| Introduction | | | | c-myc, which regulates the expression of the human |
| Cancer – although there are over | | | | telomerase reverse transcriptase gene (hTERT) via |
| hundred types of it, claims millions of lives every year | | | | its promoter region. |
| throughout the world (American Cancer Society, | | | | The remainder of human cancers |
| 2007); which is a class of diseases in which a group | | | | activate the Alternative Lengthening of Telomeres |
| of cells display uncontrolled growth, invade adjacent | | | | (ALT) pathway, which relies on |
| tissues and spread to other locations in the body | | | | recombination-mediated elongation and does not need |
| and as a result if not treated in time, leads to death | | | | telomerase. As human telomeres grow shorter, |
| (Pecorino 2008, p.2). On the other hand, Telomeres | | | | eventually cells reach the limit of their replicative |
| are repetitive DNA sequences and protein complexes | | | | capacity and progress into senescence. Senescence |
| added by an enzyme called telomerase and are | | | | involves the p53 and pRb pathways and leads to the |
| located at the end of chromosomes, which stabilises | | | | arrest of cell proliferation and plays an important role |
| the chromosome and protects it from deterioration. | | | | in suppression of appearance of cancer (Campisi, |
| They also have a capping role because telomeres do | | | | 2005). However, by inactivating the p53 and pRb |
| not perform homologous recombination and prevent | | | | pathways further cell proliferation can be achieved; |
| non homologous end joining; this is because in | | | | also cells entering proliferation after inactivation of |
| contrast to linear DNA, telomeres are structures | | | | p53 and pRb pathways undergo abnormal |
| made up of t-loops and four stranded conformations | | | | chromosomal rearrangements and leads to genome |
| named G quadruplexes. In mammalian cells, the | | | | instability, and (almost) all cells die. Rare cells emerge |
| telomeric sequence is a repetition of a hexanucleotide | | | | from crisis immortalized through telomere elongation |
| motif, TTAGGG (Desmaze et al., 2003) varying from | | | | by either activating telomerase or ALT. The first |
| 3 to 20 kilobase pairs in length. | | | | description of an ALT cell line demonstrated that the |
| Cancer is caused (usually) by | | | | telomeres were highly heterogeneous in length and |
| abnormalities and/or mutations found in the genetic | | | | predicted a mechanism involving recombination. ALT |
| material of transformed cells (Pecorino 2008, p.4), | | | | cells produce abundant t-circles and if the telomeres |
| and as time passes, due to the immense damage | | | | become too short, they will (potentially) unfold from |
| caused to the cell's defense mechanisms (e.g. DNA | | | | their presumed closed structure. The cell turns on |
| repair), these accumulate. When coupled with | | | | certain mechanisms which detects and understands |
| environmental factors like poor diet, smoking, stress | | | | this uncapping as "DNA damage" and then enters |
| etc the cells become weaker, quicker; and cancer | | | | cellular senescence, growth arrest or apoptosis, |
| probability increases in accordance. There are two | | | | depending on the cell's p53 status. Chromosomal |
| major types of genes which contribute to | | | | fusions can also result in uncapped telomeres. Since |
| carcinogenesis, called oncogenes and tumor | | | | this damage cannot be repaired in normal somatic |
| suppressor genes. These genes regulate growth and | | | | cells, the cell may even go into apoptosis. Many |
| division of cells thus mutations within these genes, | | | | aging-related diseases are linked to shortened |
| cause malfunctioning and abnormal growth of cells | | | | telomeres. Organs deteriorate as more and more of |
| which is the foundation of cancer; so one could say | | | | their cells die off or enter cellular senescence – |
| cancer is a genetic disease at the cellular level. | | | | eventually leading to the "inevitable". |
| Unlike prokaryotes, (most) eukaryotic | | | | Chromosomes that lack telomeres |
| (this includes humans also) chromosomes are linear | | | | remain unstable until they are capped. Broken |
| which means they have free ends. This detail alone | | | | chromosomes that do not gain telomeres can |
| causes problems due to the fact that DNA replication | | | | undergo sister chromatid fusions involving non |
| progresses 5' to 3' which leads to discontinuity in the | | | | homologous end joining. These fusions induce |
| lagging strand, therefore the nucleotide adding | | | | chromosome instability resulting from breakage/fusion |
| enzyme DNA polymerase cannot finish the | | | | anaphase bridge (B/F/A) cycles. Coming back to the |
