Telomeres The strands of time
Submitted by, Devarapalli Pratap GEN-2010-05-02.
Telomeres In the core of every aging theory, telomere-shortening accounts for major diseases of aging that are derived during cell senescence. Telomeres are protective ends of chromosomes. They are like long strings and akin to static DNA. Telomeres are responsible for the programming of genetic information. They are accountable for the consistency of the information held in chromosomes through the cell division process. Yet, during the process of cell division, the replication of chromosomes with its DNA generates a shorter protection at the end. However, the shortening of telomere is of little value as the genetic information remains preserved with high integrity. The telomeres of humans consist of as many as 2000 repeats of the sequence 5' TTAGGG 3'.
Stabilization of chromosomes by telomere DNA
Replication of linear chromosomes presents a special problem DNA polymerase can only synthesize a new strand of DNA as it moves along the template strand in the 3' – 3' – > 5' direction. This works fine for the 3' – 3' – > 5' strand of a chromosome as the DNA polymerase
can move uninterruptedly from an origin of replication until it meets another bubble of replication or the end of the chromosome. However, synthesis using the 5’ –> 3’ strands as the template has to be discontinuous. When the replication fork opens sufficiently, DNA polymerase can begin to
synthesize a section of complementary strand called an Okazaki fragment working in the opposite direction. Later, a DNA ligase ("DNA ligase I") stitches the Okazaki fragments together.
As the replication fork nears the end of the DNA, there is no longer enough template to continue forming Okazaki fragments. So the 5' end of each newly-synthesized strand cannot be completed. Thus each of the daughter chromosomes will have a shortened telomere. It is estimated that human telomeres lose about 100 base pairs from their telomeric DNA at each mitosis. This represents about 16 TTAGGG repeats. At this rate, after 125 mitotic divisions, the telomeres would be completely gone.
Telomerase Telomerase is an enzyme that adds telomere repeat sequences to the 3' end of DNA strands. By lengthening this strand, DNA polymerase is able to complete the synthesis of the "incomplete ends" of the opposite strand. Telomerase is a ribonucleoprotein. Its single snoRNA molecule called TERC ("Telomere RNA Component") provides an AAUCCC (in mammals) template to guide the insertion of TTAGGG. Its protein component called TERT ("Telomere Reverse Transcriptase") provides the catalytic action. Thus telomerase is a reverse transcriptase. Telomerase is generally found only in the cells of the germline, including embryonic stem (ES) cells; unicellular eukaryotes like Tetrahymena thermophila; some "adult" stem cells and "progenitor" cells enabling them to proliferate and in cancer cells.
Telomeres and Cellular Aging Telomeres are important so their steady shrinking with each mitosis might impose a finite life span on cells. This, in fact, is the case. Normal (non-cancerous) cells do not grow indefinitely when placed in culture. Cells removed from a newborn infant and placed in culture will go on to divide almost 100 times. Well before the end, however, their rate of mitosis declines (to less than once every two weeks). Were my cells to be cultured (I am 80 years old), they would manage only a couple of dozen mitoses before they ceased dividing and died out. This phenomenon is called replicative senescence.
Some cells do not undergo replicative senescence:
The cells of the germline (the germplasm);
Unicellular eukaryotes like Tetrahymena thermophila;
Some cancer cells.
It turns out that these cells are able to maintain the length of their telomeres. They do so with the aid of an enzyme telomerase.
Telomerase and Cancer Most cancers arise from somatic cells. But one of the crucial features that distinguishes a cancer cell from a normal somatic cell is its i ts ability to divide indefinitely. It turns out that most (85 – 90%) 90%) cancer cells have regained the ability to synthesize high levels of telomerase throughout the cell cycle, and thus are able to prevent further shortening of their telomeres. Perhaps agents that prevent the expression of the t he gene for telomerase or prevent the action of
the enzyme will provide a new class of weapons in the fight against cancer. But if telomerase activity is essential for all cells, we had better be careful, and if lack of telomerase hastens replicative senescence, it may also hasten the aging of the tissues that depend on newly-formed cells for continued health a tradeoff that may not be worth making.
Hereditary disease syndromes Germ line mutations in the genes encoding the TERT or the Telomerase RNA Component (TERC) subunits of human telomerase, or in genes encoding some telomere ‐binding proteins, have been genetically linked to acquired and congenital aplastic anemias. The syndrome X ‐linked Dyskeratosis Congenita (DKC) presents with mutations in the gene DKC, encoding a protein that associates with ribosomal RNA and TERC. Other forms of autosomal dominant dyskeratosis congenita are due to mutations in TERC , TERT or other genes encoding proteins involved in telomere maintenance, providing convincing evidence that telomerase deficiency is an underlying cause. The key role of telomerase dysfunction in DKC provides a link between short telomeres and a human disease characterized by signs of premature aging such as hair loss/greying, dental loss and osteoporosis, in addition to the defining features of nail dystrophy, oral leukoplakia and abnormal skin pigmentation. Additional related syndromes have been associated with TERC mutations. Heterozygous germ line mutations in TERT and TERC as well as short telomeres have been found in some patients with familial idiopathic pulmonary fibrosis. As expected for a broadly conserved cellular function of profound importance, genetic defects compromising telomere and telomerase integrity are disease causing. Knowledge about the underlying molecular mechanisms provides diagnostic possibilities and raises the hope of developing future therapies.
Conclusion The conserved function of chromosomal telomere repeat sequences protects against degradation and recombination events and has identified a new enzyme complex, telomerase that is responsible for the synthesis of telomere DNA. Studies of telomerase and telomere maintenance have provided very important insights into areas of high medical relevance such as cancer, ageing and hereditary disease syndromes although the connections are more complex than initially anticipated. The discoveries have also led to the development of new therapeutic strategies for cancer treatment based on the targeting of telomerase activity or expression that are now undergoing clinical testing.
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