TELOMERE AND TELOMERASE Essay, Research Paper

An Introduction To Telomere and Telomerase

The telomere-telomerase hypothesis of aging and cancer is based on the findings that most human tumors have telomerase activity while normal human somatic cells do not.

An emerging hypothesis is that the up regulation or reexpression of telomerase is a critical event responsible for continuous tumor cell growth. In contrast to normal cells, tumor cells show no loss of average telomere length with cell division. Through this suggestion immortalization may occur through a mutation of gene in the telomerase repression pathway allowing the expression of telomerase in cancer cells.

Telomerase is a ribonucleoprotein enzyme which stabilizes telomer length by adding hexametric(TTAGGG) repeats to telomeric ends of the chromosomes, thus compensating for the continued erosion of telomeres that occurs in its absence. Telomerase is normally only in cells that give rise to sperm and egg or in some stem cell lines, it maintains the integrity of the chromosomes. the sex cells are the only part of the body that are biologically required to be immortal, because if there was a progressive loss of chromosomes with each generation then this would lead to extinction. However when cells become cancerous, the enzyme telomerase is activated, this enables the cancerous cells to replicate without a limit and this process makes the cells immortal.

According to a research done by a team of researchers at the University of Texas,

An evaluation of cell lines from 18 different human tissues revealed the presence of telomerase in 98 of the 100 immortal cell lines, telomerase was not found in any of the 22 mortal cell lines.

Telomeres is a repeated DNA sequence(TTAGGG) found at the ends of linear chromosomes that protect the ends of the chromosome from degradation, or telomere can be defined as DNA sequences found at the ends of eukaryotic chromosomes which maintain the fidelity of genetic information during replication. At birth as determined by terminal restriction fragment analysis, telomeres consist of about 15,000 base pairs of repeated TTAGGG DNA sequences, which become shorter with each cell division owing to the end replication problem. Every time a cell divides it loses 25-200 DNA base pairs off the telomere ends. once this pruning has occurred about 100 times a cell ages and does not continue to divide. It has been proposed that telomere shortening may be a molecular clock that count the number of times a cell has divided and determines when cellular senescence occurs (cellular senescence is the limited capacity of cells to divide beyond a finite number of population doubling. In a lay man?s understanding this means cellular death. Normal diploid human cells have limited capacity to proliferate (are mortal).

There appear to be two mechanisms responsible for the proliferative failure of normal cells. The first, mortality stage 1, occurs when there are still at least several thousand base pairs of telomeric sequence left at the end of most of the chromosomes. It is possible that mortality stage 1 may be induced by the activation of genes located in the immediately

subtelomeric region of the chromosomes.

The second is the mortality stage 2 which represent the physiological result of critically short telomeres when cells are no longer able to protect the ends of the chromosomes, so that the end degradation and end to end fusion occurs and causes genomic instability and cell death).

While researching on a topic like this, couple of important questions came to mind, so I made effort to research and address some of these questions which might be considered important.

One of such questions is why do telomeres shorten?

the mechanism of DNA replication is different in linear chromosomes is different for each of the two strands, known as leading and lagging strands. the lagging strand is made as series of discrete fragment, each one requiring a new RNA primer to initiate synthesis. the DNA between the last RNA priming event and end of the chromosome cannot be filled in. {this process is known as the end replication problem} since a strand cannot copy its end, telomeres shortening is required to occur during progressive cell divisions. the shortened telomeres are inherited by daughter cells and process repeats itself again.

The mind may inquire if stopping the shortening of telomeres whether that will prevent the body parts from aging; according to researchers, slowing down the rate of telomere shortening might help reduce the extent at which the body ages. An experiment done by a group of researchers from the University of Texas helps clarify this statement in full, hybrids between immortal cells that express telomerase, and normal cells that lack telomerase, creates a cell with limited lifespan. Also experiments show that treatment of immortal human cell lines with oligonucleotide will resulted in telomere elongation.

Using this finding, the researchers tested the hypothesis that elongation of telomeres could extend the lifespan of a cell, this was done by treating an immortal human cell line with oligonucleotides to lengthen its telomere, and then fusing the cell to a mortal cell. this experiment showed that the hybrid cells had a longer lifespan, than the hybrids without elongated telomeres. This gives the hypothesis that telomere length may determine the human lifespan.

Many might not know, but telomerase pays an important part the longevity of cancer cells, which makes it one of the prominent aids in the ability of cancer cells to thrive. The enzyme telomerase aids cancer cells by halting the telomere shortening in cancer cell, thereby allowing the cell to divide indefinitely. Scientist are struggling to develop a therapy to inhibit telomerase activity in cancer cells which they believe will force the cells into a normal pattern of senescence and death.