| polymerisation process neatly when it reaches the | | | | dicentric bridge formed at anaphase (mentioned in |
| end of the chromosomes. A small piece of DNA is | | | | introduction), the two centromeres of a dicentric |
| left unreplicated at the end of each cell cycle which | | | | chromosome are pulled towards opposite spindle |
| results in that amount of DNA to be lost and if this | | | | poles creating an anaphase bridge. The chromosome |
| process carries on the way it does, then this will | | | | would then break, resulting in novel chromosomal |
| eventually cause the essential, protein-coding regions | | | | rearrangements by fusion of broken ends, and |
| of the genome to be lost. This is where Telomeres | | | | perpetuating a B/F/A cycle. Anaphase bridges can |
| come into play, since they are at the end of | | | | also cause whole chromosome losses or the collapse |
| chromosomes and they only consist of non coding | | | | of the cytokinetic process leading to numerical |
| regions (in the form of repeats); therefore although | | | | chromosome aberrations. Chromosome |
| some of it is lost, the cell can divide many times | | | | rearrangements that can theoretically result from |
| before reaching the essential parts of the | | | | successive B/F/A cycles are similar to those |
| chromosomes. This problem is not present in (most) | | | | observed in human carcinomas. This process results in |
| prokaryotes because the genome is circular and the | | | | highly rearranged chromosomes that eventually |
| end-problem does not occur because there is no | | | | acquire a new telomere through gene amplification |
| lagging strand. | | | | cycles which is a common consequence of genome |
| Moving on to humans, it has been | | | | instability in tumour cells and can be the basis of |
| observed that somatic cells cease to divide after a | | | | oncogene activation and drug resistance. |
| limited number of divisions, the number ranging from | | | | There is also evidence that |
| twenty to ninety depending on the age of the | | | | chromosomes with shorter telomeres tend to be |
| person the cell is being taken from; a phenomenon | | | | more affected by radiation; more double strand |
| known as "cellular aging" (Solomon et al. 2002, p.256); | | | | breaks, deletions and translocations seem to occur in |
| for example, cells taken from a 70 year old man can | | | | these chromosomes (Desmaze et al., 2003). This |
| divide 20-30 times compared to one extracted from | | | | phenomenon could also increase the chance of |
| an infant which can divide 80-90 times (Bodnar et | | | | cancer progression as this also can also cause |
| al.,1998). What was observed is that telomeres were | | | | genome instability. All of the above gives strong |
| much shorter in the older people, and other studies | | | | evidence that telomeres are related with cancer, |
| (Cancer Research UK, 2010) also show that as | | | | directly and/or indirectly. |
| people aged, their risk of being cancer and the | | | | Conclusion |
| percentage of people diagnosed with cancer | | | | To conclude, excess shortening of |
| increased which gave evidence that the two could be | | | | telomeres enhances chromosomal instability in cancer |
| linked to one another. Further research into telomere | | | | cells and the loss of one telomere leads to gene |
| function showed that they had three important | | | | amplification and chromosome imbalances as well as |
| functions: Prevent DNAses from degrading the ends | | | | chromosomal instability. Telomeres have important |
| of the linear DNA molecules, prevent fusion of the | | | | functions in genome stabilisation; and when they are |
| ends with other DNA molecules and facilitate | | | | not present or not fully functional there is evidence |
| replication of the ends of the linear DNA molecules | | | | that these abnormalities – caused due to the |
| without loss of essential genetic material (Snustad | | | | shortening or total loss of telomeres, help trigger |
| and Simmons 2006, p.230); and if anything goes | | | | cancer. Telomeres and cancer are certainly linked but |
| wrong with these mechanisms it is highly likely that | | | | whether telomere shortening is the main cause, the |
| cancer could progress within the cells where the | | | | consequence or is involved in (just) one of the steps |
| malfunctioning occurs, so the question is: how does | | | | leading to cancer still needs further research. |
| telomeres play a role in cancer development? | | | | In my opinion, (maybe) in the near |
| Telomeres and Cancer | | | | future, measuring telomerase presence/activity could |
| Approximately 85% of cancers | | | | be considered a new way to detect cancer; also if |
