Researchers
delivered a modified RNA that encodes a telomere-extending protein to
cultured human cells. Cell proliferation capacity was dramatically
increased ...
Telomere
From Wikipedia, the free encyclopedia
A
telomere is a region of repetitive
nucleotide sequences at each end of a
chromosome,
which protects the end of the chromosome from deterioration or from
fusion with neighboring chromosomes. Its name is derived from the Greek
nouns telos (
τέλος) "end" and merοs (
μέρος, root:
μερ-) "part". For
vertebrates, the sequence of nucleotides in telomeres is
TTAGGG, with the
complementary DNA strand being AATCCC, with a single-stranded TTAGGG
overhang. This sequence of TTAGGG is repeated approximately 2,500 times in humans.
[1] In humans, average telomere length declines from about 11
kilobases at birth
[2] to less than 4 kilobases in old age,
[3] with average rate of decline being greater in men than in women.
[4]
During
chromosome replication, the
enzymes
that duplicate DNA cannot continue their duplication all the way to the
end of a chromosome, so in each duplication the end of the chromosome
is shortened
[5] (this is because the synthesis of
Okazaki fragments requires
RNA primers
attaching ahead on the lagging strand). The telomeres are disposable
buffers at the ends of chromosomes which are truncated during cell
division; their presence protects the
genes before them on the chromosome from being truncated instead. The telomeres themselves are protected by a complex of
shelterin proteins, as well as by the RNA that telomeric DNA encodes (
TERRA).
Over time, due to each cell division, the telomere ends become shorter.
[6] They are replenished by an enzyme,
telomerase reverse transcriptase.
Discovery
In the early 1970s, Russian theorist
Alexei Olovnikov first recognized that chromosomes could not completely replicate their ends. Building on this, and to accommodate
Leonard Hayflick's idea of limited
somatic cell
division, Olovnikov suggested that DNA sequences are lost every time a
cell/DNA replicates until the loss reaches a critical level, at which
point cell division ends.
[7][8]
However, Olovnikov's prediction was not widely known except by a
handful of researchers studying cellular aging and immortalization.
[9]
In 1975–1977,
Elizabeth Blackburn, working as a postdoctoral fellow at Yale University with
Joseph Gall, discovered the unusual nature of telomeres, with their simple repeated DNA sequences composing chromosome ends.
[10] Blackburn,
Carol Greider, and
Jack Szostak were awarded the 2009
Nobel Prize in
Physiology or Medicine for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase.
[11]
Nevertheless, in the 1970s there was no recognition that the
telomere-shortening mechanism normally limits cells to a fixed number of
divisions, nor was there any animal study suggesting that this could be
responsible for aging on the cellular level. There was also no
recognition that the mechanism set a limit on lifespans.
[12][13]
It remained for a privately funded collaboration from biotechnology company
Geron to isolate the genes for the
RNA and protein component of human telomerase in order to establish the role of telomere shortening in
cellular aging and telomerase reactivation in cell immortalization.
[14]
Nature and function
Structure, function and evolutionary biology
loss of genetic material can be caused be telomere shortening.
Telomeres are repetitive
nucleotide sequences located at the termini of linear chromosomes of most
eukaryotic organisms. For vertebrates, the sequence of nucleotides in telomeres is
TTAGGG. Most
prokaryotes,
lacking this linear arrangement, do not have telomeres. Telomeres
compensate for incomplete semi-conservative DNA replication at
chromosomal ends. A protein complex known as
shelterin serves to protect the ends of telomeres from being recognised as
double-strand breaks by inhibiting
homologous recombination (HR) and
non-homologous end joining (NHEJ).
[15][16]
Telomeres are found at the termini of chromosomes. The end of a telomere
inserts back into the main body of the telomere to form a T-loop
In most prokaryotes, chromosomes are circular and, thus, do not have ends to suffer premature
replication termination. A small fraction of
bacterial chromosomes (such as those in
Streptomyces,
Agrobacterium, and
Borrelia)
are linear and possess telomeres, which are very different from those
of the eukaryotic chromosomes in structure and functions. The known
structures of bacterial telomeres take the form of
proteins bound to the ends of linear chromosomes, or hairpin loops of single-stranded DNA at the ends of the linear chromosomes.
