Researchers from the University of Colorado at Boulder and Geron Corp. have discovered the human gene for the active component of an enzyme known as telomerase that lengthens the ends of chromosomes, a finding that may lead to improved cancer diagnosis and treatment.
The end portions of chromosomes, called telomeres, contain repeating sequences of DNA that protect the chromosomes from damage, said Toru Nakamura, a CU-Boulder researcher, Howard Hughes Medical Institute scientist and lead author on the study. Since portions of the telomeres are lost each time a cell divides, telomere shortening is thought to act as a molecular clock of sorts by signaling the cell to stop dividing after repeated cell divisions.
But the telomerase enzyme counteracts telomere shortening by adding DNA back onto the chromosome ends, he said. Normal cells do not contain telomerase, and their telomeres shorten with each cell division until they stop dividing. In cancer cells, however, telomerase is thought to grant the cell immortality by maintaining telomere length so that the cell never receives a signal to stop dividing.
聯Correlation of telomerase activity and cancer has been shown previously, but there has been little evidence for a causal relationship between the two,聰 said Nakamura. 聯Having the human telomerase gene may aid in testing the relationship.聰
The discovery of the gene for the protein called Telomerase Reverse Transcriptase is reported in the Aug. 15 issue of Science.
Authors of the Science paper include Nakamura, Joachim Lingner and Thomas Cech of CU-Boulder and the Howard Hughes Medical Institute, and Gregg Morin, Karen Chapman, Scott Weinrich, William Andrews and Calvin Harley of Geron Corp. of Menlo Park, Calif.
Before the discovery of the telomerase gene, 聯Cancer researchers knew telomerase only indirectly, by following the reaction it catalyzed,聰 said Cech, who shared the 1989 Nobel prize for chemistry. 聯Now we have the ability to make lots of pure telomerase to understand its properties and learn how to inhibit it.聰
The team cloned telomerase genes in two evolutionarily diverse species, yeast and humans. The genes were found to be similar, indicating telomerase was first developed by an ancient organism and subsequently inherited by all eukaryotes -- organisms whose cells have a separate nucleus and cytoplasm, including humans.
聯It means that studies on simple organisms like yeast are relevant to the human enzyme,聰 said Cech.
Telomerase contains both RNA and protein components. The RNA portion of the enzyme binds to the DNA in the telomere while the protein component lures DNA subunits into the region and attaches them to the end of the chromosome. 聯The protein we describe in our paper forms a complex with the telomerase RNA and does the job of telomeric DNA synthesis,聰 said Nakamura.
Telomerase belongs to a class of enzymes known as reverse transcriptases that use RNA as a template for creating DNA. Retroviruses like HIV also belong to this class. Since reverse transcriptases share a common amino acid sequence, they are expected to have similar three-dimensional structures. This indicates that variants of 聯inhibitors such as AZT developed for treatment of AIDs may be able to inhibit telomerase,聰 Nakamura said.
Many researchers believe telomerase聮s most promising application may be in diagnosing cancer. By developing ways to detect telomerase activity in cells, it may be possible to diagnose cancer before palpable tumors have formed.
But Nakamura urges caution in heralding telomerase as the newest cure for cancer. 聯Nothing has been shown to work yet,聰 he said.