TELOMERASE, also called TERMINAL TRANSFERASE, is a ribonucleoprotein
that adds a species-dependent telomere repeat sequence to the 3\' end
of telomeres . A telomere is a region of repetitive sequences at each
end of eukaryotic chromosomes in most eukaryotes .
the end of the chromosome from DNA damage or from fusion with
neighbouring chromosomes. The fruit fly
Drosophila melanogaster lacks
telomerase, but instead uses retrotransposons to maintain telomeres.
Telomerase is a reverse transcriptase enzyme that carries its own RNA
molecule (e.g., with the sequence "C C C A A U C C C " in vertebrates)
which is used as a template when it elongates telomeres. (Beyond
unicellular organisms )
Telomerase is active in normal stem cells and
most cancer cells, but is normally absent from, or at very low levels
in, most somatic cells .
* 1 History
* 2 Human telomerase structure
* 3 Mechanism
* 4 Clinical implications
* 4.1.1 Premature aging
* 4.2.1 Drugs
* 184.108.40.206 Targeted apoptosis
* 4.3 Heart disease, diabetes and quality of life
* 4.4 Rare human diseases
* 5 See also
* 6 References
* 7 Further reading
* 8 External links
The existence of a compensatory mechanism for telomere shortening was
first found by Soviet biologist
Alexey Olovnikov in 1973, who also
suggested the telomere hypothesis of aging and the telomere's
connections to cancer.
Telomerase in the ciliate
Tetrahymena was discovered by Carol W.
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.
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 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.
HUMAN TELOMERASE STRUCTURE
The molecular composition of the human telomerase enzyme complex was
determined by Dr Scott Cohen and his team at the Children's Medical
Research Institute (Sydney Australia) and consists of two molecules
each of human telomerase reverse transcriptase (TERT), telomerase RNA
(TR or TERC), and dyskerin (DKC1). The genes of telomerase subunits,
which include TERT, TERC, DKC1 and TEP1, are located on different
chromosomes. The human TERT gene (hTERT) is translated into a protein
of 1132 amino acids . TERT polypeptide folds with (and carries) TERC,
RNA (451 nucleotides long). TERT has a 'mitten' structure
that allows it to wrap around the chromosome to add single-stranded
TERT is a reverse transcriptase , which is a class of enzyme that
creates single-stranded DNA using single-stranded
RNA as a template.
An image illustrating how telomerase elongates telomere ends
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,
RNA polymerases and bacteriophage B-family DNA polymerases.
TERT proteins from many eukaryotes have been sequenced.
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'.
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
Telomerase replaces short bits of DNA known as telomeres , which are
otherwise shortened when a cell divides via mitosis .
In normal circumstances, absent telomerase, if a cell divides
recursively, at some point the progeny reach their
Hayflick limit ,
which is believed to be between 50–70 cell divisions. At the limit
the cells become senescent and cell division stops.
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 .
Embryonic stem cells
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 sperm cells but also in epidermal cells , in activated
B cell lymphocytes , as well as in certain adult stem cells ,
but in the great majority of cases somatic cells do not express
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 post-mitotic 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.
Telomerase also favors tumorogenesis , which leads
to questions about its potential as an anti-aging therapy. On the
other hand, one study showed that activating telomerase in
cancer-resistant mice by overexpressing its catalytic subunit extended
T lymphocytes from HIV-infected human donors to a small
molecule telomerase activator (TAT2 ) retards telomere shortening,
increases proliferative potential and enhances cytokine/chemokine
production and antiviral activity.
A study that focused on
Ashkenazi Jews found that long-lived subjects
inherited a hyperactive version of telomerase.
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,
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
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.
Premature aging syndromes including
Werner syndrome , Ataxia
telangiectasia , Ataxia-telangiectasia like disorder,
Bloom syndrome ,
Fanconi anemia and
Nijmegen breakage syndrome
Nijmegen breakage syndrome are associated with
short telomeres. However, the genes that have 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.
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). 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 crisis. In a typical situation, the
telomeres are shortened 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 (religating) 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.