| (Pecorino 2008, p.2) occurring in human adults are of | | | | scientists can learn how to stop telomerase |
| epithelial origin, called carcinomas. These tumours | | | | production and/or inhibit its function, they may be |
| have extremely rearranged karyotypes with a high | | | | able to remove cancer by causing cancer cells to age |
| frequency of translocations which are closely linked | | | | and die. Also further research into why and how |
| to cancer development due to the generation of | | | | some cancer cells activate the ALT pathway instead |
| fusion genes, modification of gene copy number and | | | | of telomerase can also give clues in to how cancer |
| or deregulation of the expression of several | | | | could be treated and possibly lead to development of |
| oncogenes. In telomerase knockout mice, telomere | | | | drug treatments. It is easy to say however, as |
| shortening below a critical length results in increased | | | | scientists discover more secrets about telomeres and |
| end-to-end chromosome fusions which results in | | | | telomerase, their understanding of cancer will increase |
| dicentric chromosomes and this also generates | | | | in accordance. |
| instability in the genome. These fused chromosomes | | | | References |
| can break at any random point during anaphase of | | | | - Alberts, B. et al., 2008. Molecular Biology of The Cell, |
| mitosis and may cause loss of tumour suppressing | | | | 5th Ed. New York: Garland Science, Taylor & |
| genes and/or activate oncogenes – which code | | | | Francis Group |
| for products that have the ability of transforming a | | | | - American Cancer Society (Dec 2007). "Report sees |
| normal cell in to a cancer cell. | | | | 7.6 million global 2007 cancer deaths". Reuters. |
| Under normal conditions, telomere | | | | (Retrieved Apr 2010) |
| shortening only causes limitations to the number of | | | | - Bermudez, A. et al., 2009. Genome Integrity, Repair |
| cell divisions. Telomeres protect a cell's chromosomes | | | | and Replication. Nucleic Acids Research,37(18), |
| from fusing with each other or rearranging and can | | | | pp.6225-6238 |
| induce replicative senescence which blocks cell | | | | - Bodnar, G. et al., 1998. Extension of Life-span by |
| division. In normal circumstances cells which have | | | | Telomerase into Normal Human Cells. Science, |
| shorter telomeres than the threshold enter a stable | | | | 279(5349), pp.349-352 |
| and irreversible state of growth and if they evade | | | | - Campisi, J. 2005. Senescent Cells, Tumor |
| this stage due to mutations, their telomeres become | | | | Suppression, and Organismal Aging: Good Citizens, |
| even shorter, chromosomal instability occurs and | | | | Bad Neighbours. Cell, 120(4), pp.513-522 |
| tumour suppressing genes are lost, which is | | | | - Cancer Research UK (Apr 2010). "What causes |
| recognised by specific mechanisms within the cell and | | | | cancer?" (Retrieved Apr 2010) |
| these cells are destroyed by another defence | | | | - Desmaze, C. et al., 2003. Telomere-driven genomic |
| mechanism called apoptosis. Most cancers however, | | | | instability in cancer cells. Cancer Letters, 2(194), |
| are the result of forever-dividing cells which have | | | | pp.173-182 |
| ways of evading this programmed destruction. | | | | - Londoño-Vallejo, J., 2008. Telomere instability and |
| Malignant cells which bypass these mechanisms | | | | cancer. Biochimie, 1(90), pp.73-82 |
| become "immortalized" by telomere extension mostly | | | | - Opitz, OG. 2005. Telomeres, Telomerase and |
| due to the activation of telomerase - a reverse | | | | malignant transformation. Current Molecular Medicine, |
| transcriptase enzyme responsible for the synthesis | | | | 5(2), pp.219-226 |
| addition of telomeres. Telomerase promotes | | | | - Pantic, M. et al., 2006. Telomere dysfunction and |
| telomere repair and functions by adding bases (in the | | | | loss of p53 cooperate in defective mitotic |
| form of repeats) to the ends of the telomeres. It is | | | | segregation of chromosomes in cancer cells. |
| not active in most mammalian cells – only in stem | | | | Oncogene, 25, pp.4413-4420 |
| cells, germ cells and hair follicles; but in contrast, is | | | | - Pecorino, L., 2008. Molecular Biology of Cancer – |
| active in 90 percent of cancer cells, thus there is | | | | Mechanisms, Targets, and Therapeutics, 2nd Ed. |
| strong evidence that telomerase and telomeres are | | | | NewYork: Oxford University Press |
| linked to tumorigenesis. Several oncogenes have also | | | | - Snustad, P. Simmons, M., 2006. Principles of Genetics |
| been demonstrated to have a direct link with | | | | 4th Ed. Hoboken, NJ: John Wiley & Sons, Inc. |
| telomerase. One of them is the transcription factor | | | | - Solomon, E.Berg, L. Martin, D., 2002. Biology 6th Ed. |