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Discovery In Chromosome Replication Process May Prove Valuable In Cancer Diagnosis

University of Colorado at Boulder

An international research team has discovered the key protein in an enzyme responsible for lengthening the ends of chromosomes, a surprising finding that potentially could lead to the development of new ways to detect and treat cancer.

Ironically, the protein is nearly identical to the protein responsible for some viral diseases, including HIV, said Thomas Cech, a professor of chemistry and biochemistry at the University of Colorado and a Howard Hughes Medical Institute Investigator. The enzyme in which the protein was found, telomerase, is unusual because it contains a form of genetic material known as RNA.

The researchers showed the newly identified protein in yeast acts as the "catalytic center of telomerase, the heart of the enzyme," which is selectively activated in many cancer cells, said Cech.

The protein type, known as a "reverse transcriptase," also facilitates the onset and spread of HIV and other retroviruses by copying RNA into DNA and inserting it into the chromosome of hosts. Reverse transcriptase proteins also have been known to shuffle genetic information within the cells, he said.

Such proteins had not been thought to have an essential function in normal cells prior to the discovery, reported in the April 25 issue of Science. Co-authors of the study included Cech and Joachim Lingner of CU and HHMI, Tim Hughes and Victoria Lundblad of the Baylor College of Medicine in Houston, and Andrej Shevenko and Matthias Mann of the European Molecular Biology Laboratory in Heidelberg.

"It is a great irony that a protein essential for complete replication of chromosomes has the same detailed shape as the protein responsible for the replication of HIV," said Cech, who shared the 1989 Nobel Prize in chemistry.

Telomerase has been heralded by some as a promising new approach to the diagnosis and treatment of cancer. If current theories regarding its role in human cancer prove accurate, then variants of pharmaceuticals like AZT currently being used to treat AIDS patients may prove useful as anti-cancer agents, Cech said.

Telomerase, which has been shown to be active in about 85 percent of cancer cells, is not found in adjacent, healthy cells, said the researchers. It may be possible to develop a drug that could "turn off" the production of telomerase in cancer cells, causing them to revert to normal activity, the researchers speculated.

In the Science paper, the researchers showed that changing even a single amino acid out of the 884 acids in the enzyme's chain prevented telomerase from working in living yeast cells. Cells carrying a mutant telomerase protein gradually lost DNA from their chromosome ends and ceased growing after about 75 generations.

A University of Colorado patent covering the new discovery has been licensed to Geron Corp. of Menlo Park, Calif., through the University Technology Corp.

"This breakthrough discovery of the only known essential protein component of telomerase in diverse species shows it is very widespread in biology," said Dr. Calvin Harley, Geron's vice president for research. "We think it likely that it will lead to the discovery of the key human protein, which, together with the known essential RNA component, should accelerate the discovery of therapeutics targeting telomerase."

The pathway to the discovery began in 1994, when CU postdoc Joachim Lingner began purifying telomerase from a single-celled pond organism known as Euplotes containing millions of small chromosomes rather than the 46 large ones found in human cells. Although Euplotes had much larger amounts of telomerase per cell, it nevertheless took two years to purify and analyze it with the help of high-tech mass spectrometry work conducted by the Heidelberg team.

A computer search of Genome Project data by the researchers identified a close relative of the gene for the Euplotes telomerase among chromosomes of baker's yeast. The Colorado team learned that Lunblad's Baylor lab in Houston had found the same yeast gene -- one of only four yeast genes known to result in shorter chromosome ends, or telomeres, when mutated.

Finding the yeast gene corresponding to the telomerase protein allowed the researchers to test the hypothesis that the reverse transcriptase action of the protein was essential for chromosome replication. The CU and Baylor groups introduced single amino-acid mutations into the proposed reverse transcriptase structure of the yeast protein.

"These changes obliterated telomerase activity in living cells and in the test tube, providing strong evidence the new protein provides the active center of the telomerase," said Cech.

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