Product Code Database
Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of . A telomere is a region of repetitive sequences at each end of the of most . Telomeres protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. The fruit fly Drosophila melanogaster lacks telomerase, but instead uses to maintain telomeres.
Telomerase is a reverse transcriptase enzyme that carries its own RNA molecule (e.g., with the sequence 3′-CytosineAdenineUracil-5′ in Trypanosoma brucei) which is used as a template when it elongates telomeres. Telomerase is active in and most cancer cells, but is normally absent in most .
Telomerase in the ciliate Tetrahymena was discovered by Carol W. Greider and Elizabeth Blackburn in 1984. Together with Jack W. Szostak, Greider and Blackburn were awarded the 2009 Nobel Prize in Physiology or Medicine for their discovery. Later the cryo-EM structure of telomerase was first reported in T. thermophila, to be followed a few years later by the cryo-EM structure of telomerase in humans.
The role of telomeres and telomerase in cellular aging and cancer was established by scientists at biotechnology company Geron with the cloning of the RNA and catalytic components of human telomerase and the development of a polymerase chain reaction (PCR) based assay for telomerase activity called the TRAP assay, which surveys telomerase activity in multiple types of cancer.
The negative stain electron microscopy (EM) structures of human and Tetrahymena telomerases were characterized in 2013. Two years later, the first cryo-electron microscopy (cryo-EM) structure of telomerase holoenzyme ( Tetrahymena) was determined. In 2018, the structure of human telomerase was determined through cryo-EM by UC Berkeley scientists.
The protein consists of four conserved domains (RNA-Binding Domain (TRBD), fingers, palm and thumb), organized into a "right hand" ring configuration that shares common features with retroviral reverse transcriptases, viral and bacteriophage B-family DNA polymerases.Gillis AJ, Schuller AP, Skordalakes E. Structure of the Tribolium castaneum telomerase catalytic subunit TERT. Nature. 2008 Oct 2;455(7213):633-7Mitchell M, Gillis A, Futahashi M, Fujiwara H, Skordalakes E. Structural basis for telomerase catalytic subunit TERT binding to RNA template and telomeric DNA. Nat Struct Mol Biol. 2010 Apr;17(4):513-8
TERT proteins from many eukaryotes have been sequenced.NCBI -
target="_blank" rel="nofollow"> telomerase reverse transcriptase
By using TERC, TERT can add a six-nucleotide repeating sequence, 5'-ThymidineGuanine (in 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'.
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. Telomerase reverses telomere shortening.
In normal circumstances, where telomerase is absent, if a cell divides recursively, at some point the progeny reach their Hayflick limit, which is believed to be between 50 and 70 cell divisions. At the limit the cells become senescent and cell division stops.Siegel, L (2013). Are Telomeres the Key to Aging and Cancer? The University of Utah. Retrieved 30 September 2013 Telomerase allows each offspring to replace the lost bit of DNA, allowing the cell line to divide without ever reaching the limit. This same unbounded growth is a feature of cancer.
Embryonic stem cells express telomerase, which allows them to divide repeatedly and form the individual. In adults, telomerase is highly expressed only in cells that need to divide regularly, especially in male , but also in epidermis, in activated T cell and B cell , as well as in certain adult stem cells, but in the great majority of cases somatic cells do not express telomerase.
A comparative biology study of mammalian telomeres indicated that telomere length of some mammalian species correlates inversely, rather than directly, with lifespan, and concluded that the contribution of telomere length to lifespan is unresolved. Telomere shortening does not occur with age in some postmitotic tissues, such as in the rat brain. In humans, skeletal muscle telomere lengths remain stable from ages 23 –74. In baboon skeletal muscle, which consists of fully differentiated postmitotic cells, less than 3% of myonuclei contain damaged telomeres and this percentage does not increase with age. 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. Another study found little evidence that, in humans, telomere length is a significant biomarker of normal aging with respect to important cognitive and physical abilities.
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. On the other hand, one study showed that activating telomerase in cancer-resistant mice by overexpressing its catalytic subunit extended lifespan. A study found that long-lived subjects inherited a hyperactive version of telomerase.
