Is telomerase the Holy Grail of molecular biology?
By: Lionel Perez Valenzuela
At the heart of most human cancers is present an enzyme, this enzyme called telomerase is so important. Almost 95% of cancer cells show active telomerase.
Telomerase expression shows a particular pattern and is active only in embryonic stem cells, stem cells adult, germ cells and tumor cells. While in somatic cells are those that are most differentiated tissues is inactive.
recently discovered the structure of a key catalytic component of the enzyme, opening the way for better anti-cancer drugs and perhaps some kind of anti-aging therapy.
What happens in somatic cells with the telomerase?
somatic cells carried the cell cycle. First G1 phase of high metabolic activity, then the S phase where DNA is replicated, and finally the G2 stage, last stage before perform mitotic division.
The telomerase gene is not expressed in somatic cells and each time the cell divides, because of the mechanism of DNA replication, telomeres shorten. Thus, with each ensuing mitotic division telomeres becoming shorter, it somehow affect the stability of chromosomes prevents the cells can divide indefinitely.
When the cell can no longer divide more due to shortened telomeres, die. Some researchers believe this limit to the number of cell divisions that a cell can make is a form of protection against cancer.
As stated above, telomerase is inactive in most tissues and is active only in stem cells (especially in embryonic stem cells) in germline cells and tumor cells.
tumor cell lines grown "in vitro" is said to be "immortal." Ie the cell itself is not immortal, but can be divided indefinitely, unlike the somatic tissue cells that have a defined number of divisions.
What is replicative senescence?
The senescence comes from the Greek word senex (old) and refers to biological aging.
When eukaryotic cells extracted from tissues are placed in a cell culture medium, begin to divide but do not indefinitely. Initially divide very rapidly, but slowly began to make less mitosis and finally did not fall over and die. Cells can not move beyond the stage G1 to S. This process is called replicative senescence. For example, human cells can replicate a young adult between 60-80 times, but an elderly person may not exceed 20 divisions.
Consider that for decades scientists believed that both plant and animal cells, could be replicated indefinitely in cell culture. But in 1961 U.S. researcher Leonard Hayflick showed that this was a misconception. Fibroblasts showed lung and skin cells cultured in vitro initially multiply vigorously but then decline and eventually die. The limit of cell divisions that can make normal cells is called "Hayflick Limit." Cancer cells can be grown "in vitro" indefinitely.
How can they be related cancer and cell aging?
Telomerase is responsible for adding a repetitive sequence at the ends of chromosomes, called telomeres. Telomeres protect the chromosomes, preventing their breakdown, degradation and other problems. If telomeres become too short, start occurring chromosomal abnormalities. Recall that one of the hallmarks of cancer are these abnormalities. If the cell could somehow detect this condition so risky (the shortening of telomeres) would be divided. Thus, the shortening of telomeres is one way to prevent the disappearance of tumor cells and the cost would replicative senescence.
remember that there are two key genes that can halt the cell cycle before the accumulation of mutations, these genes are p53 and p16. The result of stopping the cell cycle, Antel accumulation of mutations or the inability to repair damaged DNA is replicative senescence.
This would explain several of the syndromes that affect humans, related to premature aging or accelerated. The common denominator that appears in these diseases is the mutation of genes related to DNA repair or maintain the integrity of the genome.
For example, Werner syndrome, affected people have gray hair at age 20 and most die before age 50. Suffer from several enfrmedades associated with aging such as osteoporosis, cataracts and arteriosclerosis. Even at a young age their cells undergo replicative senescence luegode make only 20 cell divisions, normal is 70 or 80 divisions. This syndrome is caused by a mutation in the gene WRN , which encodes a helicase required for the repair and maintenance of DNA and telomeres. The accumulation of mutations, the problems at telomeres activate the mechanisms of p53 and p16 to arrest the cell cycle and cause replicative senescence.
Another syndrome of premature aging is the Progeria (Aging) or Hutchinson-Gilford Syndrome (HGPS). Children born with this rare disease already showing signs of premature aging by two years and usually die before the age of ten. have mutated the gene LMNA, which encodes intermediate filament to the nuclear lamina. The machinery of DNA repair, transcription and replication are intensive in the face of the nuclear envelope. These children show high rates of DNA damage and other defects in gene expression.
