TELOMERASE and CANCER
Introduction
Telomeres are DNA sequences found at the ends of eukaryotic chromosomes,
which maintain the fidelity of genetic information during replication. Under normal
circumstances the telomeres become shorter and shorter with each cycle of cell
division. A sufficiently short telomere is believed to signal the cells to stop
dividing. The telomerase enzyme is a ribonucleic protein that synthesizes
telomeric DNA on chromosome ends.
This single enzyme, telomerase, appears to be responsible for the unchecked
growth of cells seen in human cancers, report researchers from the University of
Texas. The finding could offer researchers an entirely new approach to the
diagnosis and treatment of cancer.
Researches
An evaluation of cell lines from 18 different human tissues revealed the presence
of telomerase in 98 of 100 immortal cell lines. Telomerase was not found in any of
22 mortal cell lines. Subsequent assays of tumor biopsies revealed the presence of
telomerase in 90 of 101 specimens representing 12 different tumor types. None of
50 normal somatic tissue specimens tested positive for telomerase.
"Telomerase appears to be stringently repressed in normal human somatic tissues
but reactivated in cancer, where immortal cells are likely required to maintain
tumor growth", the researchers report in a recent issue of Science.
Previous attempts to measure telomerase activity in actual tumor specimens have
been limited by insufficient sample sizes and insufficiently sensitive assays. The
assay developed by the University of Texas researchers, called TRAP (telomeric
repeat amplification protocol), should make analysis of telomerase activity in
primary tumor specimens feasible, the researchers believe.
The fact that telomerase appears to be expressed in virtually all advanced
malignancies should lead to new diagnostic and therapeutic applications. Assays for
telomerase could help clinicians determine the status of suspect tumors, while a
drug that block telomerase could have significant anti-cancer effects.
Curiosity
A team of researchers has now identified the catalytic protein subunit of
telomerase. Amazingly, the protein, called p123, closely resembles reverse
transcriptase, an enzyme essential for replication of retroviruses including HIV.
Reverse transcriptase facilitates the onset and spread of HIV by copying RNA
into DNA and inserting it into the chromosome of hosts. Reverse transcriptase
proteins can also shuffle genetic information within the cells.
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.
These changes eliminated telomerase activity in living cells and in the test tube,
providing strong evidence the new protein provides the active center of the
telomerase. 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.
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. Conversely, treatments for AIDS targeting reverse transcriptase may
prove to be useful anti-cancer agents.
Homework done by:
Camilo Mancera Arias