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Tribolium castaneum telomerase catalytic subunit, TERT, bound to putative RNA template and telomeric DNA
RNA-directed DNA polymerase
A conceptual diagram showing the protein component of telomerase (TERT) in grey and the RNA component (TR) in yellow
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Telomerase also called telomere terminal transferase [1] is a ribonucleoprotein that is an enzyme that adds DNA sequence repeats ("TTAGGG" in all vertebrates) to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains noncoding DNA and hinders the loss of important DNA from chromosome ends. As a result, every time the chromosome is copied, only 100–200 nucleotides are lost, which causes no damage to the organism's DNA. Telomerase is a reverse transcriptase that carries its own RNA molecule, which is used as a template when it elongates telomeres, which are shortened after each replication cycle.

The existence of a compensatory mechanism for telomere shortening was first predicted by Soviet biologist Alexey Olovnikov in 1973,[2] who also suggested the telomere hypothesis of aging and the telomere's connections to cancer. Telomerase was discovered by Carol W. Greider and Elizabeth Blackburn in 1984 in the ciliate Tetrahymena.[3] Together with Jack W. Szostak, Greider and Blackburn were awarded the 2009 Nobel Prize in Physiology or Medicine for their discovery.[4]

The role of telomeres and telomerase in cell aging and cancer was established by scientists at biotechnology company Geron with the cloning of the RNA and catalytic components of human telomerase [5] and the development of a PCR- based assay for telomerase activity called the TRAP assay allowing for a survey of telomerase activity in multiple types of cancer.[6]

Structure[edit]

Human telomerase consists of molecules each of human telomerase reverse transcriptase (TERT), telomerase RNA (TR or TERC), and dyskerin (DKC1).[7] The genes of telomerase subunits, which are TERT,[8] TERC,[9] DKC1,[10] and TEP1[11] etc, are located on different chromosomes in the human genome. Human TERT gene (hTERT) is translated into a protein of 1132 amino acids.[12] TERT proteins from many eukaryotes have been sequenced.[13] TERT polypeptide folds with TERC, a non-coding RNA (451 nucleotides long in human). 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 enzyme that creates single-stranded DNA using single-stranded RNA as a template. As stated above, TERT carries its own template, TERC.

An image illustrating how telomerase elongates telomere ends progressively.

The protein composition of human telomerase was identified in 2007 by Scott Cohen and his team at the Children's Medical Research Institute in Australia.[7] The high-resolution protein structure of the Tribolium castaneum catalytic subunit of telomerase TERT was decoded in 2008 by Emmanuel Skordalakes and his team at The Wistar Institute in Philadelphia.[14] The structure revealed that the protein consists of four conserved domains (RNA-Binding Domain (TRBD), fingers, palm and thumb), organized into a ring configuration that shares common features with retroviral reverse transcriptases, viral RNA polymerases and bacteriophage B-family DNA polymerases.

Function[edit]

By using TERC, TERT can add a six-nucleotide repeating sequence, 5'-TTAGGG (in 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'.[15] 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. (For an explanation on why this elongation is necessary see Telomere shortening.)

Clinical implications[edit]

Aging[edit]

The enzyme telomerase allows for replacement of short bits of DNA known as telomeres, which are otherwise shortened when a cell divides via mitosis.

In normal circumstances, without the presence of telomerase, if a cell divides recursively, at some point all the progeny will reach their Hayflick limit,[16] which is believed to be between 50–70 cell divisions until the cells become senescent and cell division stops.[17] With the presence of telomerase, each dividing cell can replace the lost bit of DNA, and any single cell can then divide unbounded. While this unbounded growth property has excited many researchers, caution is warranted in exploiting this property, as exactly this same unbounded growth is a crucial step in enabling cancerous growth.[18]

Embryonic stem cells express telomerase, which allows them to divide repeatedly and form the individual. In adults, telomerase is highly expressed in cells that need to divide regularly especially in male germ cells but also in activated lymphocytes and certain adult stem cells, whereas other somatic cells do not express it.[19]

A variety of premature aging syndromes are associated with short telomeres.[20] These include Werner syndrome, Ataxia telangiectasia, Ataxia-telangiectasia like disorder, Bloom syndrome, Fanconi anemia, and Nijmegen breakage syndrome. However, the genes that have been mutated in these diseases all have roles in the repair of DNA damage and the increased DNA damage may, itself, be a factor in the premature aging (see DNA damage theory of aging). An additional role in maintaining telomere length is an active area of investigation.

