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Telomerase is an enzyme that adds specific DNA sequence repeats ("TTAGGG" in all vertebrates) to the 3' ("three prime") end of DNA strands in the telomere regions at the ends of chromosomes. These telomeres contain condensed DNA material during replication. The enzyme is a reverse transcriptase that carries its own RNA template; this RNA is used as a template for eukaryotic DNA replication.
Structure
Human telomerase is composed of at least two sub-units, human Telomerase Reverse Transcriptase (TERT) and human Telomerase RNA (hTR or TERC). These two subunits are coded for by two different genes in the genome. The coding region of the TERT gene is 3396bp, and translates to a protein of 1131 amino acids. The polypeptide folds with TERC (451 nucleotides long), which is not translated and remains as RNA. TERT has a 'mitten' structure that allows it to wrap around the chromosome to add single-stranded telomere repeats.
TERT is a reverse transcriptase, which is a class of enzymes that creates single stranded DNA using single stranded RNA as a template. Enzymes of this class (but not TERT specifically) are utilized by scientists in the molecular biological process of Reverse Transcriptase PCR (RT-PCR), which allows the creation of several DNA copies of a target sequence using RNA as a template. TERT carries its own template around, TERC.
Function
By using TERC, TERT can add a six nucleotide repeating sequence, 5'-TTAGGG (in humans and all vertebrates...the sequence differs in other organisms) to the 3' strand of chromosomes. These TTAGGG repeats, with their various protein binding partners are called telomeres. The template region of TERC is 3'-CAAUCCCAAUC-5'. This way, telomerase can bind the first few nucleotides of the template to the last telomere sequence on the chromosome, add a new telomere repeat (5'-GGTTAG-3') sequence, let go, realign the new 3'-end of telomere to the template, and repeat the process
Clinical implications
Aging
A variety of premature aging syndromes are associated with short telomeres These include Werner syndrome, Ataxia telangiectasia, Bloom syndrome, Fanconi anemia, Nijmegen breakage syndrome and ataxia telangiectasia-like disorder. The genes which have been mutated in these diseases all have roles in the repair of DNA damage, and their precise roles in maintaining telomere length are an active area of investigation. While it is currently unknown to what extent telomere erosion contributes to the normal aging process, maintenance of DNA in general, and telomeric DNA specifically, have emerged as major players. Dr. Michael Fossel has suggested that telomerase therapies [http://smartpub.web01.yourhost.com/articles/060116-fossel.php may be used not only to combat cancer, but to actually reverse human aging and extend lifespan significantly. He believes human trials of telomerase-based therapies for extending lifespan will occur within the next 10 years. This timeline is significant because it coincides with the retirement of Baby Boomers in the United States and Europe.Cancer
When modeling human cell growth approaching the Hayflick limit in cell culture, the time to senescence can be extended by the inactivation of the tumor suppressor proteins - TP53 and Retinoblastoma protein (pRb). Cells which have been thus altered will eventually undergo an event termed a "crisis" when the majority of the cell in the culture die. Sometimes, a cell does not stop dividing once it reaches crisis. Typically the telomeres are lost, and the integrity of the chromosomes declines with every subsequent cell division. Exposed chromosome ends are interpreted as a double stranded breaks (DSB) in DNA; such damage is usually repaired by reattaching (religating) the broken ends together. When the cell does this due to telomere shortening, the ends of different chromosomes can be attached together. This temporarily solves the problem of no telomeres, but during anaphase of cell division the fused chromosomes are randomly ripped apart causing many mutations and chromosomal abnormalities. As this process continues, the cell's genome becomes unstable. Eventually, either sufficient damage will be done to the cell's chromosomes such that programmed cell death (apoptosis) occurs, or an additional mutation will take place that activates telomerase.Immortal cancer cells. With the activation of telomerase, some types of cells and their offspring become immortal. Cancer cells are considered 'immortal' because telomerase activity allows them to divide forever, which is why they can form a tumor. A good example of cancer cells' immortality is HeLa cells. HeLa cells were originally removed from the cervical cancer of Henrietta Lacks in 1951 and are still used in laboratories as a model cell line. They are indeed immortal - daily production of HeLa cells is estimated at several tons - all from the few cells taken from Ms. Lacks' tumor.