Someone might ask if it where possible to revert old cells into young cell: according to my research, technically its possible, thus if cells are completely senescent it may not be possible to get them to grow again even if the telomere is elongated, however telomere?s are rate limiting for growth, so a few division may do the trick of resetting the clock.

Due to the fact that telomerase aids cancer cell, an individual might ask why the introduction of telomerase not lead to cancer?

First a fact should be stated that telomerase are found present in specialized reproductive cells and most cancer cells that appear to divide indefinitely, but the main function of telomerase is to maintain telomeres and permit continued cell growth.

So its important to understand that cancer is caused by accumulation of several alterations that occur over a lifetime, and which affects processes controlling cellular growth rates, and ability to invade and undergo metastasis, while telomerase only affect the counting of the number of times a cell has divided, not the rate of cell growth. thus all telomerase do is permit continued cell growth that would otherwise be limited by shortened telomeres, so that does not make it a cause of cancer.

Another question that personally i was interested in while researching about telomerase is ? would telomerase therapy attack other cells such as reproductive cells?

According to my research anti telomerase therapy could affect germ line {reproductive cell and possibly stem cells of renewal tissues {basal cells of skin}. but luckily the telomeres of such cells have longer telomeres than cancer cells, so it might be possible to inhibit telomerase in cancer cells and cause their death, without causing the other cells to run out of telomeres.

Another situation, i feel will be of great inquiry among knowledge filled minds is; according to multiple researches, its been proven that not all cancer sells express telomerase, if so how are they maintaining their telomeres growth?

Scientists state that approximately 85-90% of cancer cells displays telomerase activity, which brings us back to the main question. According to scientific researchers cancer cells, which do not show sign of telomerase activity, may be involved in one of these activities:

1, the cell may not have yet been immortalized, thereby making the appearance of telomerase activity absent.

2, also lot of scientist believes that some cancer cells have an alternative pathway for maintaining telomeres. This telomere is believed to be of heterogeneous length, varying from big to small, and this aiding as confusion to the structure responsible for cell death.

One of the main focus of researchers in the study of cancer is using the detection of telomerase activity to predict cancer; telomerase activity is easily detected in many pre-malignant specimens (lung and breast cancer), while colon and pancreatic cancers can?t be detected until later stage. The ability to use almost any clinical specimen and to demonstrate telomerase may allow the detection of cancers at an earlier stage.

much progress has been made in the development of more accurate molecular based cancer tests to assess tissue specimen. unluckily most of this method do not have sufficient specificity (ability to differentiate between normal, precancerous, and cancerous cells) and sensitivity (accuracy in detecting the presence of cancer) to identify a wide variety of cancer types. Therefore, new clinical method, applicable to all cancer types is needed.

currently researchers are working on that, though a product called a PCR based telomerase method was produced in 1994, it still had a couple of little set backs and didn?t live up to its expectation fully.

Finally a question, which must be of interest to anyone interested in the evolution of telomerase, is how long before telomerase can have a medical impact, such as cancer screening/ telomerase therapy?

This is a statement i found in the internet addressing the question, ?since telomerase is detected in almost all tumors and in some cases early in the development of the cancer, then early cancer detection using telomerase may be a promising approach.

There are already a number of situations where knowledge of the presence of telomerase may have value in risk stratifying patients into those that are likely to have favorable outcomes and those that are not. There is a major effort at the national cancer institute to establish a series of molecular markers for cancer, and it is expected that within a few years we will have perhaps one hundred or more molecular markers that may indicate the presence of cancer. Its predictable that within the next ten years, scientist will be able to take a few cells, do micro array analysis and determine not only if a person has cancer, but also the type of cancer, the genes that are altered, and hopefully a therapeutic

method that goes to work and destroy the cancer immediately?.

Conclusion:

While there is justifiable optimism regarding telomerase activity, its important to understand that their is still much to acquire about this enzyme, and additional validation studies will be required before knowledge of telomerase can be used to the fullest in medical practice. Finally the utility of inhibitors of telomerase in the therapy of cancer is awaited to with great anticipation.

Note- even though telomerase aids cancer cells in longetivity (avoiding cell senescence) still telomerase as an enzyme has nothing to do with the development of cancer cells, its just a helping aide, so all blames should not be put on it.

REFERENCES:

Shay JW: Telomerase activity in human cancer. 1996

Bacchetti S, counter CM: telomerase: a key to cell immortality. 1995

And a whole lot of notes taken from Internet site.