However, a study of the comparative biology of mammalian telomeres indicated that telomere length of different mammalian species correlates inversely, rather than directly, with lifespan, and it was concluded that the contribution of telomere length to lifespan remains controversial.[21] Also, telomere shortening does not occur with age in some postmitotic tissues, such as in the rat brain.[22] In humans, skeletal muscle telomere lengths remain stable from ages 23 –74.[23] In the baboon skeletal muscle, that consists of fully differentiated post-mitotic cells, less than 3% of myonuclei contain damaged telomeres and this percentage does not increase with age.[24] Thus, telomere shortening does not appear to be a major factor in the aging of the differentiated cells of brain or skeletal muscle. In human liver, cholangiocytes and hepatocytes show no age-related telomere shortening.[25] Furthermore, Harris et al. found little evidence that, in humans, telomere length is a significant biomarker of normal aging with respect to important cognitive and physical abilities.[26]

Some experiments have raised questions on whether telomerase can be used as an anti-aging therapy, namely, the fact that mice with elevated levels of telomerase have higher cancer incidence and hence do not live longer. Certain premature aging syndromes have been associated with telomere shortening. But telomerase also favors tumorogenesis, which leads to questions about its potential as an anti-aging therapy.[27] On the other hand, one study showed that activating telomerase in cancer-resistant mice by overexpressing its catalytic subunit extended lifespan.[28] The potential remains for telomerase activators to contribute to the development of cancer.

Exposure of T lymphocytes from HIV-infected human donors to a small molecule telomerase activator (TAT2) retards telomere shortening, increases proliferative potential, and, what is highly significant, enhances cytokine/chemokine production and antiviral activity.[29]

A study that focused on Ashkenazi Jews found that those that live the longest inherit a hyperactive version of telomerase that rebuilds telomeres.[30]

Mice engineered to block the gene that produces telomerase, unless they are given a certain drug, aged at a much faster rate and died at about six months, instead of reaching the average mouse lifespan of about three years. Administering the drug at 6 months turned on telomerase production and caused their organs to be "rejuvenated," restored fertility, and normalized their ability to detect or process odors. The finding raises hope for treatment of conditions such as progeria and other accelerated aging disorders, as well as possible organ regeneration therapies, such as repair of liver damage due to hepatitis or alcoholism.[31][32]

A 2012 study reported that introducing the TERT gene into healthy one-year-old mice using an engineered adeno-associated virus led to a 24% increase in lifespan, without any increase in cancer.[33]

Cancer[edit]

When cells are approaching the Hayflick limit in cell cultures, the time to senescence can be extended by the inactivation of the tumor suppressor proteins - p53 and Retinoblastoma protein (pRb)[citation needed]. Cells that have been so-altered will eventually undergo an event termed a "crisis" when the majority of the cells in the culture die. Sometimes, a cell does not stop dividing once it reaches crisis. In a typical situation, the telomeres are shortened,[34] and the integrity of the chromosomes declines with every subsequent cell division. Exposed chromosome ends are interpreted as 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 lacking 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 cell dies (via programmed cell death, apoptosis), or an additional mutation that activates telomerase will take place.[citation needed]

With the activation of telomerase, some types of cells and their offspring become immortal; that is, their chromosomes will not become unstable no matter how many cell divisions they undergo (they bypass the Hayflick limit), thus avoiding cell death as long as the conditions for their duplication are met. Many cancer cells are considered 'immortal' because telomerase activity allows them to divide virtually forever, which is why they can form tumors. A good example of cancer cells' immortality is HeLa cells, which have been used in laboratories as a model cell line since 1951.

