Telomere

Immortal cancer cells escape telomere loss by switching on a gene that expresses an enzyme called telomerase. This unusual enzyme is a reverse transcriptase that has an RNA template and a catalytic portion. At each round of DNA replication, telomerase adds onto the existing telomeres the nucleotides that would otherwise have been lost, thus maintaining a constant telomere length. In other words, telomerase acts as an "immortalizing" enzyme. In addition, it has several associated proteins whose roles are still under investigation.

Using what is called the TRAP assay (telomeric repeat amplification protocol), it has been found that about 90 percent of all human tumors produce telomerase, whereas the only normal adult somatic cells that produce telomerase are stem cell populations found, for example, in skin, the hematopoietic system, germ cells, and gut epithelia. In fact, the presence or absence of telomerase is the most specific property that distinguishes cancer cells from normal cells. This difference is currently under investigation as a diagnostic tool. If a chemical could be found to interfere with telomerase activity in cancer cells, an effective control of this disease might be found. Several candidate substances have been identified and are undergoing extensive studies in animals.

Telomerase is switched on in virtually all human cells at the moment of conception, but as the embryo matures the telomerase becomes repressed in all but the germ cells and stem cell populations. Further, the level of telomerase expressed in stem cells is much less than that expressed in cancer cells. Interestingly, telomerase expression has been found to occur in all the cells of animals that age slowly or not at all. These are animals, such as the American lobster and the rainbow trout, that do not stabilize at a fixed size in adulthood.

On the human genome, an enzyme known as human telomerase reverse transcriptase (hTERT) is found on the most distal gene on chromosome 5p. The transfection (introduction) of hTERT into cultured normal human fibroblasts has resulted in telomere elongation, telomerase expression, and the immortalization of these otherwise mortal cells. After several hundred population doublings, the transfected cells exhibit some drift from the diploid number of chromosomes but cancer cell properties do not occur. This experiment proves that telomerase is not a cancer enzyme but an immortalization enzyme. The ability to immortalize normal human cells via hTERT has important potential applications. Some immortalized cells could be cultured in the lab to produce therapeutically useful molecules. Others might be used directly within the body to repair tissue or replace lost or damaged cells.