Telomeres Are Structures At The Ends Of Chromosomes That Are Produced By The Activity Of The Enzyme – Literature review Example
Telomerase – Significance in Cellular Ageing and Cancer Introduction Telomerase or telomere terminal transferase is an enzyme that has gained immense research interest in recent years because of its significance in cellular ageing and cancer. This report discusses the main biochemical actions of this enzyme and the significance of its differing levels.
The telomerase enzyme synthesizes units of telomeric DNA using its inbuilt RNA template which has a complementary sequence to the repeating unit that is characteristic of the particular species (Papachristodoulou et al. 2014). Telomeres are dynamic structures made of long arrays of repeat DNA sequences at the ends of chromosomes (Pardue and DeBaryshe 2009). The telomerase enzyme not only maintains the physical integrity of the telomeres but is also involved in replication, repair and maintenance of the genome (Pardue and DeBaryshe). Telomerase is a cellular RNP (ribonucleoprotein) reverse transcriptase (RT) (Blackburn 2005).
The core part of the enzyme has the TERT protein (with a RT homology domain in addition to other conserved domains) and an RNA component called TER (Blackburn 2005). Telomerase copies a short template sequence in its intrinsic RNA moiety to synthesize a DNA strand for the telomere running 50 to 30 bases toward the chromosome’s distal end, resulting in the extension of the chromosome. This phenomenon is of great importance because the telomeres of chromosomes undergo shortening with time due to the action of nucleases and also because of incomplete replication of the terminal DNA. Whenever linear DNA undergoes replication, its end is not completely replicated by the DNA polymerase enzyme, as explained in figure 1.
Figure 1: Schematic illustrating the replication of DNA. Note that without a special mechanism for replication of the end region of the linear DNA, it will keep shortening after every round of replication (Pardue and DeBaryshe 2009)
The continual degradation of ends of chromosomes results in loss of genetic information, which causes cell death if unchecked (Kim, Kaminker and Campisi 2002).
By extending the terminal ends of chromosomes, the telomerase enzyme compensates for their loss through enzymatic action and incomplete DNA replication (Papachristodoulou et al. 2014). Telemorase enzyme undergoes homeostatic regulation through protein-protein interactions between telomere-associated proteins, which prevent the over-extension of the telomeres. The “telomeric homeostasis system” promotes extension of telomeres whenever they become shortened (Blackburn 2005). The secondary core structure of the TER domain of telomerase enzyme is found to be conserved among eukaryotes, as shown in figure 2(Pardue and DeBaryshe 2009). The telomerase enzyme is also found to prevent fusion of chromosomes (Blackburn 2005).
Figure 2: The telomerase RNA core sequence is universally concerned across eukaryotes (Blackburn 2005)
Varying Levels of Telomerase
The activity of telomerase enzyme in most somatic cells in humans is turned off (Pardue and DeBaryshe 2009). It is due to this that the cell can divide only a specific number of times and as the telomeres shorten after each cell division, the cell undergoes senescence. This regulation evolved to protect the cell against continuous proliferation which could lead to cancer (Papachristodoulou et al. 2014). However, early embryonic and germline cells of mammals do express telomerase (Kim, Kaminker and Campisi 2002). Some adult somatic cells such as activated human T cells and telomerase-positive stem cells in skin of humans are however known to express the telomerase enzyme. In spite of the presence of telomerase activity in human T-cells, they are found to lose telomeric DNA after each division and ultimately undergo senescence. Therefore, telomerase in itself is not sufficient to prevent the erosion of telomere and senescence of cells in some cases (Kim, Kaminker and Campisi).
The telomerase enzyme is found to be involved in initiation and progression of cancer. Evidence suggests that telomerase enzyme is “more likely to promote cancer than prevent it” (Kim, Kaminker and Campisi 2002). The expression of telomerase in somatic cells is found to be more prevalent in mice than in humans. However, even after normalizing for cell number differences, mice are found to be more prone to cancer than humans are. In addition, although the expression of the telomerase enzyme is not found to cause neoplastic transformation, it is found to cooperate with oncogenic genetic alterations for the promotion of tumorigenesis. In human tumor cells, uncapping of telomeres is caused due to the expression of telomerase RNA having a mutant template (Blackburn 2005). Mutations leading to impairment of the telomerase homeostasis system could therefore be involved in infinite proliferation of cancer cells.
As presented in this report, telomerase enzyme has important implications for ageing and senescence of cells. The enzyme ensures that telomeres/chromosome ends are regenerated and the genetic information is retained. In normal somatic cells, the enzyme is inactive due to which the cells reach senescence after a specific number of divisions. However, in cancer cells, active telomerase enzyme results in continuous regeneration of telomeres causing infinite proliferation of timorous cells. This enzyme is thus of extreme relevance to cellular ageing and cancer studies.
Blackburn, E. H. (2005). Telomeres and telomerase: their mechanisms of action and the effects of altering their functions. FEBS Letters, 579, pp. 859–862.
Kim, S., Kaminker, P. and Campisi, J. (2002). Telomeres, aging and cancer: In search of a happy ending. Oncogene, 21(4), pp. 503-511.
Papachristodoulou, D., Snape, A., Elliott, W.H., and Elliott, D.C. (2014). Telomeres solve the problem of replicating the ends of eukaryotic chromosomes. In: Biochemistry and Molecular Biology, 5th edn. (Oxford: Oxford University Press), pp. 361-363.
Pardue, M. L., and DeBaryshe, G. (2009). Telomeres in Cell Function: Cancer and Ageing. In: eLS. (Chichester: John Wiley & Sons Ltd). Available: http://www.els.net [doi: 10.1002/9780470015902.a0001168.pub2].
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