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 that allow for the formation of the tumorigenic clones in the above-described experiment are not clear. Scientists have subsequently been able to address this question by the serial introduction of several mutations present in a variety of human cancers. This has led to the understanding of several combinations of mutations that 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.[citation needed] That is to say, the cell has an activated telomerase, eliminating the process of death by chromosome instability or loss, absence of apoptosis-induction pathways, and continued activation of mitosis.

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,[35] suggesting that the immortality conferred by telomerase plays a key role in cancer development. Of the tumors that have not activated TERT,[36] most have found a separate pathway to maintain telomere length termed ALT (Alternative Lengthening of Telomeres).[37] The exact mechanism behind telomere maintenance in the ALT pathway has not been made clear, but likely involves multiple recombination events at the telomere.

There have been two telomerase vaccines developed: GRNVAC1 and GV1001. GRNVAC1 isolates dendritic cells and the RNA that codes for the telomerase protein and puts it back into the patient to make the cytotoxic T cells kill the telomerase-active cells. GV1001 comes from the active site of hTERT and is recognized by the immune system and subsequently reacts by killing the telomerase-active cells.[38]

Additional roles in cancer, heart disease, diabetes and quality of life[edit]

Additional roles for telomerase per work by Elizabeth Blackburn et al., include the upregulation of 70 genes known or suspected in cancers' growth and spread through the body, and the activation of glycolysis, which enables cancer cells to rapidly use sugar to facilitate their programmed growth rate (roughly the growth rate of a fetus).[39]

E. V. Gostjeva et al. (MIT) recently imaged colon cancer stem cells and compared them to fetal colon stem cells trying to make a new colon; they were the same.[40]

Elizabeth Blackburn et al. UCSF has shown work that reveals that mothers caring for their very sick children have shorter telomeres when they report that their emotional stress is at the greatest point. She also found telomerase active at the site of blockages in coronary artery tissue. This could be why heart attacks can come on so suddenly: Telomerase is driving the growth of the blockage.

In 2009, it was shown that the amount of telomerase activity significantly increased due to psychological stress. Across the sample of patients telomerase activity increased by 18% one hour after the end of the stress. Telomerase activity was examined in peripheral blood mononuclear cells.[41]

A study in 2010 found that there was "significantly greater" telomerase activity in participants than controls after a three-month meditation retreat.[42]

Telomerase deficiency has been linked to diabetes mellitus and impaired insulin secretion in mice, due to loss of insulin-producing cells in the pancreas.[43]

There are many ways to examine telomerase and telomeres for cancer therapy, such as gene therapy, immunotherapy, small-molecule, ans signal pathway inhibitors.[38]

Role in rare human diseases[edit]

Mutations in TERT have been implicated in predisposing patients to aplastic anemia, a disorder in which the bone marrow fails to produce blood cells, in 2005.[44]

Cri du chat Syndrome (CdCS) is a complex disorder involving the loss of the distal portion of the short arm of chromosome 5. TERT is located in the deleted region, and loss of one copy of TERT has been suggested as a cause or contributing factor of this disease.[45]

Dyskeratosis congenita (DC) is a disease of the bone marrow that can be caused by some mutations in the telomerase subunits.[46] In the DC cases, about 35% cases are X-linked-recessive on the DKC1 locus[47] and 5% cases are autosomal dominant on the TERT[48] and TERC[49] loci.

Patients with DC have severe bone marrow failure manifesting as abnormal skin pigmentation, leucoplakia (a white thickening of the oral mucosa), and nail dystrophy, as well as a variety of other symptoms. Individuals with either TERC or DKC1 mutations have shorter telomeres and defective telomerase activity in vitro than other individuals of the same age.[50]

There has also been one family in which autosomal dominant DC has been linked to a heterozygous mutation in TERT.[51] These patients also exhibited an increased rate of telomere-shortening, and genetic anticipation (i.e., the DC phenotype worsened with each generation).