Why, if the stem cells have active telomerase, age? Apparently
embryonic stem cells are the only ones that have a completely telomerase active since shortly after birth, and telomeres are shortened sample of stem cells even in newborns. Ie shortly after our birth, including stem cells show a less active telomerase. This would be progressive as we age thus losing the ability to regenerate our tissues because stem cells and their daughter cells gradually lose the ability to replicate.
Based on these findings it has been postulated anti-aging therapy based on activating telomerase in different tissues. There are already numerous lines of research in this direction, showing that it is possible to activate telomerase in a given tissue and that retain their functional characteristics and tissue does not become cancerous.
What about telomerase in tumor cells?
When telomerase is expressed in tissues that should not and is more active than usual, telomeres are not shortened and the cells continue to divide beyond their limit and can become cancer cells.
The fact that telomerase is active in most tumors, has become a prime target for anticancer therapies.
When determining the three dimensional structure of an enzyme can save lives ...
Telomerase is a ribonucleoprotein.
has a small RNA of nucleolar origin (not to be confused with small nuclear RNA) and a catalytic subunit protein.
small RNA molecule provides a mold 3 `-AAUCCC-5 'in maíferos TERC and is referred to by its acronym in English (the RNA Component of Telomerase).
subunit protein is called TERT (Telomerase Reverse Transcriptase).
determine the three dimensional structure of telomerase, has been a very difficult task. As we said telomerase is a ribonucleoprotein with transcriptase activity reverse (ie an enzyme that synthesizes DNA using a template strand of RNA).
Skordalakes researcher Emanuel and his team at the Wistar Institute telomerase finally managed to produce in large quantities and crystallize, a necessary step to determine their three dimensional structure by x-ray crystallography. But producing massive amounts of telomerase was a real problem until they found they could manipulate the gene for telomerase flour beetle to produce the required amounts of protein,
structure analysis has determined that TERT (Telomerase Reverse Transcriptase Protein) is a complex structure with three domains creating a ring structure. This ring structure has a central hole that when telomeres are being synthesized can be occupied by a molecule of ribonucleic acid template.
Telomerase, a possible key anti-aging treatments and anti-tumor.
The researchers assumed that the telomerase reverse transcriptase of HIV should have a similar structure as both enzymes are reverse transcriptase. Under this assumption developed anti-telomerase drugs.
structural analysis carried out after determining the three dimensional structure of telomerase, confirm these suspicions, but also revealed that the carboxy-terminal of telomerase is unique in its structure and so far unique in its kind.
This unique structural feature of telomerase, could develop drugs that have the sole target molecule, drugs designed on the basis of a high affinity for the carboxy-terminal end.
For example treatments were successful against certain types of tumors combining paclitaxel and AZT. Paclitaxel is a cytostatic drug that stops cells divide by mitosis, and which promotes microtubule polymerization leading to interfere with normal cellular mechanisms in both interphase and during mitosis. Moreover AZT is known primarily for being the first effective drug against HIV and to inhibit virus reverse transcriptase. The researchers estimated that as telomerase reverse transcriptase also, AZT should be inhibited by preventing telomeres synthesized tumor cells, causing you to senescence. Both drugs were used together better than used in isolation. Stephen Neidle
researcher at the School of Pharmacy, University of London estimated that drugs can be designed that can bind to telomerase for its carboxy-terminal and inhibit their activity to anticancer treatments. But they could also develop drugs that stimulate the opposite effect of telomerase activity for anti-aging treatments.
In the near future therapies could be used currently in clinical trial stages, such as certain types of anti-telomerase vaccines, drugs with future anti-telomerase design.
Aubrey de Gray Methuselah Foundation, believes that if we had a really strong anti-cancer therapy against all types of tumors, a therapy could also be used, for example based on a drug to prevent aging by activating telomerase. However
many difficulties, but both animal studies and in cell cultures and in human cancers, opening new perspectives in understanding complex issues such as aging and cancer.
Sources:
Kimball's Biology Pages
Newscientist
Methuselah Foundation