[17]
While replicating DNA, the eukaryotic DNA replication enzymes (the
DNA polymerase protein complex) cannot replicate the sequences present
at the ends of the chromosomes (or more precisely the
chromatid
fibres). Hence, these sequences and the information they carry may get
lost. This is the reason telomeres are so important in context of
successful cell division: They "cap" the end-sequences and themselves
get lost in the process of DNA replication. But the cell has an enzyme
called telomerase, which carries out the task of adding repetitive
nucleotide sequences to the ends of the DNA. Telomerase, thus,
"replenishes" the telomere "cap" of the DNA. In most multicellular
eukaryotic organisms, telomerase is active only in
germ cells, some types of
stem cells such as
embryonic stem cells, and certain
white blood cells. Telomerase can be re activated and telomeres reset back to an embryonic state by somatic cell nuclear transfer.
[18]
There are theories that claim that the steady shortening of telomeres
with each replication in somatic (body) cells may have a role in
senescence and in the prevention of
cancer.
This is because the telomeres act as a sort of time-delay "fuse",
eventually running out after a certain number of cell divisions and
resulting in the eventual loss of vital genetic information from the
cell's chromosome with future divisions.
Telomere length varies greatly between species, from approximately 300
base pairs in yeast
[19] to many kilobases in humans, and usually is composed of arrays of
guanine-rich, six- to eight-base-pair-long repeats. Eukaryotic telomeres normally terminate with
3′ single-stranded-DNA overhang,
which is essential for telomere maintenance and capping. Multiple
proteins binding single- and double-stranded telomere DNA have been
identified.
[20]
These function in both telomere maintenance and capping. Telomeres form
large loop structures called telomere loops, or T-loops. Here, the
single-stranded DNA curls around in a long circle, stabilized by
telomere-binding proteins.
[21]
At the very end of the T-loop, the single-stranded telomere DNA is held
onto a region of double-stranded DNA by the telomere strand disrupting
the double-helical DNA, and base pairing to one of the two strands. This
triple-stranded structure is called a
displacement loop or D-loop.
[22]
Telomere shortening in humans can induce replicative senescence,
which blocks cell division. This mechanism appears to prevent genomic
instability and development of cancer in human aged cells by limiting
the number of cell divisions. However, shortened telomeres impair immune
function that might also increase cancer susceptibility.
[23]
If telomeres become too short, they have the potential to unfold from
their presumed closed structure. The cell may detect this uncapping as
DNA damage and then either stop growing, enter cellular old age (
senescence), or begin programmed cell self-destruction (
apoptosis) depending on the cell's genetic background (
p53
status). Uncapped telomeres also result in chromosomal fusions. Since
this damage cannot be repaired in normal somatic cells, the cell may
even go into apoptosis. Many aging-related diseases are linked to
shortened telomeres. Organs deteriorate as more and more of their cells
die off or enter cellular senescence.
Shelterin co-ordinates the T-loop formation of telomeres
Shelterin
At the very distal end of the telomere is a 300 bp single-stranded portion, which forms the T-Loop. This loop is analogous to a
knot,
which stabilizes the telomere, preventing the telomere ends from being
recognized as break points by the DNA repair machinery. Should
non-homologous end joining occur at the telomeric ends, chromosomal
fusion will result. The T-loop is held together by several proteins, the
most notable ones being TRF1, TRF2, POT1, TIN1, and TIN2, collectively
referred to as the shelterin complex. In humans, the shelterin complex
consists of six proteins identified as TRF1, TRF2, TIN2, POT1, TPP1, and
RAP1.
[15]
Shortening
Telomeres shorten in part because of the
end replication problem that is exhibited during DNA replication in
eukaryotes
only. Because DNA replication does not begin at either end of the DNA
strand, but starts in the center, and considering that all known
DNA polymerases move in the 5' to 3' direction, one finds a leading and a lagging strand on the DNA molecule being replicated.
On the leading strand, DNA polymerase can make a complementary DNA
strand without any difficulty because it goes from 5' to 3'. However,
there is a problem going in the other direction on the lagging strand.
To counter this, short sequences of
RNA acting as
primers
attach to the lagging strand a short distance ahead of where the
initiation site was. The DNA polymerase can start replication at that
point and go to the end of the initiation site. This causes the
formation of
Okazaki fragments. More RNA primers attach further on the DNA strand and DNA polymerase comes along and continues to make a new DNA strand.
Lagging strand during DNA replication
Eventually, the last RNA primer attaches, and DNA polymerase, RNA nuclease, and
DNA ligase
come along to convert the RNA (of the primers) to DNA and to seal the
gaps in between the Okazaki fragments. But, in order to change RNA to
DNA, there must be another DNA strand in front of the RNA primer. This
happens at all the sites of the lagging strand, but it does not happen
at the end where the last RNA primer is attached. Ultimately, that RNA
is destroyed by enzymes that degrade any RNA left on the DNA. Thus, a
section of the telomere is lost during each cycle of replication at the
5' end of the lagging strand's daughter.