Telomerase as a potential drug target[edit]


The ability to maintain functional telomeres may be one reason that cancer cells, but not normal cells, can grow in cell culture for decades and are considered to be immortal [52]. Telomerase activity is necessary for the immortality of many cancer types and is inactive in somatic cells, signifying that telomerase inhibition could selectively repress cancer cell growth with minimal side effects.[53] If a drug can be used to turn off telomerase in cancer cells, the telomeres will progressively shorten as these cells continue to divide, leading eventually to chromosome loss and cell death.[54]

Telomerase is a good biomarker for cancer detection because most human cancers cells express high levels of telomerase. Telomerase activity can be screened for by its catalytic protein domain (hTERT).[55] This is the center of detection as it is the rate-limiting step in the production of telomerase activity. [55] It is associated with many cancer types. Various cancer cells and fibroblasts transformed with hTERT cDNA have been found to have high telomerase activity, while normal non cancerous cells do not show telomerase expression. [55] Cells testing positive for hTERT will have positive nuclear signals. The only noncancerous cells that hTERT can be detected in is epithelial stem cell tissue and their early daughter cells.[55] The localization of hTERT expression can help elucidate the tumor burden on the body. Since hTERT expression is only dependent on the number of tumor cells within a sample, the amount of hTERT being expressed will allow one to indicate the severity of a cancer. [55]

hTERT expression can also be used to distinguish between benign tumors and malignant tumors. Malignant tumors have higher mTERT expression, whereas benign tumors have lower expression. A real-time reverse transcription polymerase chain reaction (RT-PCR) quantifying hTERT expression in various tumor samples have verified this varying expression.[56] Now we must figure out methods to target telomerase as a treatment option for cancer.[56]

Figure 4:A) Tumor cells expressing hTERT will actively degrade some of the protein and process for presenting. The major histocompatibility complex 1(MHC1), can then present the hTERT epitote. CD8- T cells that have antibodies against hTERT will then bind to the presented epitote. B) As a result of the antigenic binding, the T cells will release cytotoxins, which can be absorbed by the affected cell. C) These cytotoxins induce multiple proteases and results in apoptosis (or cell death).

Telomerase, as a drug target for cancer, is still under a lot of research and is difficult to target for various reasons. The main goal is to inhibit telomerase in its function to increase cancer cell count. The telomerase RNP and telomere complex is difficult for anticancer treatments due to telomerase exhibiting a lag phase during its inhibition. Also, to make matters more difficult, the lack of telomerase does not affect cell growth, unless and only until telomere shortening with each cell division causes cells to “die or undergo growth arrest”. [55] However, this mechanism alone, in inhibiting telomerase, would not be enough to target patients with large tumors. To target tumors with the use of telomerase inhibitors, one would also need to use it with a combination of surgery, radiation treatment, and/or chemotherapy.

Telomere Shortening[edit]

Today, most telomerase inhibition treatments rely heavily on telomere shortening. The task at hand now, in order to be able to use telomerase inhibition as a drug treatment for cancer, is to limit telomerase activity within a cell. Once this is done, the cells will begin to shorten the telomeres during successive cell divisions by limiting telomerase activity. After the telomerase over expressing cells have died, telomerase activity could be restarted and regular cells could grow. Thus, the purpose of anti-telomerase therapy would be to eliminate the proliferative potential of cancer cells before the telomere lengths in normal cells shorten sufficiently to disrupt their function. [55] This, however, is still not yet an effective treatment option because this is a very slow process. Cells may only reduce their telomere length by 50-100 base pairs per cell division, which can lead to a long lag phase. [57] This is often an obstacle for anticancer treatments, especially when long telomeres are present. Another way to eliminate cancer cells is immunotherapy directed against telomerase positive cells in which the lag phase of telomerase would be completely inhibited. [55]

Immunotherapy[edit]

Immunotherapy has been suggested to treat cancer. This treatment involves manipulating a human’s immune system to destroy its own cancerous cells. Humans have two major antigen identifying molecules: cytotoxic T-lymphocytes (CTL) and CD4+ helper T-lymphocytes. [58] These molecules have the ability to destroy cells that harm humans. Antigen receptors on the CTL can bind to a 9-10 amino acid chain that is presented by the major histocompatibility complex (MHC).[58] This process can be seen in figure 4. hTERT has been found to be a great target for this treatment. It is highly expressed by the body in almost all tumor cells and targeting through this method should result in relatively few side effects since hTERT expression is correlated with telomerase activity.[58] Telomerase expression is non-vital in most all somatic cells.[58] By creating a vaccine targeting the hTERT antigen, the body will begin developing antibodies against the hTERT protein and begin fighting the cancer in the body. Vaccines like GV1001 uses a pathway like this to treat cancer.[38]