While this method of modeling human cancer in cell culture is effective and has been used for many years by scientists, it is also very imprecise. The exact changes which allow for the formation of the tumorigenic clones in the above experiment are not clear. Scientists have subsequently been able to address this question by the serial introducation of several mutations present in a variety of human cancers. This has led to the elucidation of several combinations of mutations which are sufficient for the formation of tumorigenic cells, in a variety of cell types. While the combination varies depending on the cell type, a common theme is that the following alterations are required: activation of TERT, loss of p53 pathway function, loss of pRb pathway function, activation of the Ras or myc proto-oncogenes, and aberration of the PP2A protein phosphatase.
This model of cancer in cell culture accurately describes the role of telomerase in actual human tumors. Telomerase activation has been observed in ~90% of all human tumors, suggesting that the immortality conferred by telomerase is required for cancer development. Of the tumors which have not activated TERT, most have found a separate pathway to maintain telomere length termed ALT (Alternative Lengthening of Telomeres). The exact mechanism behind telomere maintenance in the ALT pathway has not been elucidated, but likely involves multiple recombination events at the telomere.
Role in other human diseases
Aplastic anemia. Mutations in TERT have been implicated in predisposing patients to aplastic anemia *.Cri du chat Syndrome (CdCS). Loss of one copy of TERT has been suggested as a cause or contributing factor of CdCS *.
Dyskeratosis congenita (DC) is a disease of the bone marrow which can be caused by a mutation in the telomerase RNA subunit, TERC. Mutation of TERC only accounts for 5% of all cases, and when DC occurs by this mutation, it is inherited as an autosomal dominant disorder. Mutations in the gene Dyskerin (DKC1) account for about 35% of DC cases, and in this case the inheritance pattern is X-linked recessive.
Patients with DC have severe bone marrow failure manifesting as abnormal skin pigmentation, leucoplakia (a white thickening of the oral mucosa), and nail dystophy, as well as a variety of other symtoms. Individuals with either TERC or DKC1 mutations have shorter telomeres and defective telomerase activity in vitro than other individuals of the same age *.
There has also been one family in which autosomal dominant DC has been linked to a heterozygous mutation in TERT *. These patients also exhibited an increased rate of telomere shortening, and gentic anticipation (i.e. the DC phenotype worsened with each generation).
Telomerase as a potential drug target
Cancer is a very difficult disease to fight because the immune system cannot recognize it, and cancer cells are immortal; they will always continue dividing. Because telomerase is necessary for the immortality of so many cancer types, it is thought to be a potential drug target. If a drug can be used to turn off telomerase in cancer cells, the above process of telomere shortening will resume—telomere length will be lost as the cells continue to divide, mutations will occur and cell stability will decrease. Experimental drug therapies targeting active telomerase have been tested in mouse models, and some have now entered early clinical trials. Indeed, telomerase suppression in many types of cancer cells grown in culture has led to the massive death of the cell population. However, a variety of caveats including the presence of the ALT pathway *, complicates such therapies.Trivia
- "Infinite Telomerase" is a trait inherent to Albedo Piazzola from the video game series, Xenosaga. In the game, Albedo is a character who can infinitely re-generate lost limbs and body parts--including his own head.
References
1. (R) Dyskeratosis congenita: telomerase, telomeres and anticipation. 2005 Jun;
Telomere elongation in immortal human cells without detectable telomerase activity. 1995 Sep 1;
3. The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity. 1987 Dec 24;
4. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. 1989 Jan 26;
5. Genetics: Analysis of Genes and Genomes, 6th Edition; Hartl, L. Daniel, Jones W. Elizabeth; (c)2005; Jones and Bertlett Publishers, Canada
Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. 2005 Apr 7; Free text after registration
Deletion of the telomerase reverse transcriptase gene and haploinsufficiency of telomere maintenance in Cri du chat syndrome. ;
8. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. 2005 Nov 1;
9. (R) Telomeres and human disease: ageing, cancer and beyond. 2005 Aug;
10. Lecture by Michael Tibbetts, Department of Biology, Bard College, Annandale-on-Hudson, New York, 12504
See also
DNA repair
External links
- Telomerase.org - A blog-style discussion of telomerase and anti-aging therapies.
- Three-dimensional model of telomerase
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"Telomerase"