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 cancer
cells are considered 'immortal' because telomerase activity allows
them to live much longer than any other somatic cell, which, combined
with uncontrollable cell proliferation is why they can form tumors .
A good example of immortal cancer cells 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 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 or myc proto-oncogenes , and
aberration of the PP2A protein phosphatase . 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 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).
Approaches to controlling telomerase and telomeres for cancer therapy
include gene therapy , immunotherapy , small-molecule and signal
The ability to maintain functional telomeres may be one mechanism
that allows cancer cells to grow in vitro for decades. Telomerase
activity is necessary to preserve many cancer types and is inactive in
somatic cells , creating the possibility that telomerase inhibition
could selectively repress cancer cell growth with minimal side
effects. If a drug can inhibit telomerase in cancer cells, the
telomeres of successive generations will progressively shorten,
limiting tumor growth.
Telomerase is a good biomarker for cancer detection because most
human cancers cells express high levels of it.
Telomerase activity can
be identified by its catalytic protein domain (hTERT ). This 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 a 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. 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).
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 .
Immunotherapy successfully treats some kinds of cancer, such as
melanoma. This treatment involves manipulating a human’s immune
system to destroy cancerous cells. Humans have two major antigen
identifying lymphocytes :
CD8 + cytotoxic T-lymphocytes (CTL) and CD4
+ helper T-lymphocytes that can destroy cells.
Antigen receptors on
CTL can bind to a 9-10 amino acid chain that is presented by the major
histocompatibility complex (MHC) as in Figure 4.
HTERT is a potential
target antigen. Immunotargeting should result in relatively few side
effects since hTERT expression is associated only with telomerase and
is not essential in almost all somatic cells. GV1001 uses this
pathway. Experimental drug and vaccine therapies targeting active
telomerase have been tested in mouse models, and clinical trials have
Geron Corporation received permission to resume a trial of
its drug imetelstat for myelofibrosis after addressing FDA concerns
over liver toxicity. Geron licensee Merck had approval of an IND for
one vaccine type.
Imetelstat (GRN163L) binds directly to the
RNA template. One 2015 study reported that Imetelstat
caused partial or complete remission in seven of 33 patients, while a
second reported that it decreased blood platelet levels in all 18
study patients with essential thrombocythemia , a disorder in which
the body overproduces blood platelets, increasing the risk of blood
Most of the harmful cancer-related effects of telomerase are
dependent on an intact
Cancer stem cells that use an
alternative method of telomere maintenance are still killed when
RNA template is blocked or damaged.
Two telomerase vaccines have been developed: GRNVAC1 and GV1001 .
GRNVAC1 isolates dendritic cells and the
RNA that codes for the
telomerase protein and puts them back into the patient to make
cytotoxic T cells that kill the telomerase-active cells. GV1001 is a
peptide from the active site of hTERT and is recognized by the immune
system that reacts by killing the telomerase-active cells.
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
and causes dissociation of the
Another independent approach is to use oligoadenylated
anti-telomerase antisense oligonucleotides and ribozymes to target
telomerase RNA, inducing dissociation and apoptosis (Figure 5). The
fast induction of apoptosis through antisense binding may be a good
alternative to the slower telomere shortening.
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 coronary artery tissue, possibly accelerating heart attacks.
In 2009, it was shown that the amount of telomerase activity
significantly increased following psychological stress. Across the
sample of patients telomerase activity in increased peripheral blood
mononuclear cells by 18% one hour after the end of the stress.
E. V. Gostjeva et al. found no differences between colon cancer stem
cells and fetal colon stem cells.
A study in 2010 found that there was "significantly greater"
telomerase activity in participants than controls after a three-month
Telomerase deficiency has been linked to diabetes mellitus and
impaired insulin secretion in mice, due to loss of pancreatic
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.
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 X-linked -recessive on the DKC1 locus and
5% cases are autosomal 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).
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* The Immortal Cell, by
Michael D. West , Doubleday (2003) ISBN
Telomerase Database - A Web-based tool for telomerase
* Three-dimensional model of telomerase at MUN