Targeted Apoptosis[edit]

Figure 5: A) Human telomerase RNA (hTR) is present in the cell and can be targeted. B) 2-5 anti-hTR oligonucleotides is a specialized antisense oligo that can bind to the telomerase RNA. C) Once bound, the 2-5 anti-hTR oligonucleotide recruits RNase L to the sequence. Once recruited, the RNase L creates a single cleavage in the RNA (D) and causes dissociation of the RNA sequence.

Yet another approach, which is quite independent of the last two, is to use oligoadenylated anti-telomerase antisense oligonucleotides to target telomerase RNA and induce dissociation and apoptosis(figure 5). [57] Since telomere shortening results is a time-consuming process, the fast induction of apoptosis through this antisense binding may be a good alternative. By using “oligoadenylated antisense oligonucleotides” and “ribozymes against the hTERT T-motif,” this process may be good way to inhibit telomerase in cancer cells. [57]

Other Research[edit]

Experimental drug and vaccine therapies targeting active telomerase have been tested in mouse models, and some have now entered early clinical trials[citation needed]. Geron Corporation is currently conducting four human clinical trials involving telomerase inhibition and telomerase vaccination[citation needed]. Merck, as a licensee of Geron, has recent approval of an IND for one vaccine type[citation needed]. The vaccine platform is being tested (and now jointly with Merck) using three different approaches[citation needed]. One vaccine is adenovirus/plasmid based (Merck IND). The second is an autologous dendritic cell based vaccine (GRNVAC1), formerly called TVAX when tested in Phase I clinical trials in Prostate Cancer, and it showed significant PSA doubling times as well as T-cell response[citation needed]. Geron's embryonic stem cell derived dendritic cell vaccine targeting telomerase is the third approach and is currently at the pre-clinical stage[citation needed].

These vaccine methods attempt to teach the human immune system to attack cancer cells expressing telomerase[citation needed]. Geron's telomerase inhibitor drug (GRN163L) attempts to stop cancer cell proliferation by inhibiting telomerase and it is in three separate early stage human clinical trials[citation needed]. Indeed, telomerase inhibition in many types of cancer cells grown in culture has led to the massive death of the cell population[citation needed]. However, a variety of caveats, including the presence of the ALT pathway,[36][37] complicate such therapies. Some have reported ALT methods of telomere maintenance and storage of DNA in cancer stem cells, however Geron claims to have killed cancer stem cells with their telomerase inhibitor GRN163L at Johns Hopkins. GRN163L binds directly to the RNA template of telomerase. Even a mutation of the RNA template of telomerase would render the telomerase unable to extend telomeres, and therefore not be able to grant replicative immortality to cancer, not allow glycolysis to be inititated, and not upregulate Blackburn's 70 cancer genes. [citation needed]

Since Blackburn has shown that most of the harmful cancer-related effects of telomerase are dependent on an intact RNA template[citation needed], it seems a very worthwhile target for drug development[neutrality is disputed]. If indeed some cancer stem cells use an alternative method of telomere maintenance, it should be noted that they are still killed when the RNA template of telomerase is blocked.

According to Blackburn's opinion at most of her lectures, it is a big mistake to think that telomerase is involved with only extending telomeres. Stopping glycolysis in cancer stem cells and preventing the upregulation of 70 bad genes is probably what is killing cancer stem cells if they are using alternative methods.[citation needed]

See also[edit]

References[edit]

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Further reading[edit]

Books[edit]

External links[edit]

Category:Ageing Category:Aging-related proteins Category:Aging-related enzymes Category:Anti-aging substances Category:DNA replication Category:EC 2.7.7 Category:Gerontology Category:Senescence Category:Telomere-related proteins Category:Telomeres

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