At the ends of linear eukaryotic chromosomes is a heterochromatic region of tandemly repeated DNA sequences known as a 'Telomere' (Blackburn, 1991). This region is genetically inactive (silent) as it does not contain protein-encoding genes. In humans the telomere comprises of approximately 2000 copies of the repeated hexanucleotide sequence (TTAGGG) n (ref). The telomere along with its associated specialised proteins functions in the maintenance of stability; protection of chromosome ends from recombination and degradation so therefore regulates the replicative capacity of cells (ref).
Each time a cell divides, not all the DNA is copied, so over time there is progressive reduction in the number of tandem repeat sequences causing telomeric shortening. The occurs in somatic cells and it is thought that in humans the cells replicate about 50 times before it is too short which is known as Hayflicks' limit as this was noted in human fibroblasts by Hayflick (longevity about). Cellular division will cease at the shortest length compatible with stability, a state termed replicative (mitotic) senescence' (Kappei, et al, 2007). This process stems from DNA polymerase no longer being capable of replicating the linear template. The overall impact is cell malfunctioning and even cell death.
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Currently researchers are trying to better understand the mechanisms involved with telomeres and its consequential impact on ageing and cancer.
Telomeres and telomerase (175)
Through the groundbreaking work of Carol W. Geider and Elizabeth H. Blackburn, a specific telomere transferase was discovered which is now known as telomerase. Telomerase, an enzyme-RNA complex helps to compensate for the shortening of telomeres during cell replication and division. This investigation was carried out with the use of a fresh water protozoan, Tetrahymena of which the chromosomes were examined. In the findings Blackburn compared telomere functioning to the ends of shoe-laces and keeps them from fraying. Each time a cell divides, telomerase adds telomere repeat sequences to the 3' end of the DNA strands (template strand). Through this, the DNA polymerase is able to complete its job in the completion of the 'incomplete ends' of the opposite strand (lagging strand). The activity of telomerase is regulated by certain proteins. If telomerase is constantly active, cells can grow indefinitely without the occurrence of senescence. If some telomerase is present then cell senescence would be delayed. If less telomerase is present then the processed of senescence would occur sooner. Germ cells do not undergo telomeric shortening; attributed to the fact that telomerase is present thus having an unlimited capacity to replicate never reaching replicative senescence; (ref). This complex is absent in somatic cells.
The work of Carol W. Geider and Elizabeth H. Blackburn has influence many other researchers to investigate the propose activity of the telomerase enzyme.
Telomeres, telomerase and cellular ageing (500)
The process of ageing is accompanied by the shortening of telomeres (Kappei, et al, 2007). This is also true for premature ageing syndromes and age-related disease which have an association with shortened telomeres. Both observations are central to the hypothesis that the length of telomeres in replicating cells is inversely correlated with age and thus telomere lengths have a direct influence on longevity (Kappei, et al, 2007). Cellular ageing is representative of biological ageing. Regarding age-related disorders, there are difficulties in determining whether shortened telomeres are a cause or consequence of the disorders.
There is a well known case of 'Dolly' a cloned sheep who developed arthritis in its left rear leg, this was thought to be an indication of premature ageing which isn't surprising as it was developed from somatic cells of a 6 year old sheep. Never mind the fact that the cells had before hand undergone extensive cell proliferation in vivo in the absence of the telomerase enzyme (ref). Consequently, Dolly the sheep suffered from immense erosion as well as shortened telomere present in the somatic cells. This experimentation is just one of many that are minute indications of the correlation between ageing and shortened telomeres.
Additionally, there is an age related disease called Progeria whereby young children age so rapidly they suffer and eventually from many symptoms associate with old age in their teens. When the cells of this disease was analysed, it was found that many of the cells had short telomeres which suggested that the shortening process of the telomeres contributed to the pathology of the disease and thus is in support of the hypothesis that such shortening contributes to cellular ageing. In support of this is also work done by Tahara H, et al at the Hiroshima university of medicine in Japan, where it was demonstrated that cell strains with Werner's syndrome (WRN) (a premature ageing syndrome) had telomere lengths which were drastically shortened during cell passages in comparison to normal cell strains. Both studies Werner's syndrome on Progeria are a result of errors in system involved in the maintenance of telomeric length. Also it is that those already born with shortened telomeres would senesce faster and show signs of ageing.
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Furthermore researchers used laboratory mouse models who also have the same telomerase repeat sequence of human (TTAGGG) n, and who also had defective telomerase. Through selective breeding, it was found that successive generations had signs of premature ageing as well as life spans that were shortened. The reason for this was because of the absence of telomerase so telomere shortened without replacement. From this, further evidence is provided in support of role of telomerase and thus telomeres in ageing.
Although researchers make known that ageing process in its entirety cannot be explain just by telomere shortening. It is also pointed out that there is no obvious relationship between the starting length of telomeres and a species' lifespan. This is attributing to the fact that although mice for example have a much longer telomere than humans, they only live for duration of about 2 years.
In addition, there are other factors which have an impact on cellular ageing such as oxidative damage caused by free radicals; faults in the DNA damage and its repair systems and mitochondrial ageing whereby antioxidants are produced.
Telomeres, telomerase and cancer (500)
In recent years, there has been rapid expansion in research on the association of the ribonucleoprotein enzyme, telomerase and cancer. During the screening process of various cancer forms, the telomerase was detected the vast majority of the cases. It is detailed in published articles by J.W. Shay, S. Bacchetti, N.W. Kim that due to the reason stated above, this enzyme is one of the most common markers for tumours.
The activity of telomerase performs a negative function and aids in the provision of tumour cells with unlimited growth potential (immortality) (ref). 90% of human tumours reactivate telomerase which displays hyperactivity so as well as continuous elongation of telomeres; telomerase prompts cancer cells to have a more malignant phenotype in addition to the ability to keep them immortal as they maintain the ends of chromosomes. It is detail than typically a cancer cell undergoes about 80 doublings before a tumour mass is big enough to be detected (ref). If telomerase is withdrawn from a cancer cell that has been thriving on its activity for quite a long time, there becomes a change as cancer cells ceases to multiply as much, it becomes less invasive an less malignant. J.W. Shay, S. Bacchetti notes that there is a reliance of the malignant cells on the acquisition of the immortal phenotype in order for cancer cell growth.
On the other hand, the shortening of telomeres contributes to the genomic instability which can trigger cancer. Evidence in support of short telomeres being a risk factor for cancer in humans is growing; one being that short telomeres is partly responsible for early stages of certain cancers and can push cancer to a more progressive state. Researchers at the John Hopkins University School of Medicine carried experimentations using cells taken from prostate cancer patients. A discovery was made in those telomeres taken from precancerous lesion and reveal to be up to four times shorter than cells of the surrounding tissue which was normal.
Because of the enhanced activity of telomerase in cancer cells they can be used as a diagnostic tool for early cancer so treatment can be put into place before the cancer spreads and the condition worsen. Moreover if the telomerase is made inactive, then the telomere would shorten and replicative senescence could be reached stooping the high amount of proliferation associate with cancer.
The table below is based on evidence compiled in a report by Taylor RS, Ramirez RD, Ogoshi M, Chaffins M, Piatyszek lMA, Shaw JW.
Telomerase activity in malignant and non- malignant skin conditions.
There are ongoing researches all over the world. Each have their own importance and are pieces to the puzzle that bring us closer in the understanding of telomeres, telomerase and the impacts they have on cancer and ageing. Although quite a bit of evidence is gathered, whether the activity of telomerase and its impact on the telomere length is a cause or consequence of certain disorders and diseases.