With telomerase activation some types of cells and their offspring become immortal (bypass the Hayflick limit), thus avoiding cell death as long as the conditions for their duplication are met. Many are considered 'immortal' because telomerase activity allows them to live much longer than any other somatic cell, which, combined with uncontrollable cell proliferationDr. Todd Hennessey, 2016 University at Buffalo is why they can form . A good example of immortal cancer cells is , which have been used in laboratories as a model cell line since 1951.
While this method of modelling 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 Cloning in the above-described experiment are not clear. Scientists addressed this question by the serial introduction of multiple mutations present in a variety of human cancers. This has led to the identification of mutation combinations that form tumorigenic cells in a variety of cell types. While the combination varies by cell type, the following alterations are required in all cases: TERT activation, loss of p53 pathway function, loss of pRb pathway function, activation of the Ras subfamily or C-myc proto-oncogenes, and aberration of the Protein phosphatase 2 (PP2A). 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 mitosis activation.
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 plays a key role in cancer development. Of the tumors without TERT activation, most employ a separate pathway to maintain telomere length termed Alternative Lengthening of Telomeres (ALT). The presence of this alternative pathway was first described in an SV40 virus-transformed human cell line, and based on the dynamics of the changes in telomere length, was proposed to result through recombination. However, the exact mechanism remains unclear.
Elizabeth Blackburn et al., identified the upregulation of 70 genes known or suspected in cancer 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).
Approaches to controlling telomerase and telomeres for cancer therapy include gene therapy, immunotherapy, small-molecule and signal pathway inhibitors.
Telomerase is a good biomarker for cancer detection because most human cancer cells express high levels of it. Telomerase activity can be identified by its catalytic protein domain (hTERT). is the rate-limiting step in telomerase activity. It is associated with many cancer types. Various cancer cells and fibroblasts transformed with hTERT cDNA have high telomerase activity, while somatic cells do not. Cells testing positive for hTERT have positive nuclear signals. Epithelial stem cell tissue and its early daughter cells are the only noncancerous cells in which hTERT can be detected. Since hTERT expression is dependent only on the number of tumor cells within a sample, the amount of hTERT indicates the severity of cancer.
The expression of hTERT can also be used to distinguish benign tumors from malignant tumors. Malignant tumors have higher hTERT expression than benign tumors. Real-time reverse transcription polymerase chain reaction (RT-PCR) quantifying hTERT expression in various tumor samples verified this varying expression. The lack of telomerase does not affect cell growth until the telomeres are short enough to cause cells to "die or undergo growth arrest". However, inhibiting telomerase alone is not enough to destroy large tumors. It must be combined with surgery, radiation, chemotherapy or immunotherapy.
Cells may reduce their telomere length by only 50-252 base pairs per cell division, which can lead to a long lag phase.
A telomerase activator TA-65 is commercially available and is claimed to delay aging and to provide relief from certain disease conditions. This formulation contains a molecule called cycloastragenol derived from a legume Astragalus membranaceus. Several other compounds have been found to increase telomerase activity: Centella asiatica extract 8.8-fold, oleanolic acid 5.9-fold, astragalus extract 4.3-fold, TA-65 2.2-fold, and maslinic acid 2-fold.
In 2009, it was shown that the amount of telomerase activity significantly increased following psychological stress. Across the sample of patients telomerase activity in peripheral blood mononuclear cells increased by 18% one hour after the end of the stress.
A study in 2010 found that there was "significantly greater" telomerase activity in participants than controls after a three-month meditation retreat.
Telomerase deficiency has been linked to diabetes mellitus and impaired insulin secretion in mice, due to loss of Beta cell.
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.
Dyskeratosis congenita (DC) is a disease of the bone marrow that can be caused by some mutations in the telomerase subunits. In the DC cases, about 35% cases are Sex linkage-recessive on the DKC1 locus and 5% cases are autosome dominant on the TERT and TERC 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 versus other individuals of the same age.
In one family autosomal dominant DC was linked to a heterozygous TERT mutation. These patients also exhibited an increased rate of telomere-shortening, and genetic anticipation (i.e., the DC phenotype worsened with each generation).
|
|
