Telomerase
Telomerase, also called terminal transferase,
Telomerase is a reverse transcriptase enzyme that carries its own RNA molecule (e.g., with the sequence 3′-CCCAAUCCC-5′ in Trypanosoma brucei)[3] which is used as a template when it elongates telomeres. Telomerase is active in gametes and most cancer cells, but is normally absent in most somatic cells.
History
The existence of a compensatory mechanism for telomere shortening was first found by Soviet biologist
Telomerase in the ciliate Tetrahymena was discovered by Carol W. Greider and Elizabeth Blackburn in 1984.[6] Together with Jack W. Szostak, Greider and Blackburn were awarded the 2009 Nobel Prize in Physiology or Medicine for their discovery.[7] 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.[8]
The role of telomeres and telomerase in
The
Human telomerase structure
The molecular composition of the human telomerase complex was determined by Scott Cohen and his team at the Children's Medical Research Institute (Sydney Australia) and consists of two
long). 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.
The protein consists of four
TERT proteins from many eukaryotes have been sequenced.[23]
Mechanism
The shelterin protein TPP1 is both necessary and sufficient to recruit the telomerase enzyme to telomeres, and is the only shelterin protein in direct contact with telomerase.[24]
By using TERC, TERT can add a six-nucleotide repeating sequence, 5'-TTAGGG (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'.[25]
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.
Clinical implications
Aging
Telomerase restores short bits of DNA known as
In normal circumstances, where telomerase is absent, if a cell divides recursively, at some point the progeny reach their Hayflick limit,[26] which is believed to be between 50 and 70 cell divisions. At the limit the cells become senescent and cell division stops.[27] 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 cancerous growth.[28]
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.
Some experiments have raised questions on whether telomerase can be used as an
Premature aging
Premature aging syndromes including
Cancer
In vitro, when cells approach the Hayflick limit, the time to senescence can be extended by inactivating the tumor suppressor proteins p53 and Retinoblastoma protein (pRb).[44] Cells that have been so-altered 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 a crisis. In a typical situation, the telomeres are shortened[45] and chromosomal integrity 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 the broken ends together. When the cell does this due to telomere-shortening, the ends of different chromosomes can be attached to each other. This solves the problem of lacking telomeres, but during cell division anaphase, 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 fatal damage is done to the cell's chromosomes (killing it via apoptosis), or an additional mutation that activates telomerase occurs.[44]
With telomerase activation some types of cells and their offspring become
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
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,[48] suggesting that the immortality conferred by telomerase plays a key role in cancer development. Of the tumors without TERT activation,[49] most employ a separate pathway to maintain telomere length termed Alternative Lengthening of Telomeres (ALT).[50] The exact mechanism behind telomere maintenance in the ALT pathway is unclear, but likely involves multiple recombination events at the telomere.
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).[51]
Approaches to controlling telomerase and telomeres for cancer therapy include gene therapy, immunotherapy, small-molecule and signal pathway inhibitors.[52]
Drugs
The ability to maintain functional
Telomerase is a good
The expression of hTERT can also be used to distinguish
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,
Cells may reduce their telomere length by only 50-252 base pairs per cell division, which can lead to a long
A telomerase activator
Immunotherapy
Telomerase Vaccines
Two telomerase vaccines have been developed:
Targeted apoptosis
Another independent approach is to use
Small interfering RNA (siRNA)
Heart disease, diabetes and quality of life
Blackburn also discovered that mothers caring for very sick children have shorter telomeres when they report that their emotional stress is at a maximum and that telomerase was active at the site of blockages in
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.[69]
A study in 2010 found that there was "significantly greater" telomerase activity in participants than controls after a three-month meditation retreat.[70]
Telomerase deficiency has been linked to diabetes mellitus and impaired insulin secretion in mice, due to loss of pancreatic insulin-producing cells.[71]
Rare human diseases
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.[72]
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.[73]
Dyskeratosis congenita (DC) is a disease of the bone marrow that can be caused by some mutations in the telomerase subunits.[74] In the DC cases, about 35% cases are X-linked-recessive on the DKC1 locus[75] and 5% cases are autosomal dominant on the TERT[76] and TERC[77] loci.
Patients with DC have severe bone marrow failure manifesting as abnormal
In one family autosomal dominant DC was linked to a
TERT Splice Variants
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See also
- DNA repair
- Imetelstat
- TA-65
- Telomere
- Epitalon
References
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- ^ HGNC - DKC1
- ^ HGNC - TEP1
- ^ NCBI - telomerase reverse transcriptase isoform 1
- ^ Gillis AJ, Schuller AP, Skordalakes E. Structure of the Tribolium castaneum telomerase catalytic subunit TERT. Nature. 2008 Oct 2;455(7213):633-7
- ^ Mitchell 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
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Further reading
- The Immortal Cell, by ISBN 978-0-385-50928-2
External links
- Gene Ontology: GO:0003720: telomerase activity
- Human telomerase reverse transcriptase (TERT) gene on genecards.org
- The Telomerase Database - A Web-based tool for telomerase research
- Three-dimensional model of telomerase at MUN
- Elizabeth Blackburn's Seminars: Telomeres and Telomerase
- Telomerase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: O14746 (Human Telomerase reverse transcriptase) at the PDBe-KB.
- Overview of all the structural information available in the PDB for UniProt: Q0QHL8 (Tribolium castaneum Telomerase reverse transcriptase) at the PDBe-KB.