang Chen, Ph.D., and Maria A. Blasco Ph.D.

Related Web site: http://telomerase.bs.jhmi.edu/Greiderlab

The study appeared in the March 2000 issue of Cell, vol. 100, pp. 503-514.


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