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
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
retrotransposons to maintain telomeres.
Telomerase is a reverse transcriptase enzyme that carries its own RNA
molecule (e.g., with the sequence 3′-CCCAAUCCC-5′ in Trypanosoma
brucei) 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.
2 Human telomerase structure
4 Clinical implications
4.1.1 Premature aging
4.2.4 Targeted apoptosis
4.2.5 Small interfering
4.3 Heart disease, diabetes and quality of life
4.4 Rare human diseases
5 See also
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, a non-coding
RNA (451 nucleotides
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 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
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. 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.
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 T cell and B cell lymphocytes, 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.
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
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
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 pathway
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[clarify] 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.
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
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 telomerase's
RNA template. One 2015 study reported
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 clots.
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 telomerase's 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.
siRNAs are small
RNA molecules that induce the sequence-specific
degradation of other RNAs. si
RNA treatment can function similar to
traditional gene therapy by destroying the m
RNA products of particular
genes, and therefore preventing the expression of those genes. A 2012
study found that targeting TERC with an si
RNA reduced telomerase
activity by more than 50% and resulted in decreased viability of
immortal cancer cells. Treatment with both the si
RNA and radiation
caused a greater reduction in tumor size in mice than treatment with
radiation alone, suggesting that targeting telomerase could be a way
to increase the efficacy of radiation in treating radiation-resistant
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
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)
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 US National Library of Medicine Medical Subject
DNA replication (comparing Prokaryotic to Eukaryotic)
Origin recognition complex
Autonomously replicating sequence
Single-strand binding protein
Origin of replication/Ori/Replicon
Lagging and leading strands
DNA polymerase III holoenzyme
Prokaryotic DNA polymerase:
DNA polymerase I
Replication factor C
Replication protein A
Eukaryotic DNA polymerase:
Control of chromosome duplication
RNA-binding protein: Ribonucleoproteins
70K/U1 spliceosomal RNA
Major vault protein
Signal recognition particle
Transferases: phosphorus-containing groups (EC 2.7)
2.7.1: OH acceptor
Class I PI 3
Class II PI 3
2.7.2: COOH acceptor
2.7.3: N acceptor
2.7.4: PO4 acceptor
DNA-directed DNA polymerase
RNA-directed DNA polymerase
DNA nucleotidylexotransferase/Terminal deoxynucleotidyl transferase
RNA polymerase I
3' to 5' exoribonuclease
RNA capping enzyme
2.7.10-2.7.13: protein kinase
(PO4; protein acceptor)
see tyrosine kinases
see serine/threonine-specific protein kinases
see serine/threonine-specific protein kinases
Catalytically perfect enzyme
List of enzymes
EC1 Oxidoreductases (list)
EC2 Transferases (list)
EC3 Hydrolases (list)
EC4 Lyases (list)
EC5 Isomerases (list)
EC6 Ligases (list)
Molecular and Cellu