However,
test-tube studies have shown that telomeres are highly susceptible to
oxidative stress. There is evidence that oxidative stress-mediated DNA damage is an important determinant of telomere shortening.
[24]
Telomere shortening due to free radicals explains the difference
between the estimated loss per division because of the end-replication
problem (c. 20 bp) and actual telomere shortening rates (50–100 bp), and
has a greater absolute impact on telomere length than shortening caused
by the end-replication problem. Population-based studies have also
indicated an interaction between anti-oxidant intake and telomere
length. In the Long Island Breast Cancer Study Project (LIBCSP), authors
found a moderate increase in breast cancer risk among women with the
shortest telomeres and lower dietary intake of beta carotene, vitamin C
or E.
[25]
These results suggest that cancer risk due to telomere shortening may
interact with other mechanisms of DNA damage, specifically oxidative
stress.
Telomere shortening is associated with aging, mortality and
aging-related diseases. In 2003, Richard Cawthon discovered that those
with longer telomeres lead longer lives than those with short telomeres.
[26] However, it is not known whether short telomeres are just a sign of cellular age or actually contribute to the aging process.
[citation needed]
Lengthening
The average cell will divide between 50 and 70 times before cell death.
As the cell divides the telomeres on the end of the chromosome get
smaller. The
Hayflick limit
is the theoretical limit to the number of times a cell may divide until
the telomere becomes so short that division is inhibited and the cell
enters senescence.
The phenomenon of limited cellular division was first observed by
Leonard Hayflick, and is now referred to as the
Hayflick limit.
[27][28] Significant discoveries were subsequently made by a group of scientists organized at
Geron Corporation by Geron's founder
Michael D. West that tied telomere shortening with the Hayflick limit.
[29]
The cloning of the catalytic component of telomerase enabled
experiments to test whether the expression of telomerase at levels
sufficient to prevent telomere shortening was capable of immortalizing
human cells. Telomerase was demonstrated in a 1998 publication in
Science to be capable of extending cell lifespan, and now is well-recognized as capable of immortalizing human somatic cells.
[30]
It is becoming apparent that reversing shortening of telomeres
through temporary activation of telomerase may be a potent means to slow
aging. The reason that this would extend human life is because it would
extend the Hayflick limit. Three routes have been proposed to reverse
telomere shortening: drugs, gene therapy, or metabolic suppression,
so-called, torpor/hibernation. So far these ideas have not been proven
in humans, but it has been demonstrated that telomere shortening is
reversed in hibernation and aging is slowed (Turbill, et al. 2012 &
2013) and that hibernation prolongs life-span (Lyman et al. 1981). It
has also been demonstrated that telomere extension has successfully
reversed some signs of aging in laboratory mice
[31][32] and the
nematode worm species
Caenorhabditis elegans.
[33]
It has been hypothesized that longer telomeres and especially
telomerase activation might cause increased cancer (e.g. Weinstein and
Ciszek, 2002). However, longer telomeres might also protect against
cancer, because short telomeres are associated with cancer. It has also
been suggested that longer telomeres might cause increased energy
consumption.
[23]
Techniques to extend telomeres could be useful for
tissue engineering,
because they might permit healthy, noncancerous mammalian cells to be
cultured in amounts large enough to be engineering materials for
biomedical repairs.
Two recent studies on long-lived
seabirds demonstrate that the role of telomeres is far from being understood. In 2003, scientists observed that the telomeres of
Leach's storm-petrel (
Oceanodroma leucorhoa) seem to lengthen with chronological age, the first observed instance of such behaviour of telomeres.
[34] In 2006, Juola
et al.[35] reported that in another unrelated, long-lived seabird species, the
great frigatebird (
Fregata minor),
telomere length did decrease until at least c. 40 years of age (i.e.
probably over the entire lifespan), but the speed of decrease slowed
down massively with increasing ages, and that rates of telomere length
decrease varied strongly between individual birds. They concluded that
in this species (and probably in
frigatebirds
and their relatives in general), telomere length could not be used to
determine a bird's age sufficiently well. Thus, it seems that there is
much more variation in the behavior of telomere length than initially
believed.
Furthermore, Gomes et al. found, in a study of the comparative
biology of mammalian telomeres, that telomere length of different
mammalian species correlates inversely, rather than directly, with
lifespan, and they concluded that the contribution of telomere length to
lifespan remains controversial.
[36]
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.
[37] Gilley and Blackburn tested whether cellular senescence in
paramecium is caused by telomere shortening, and found that telomeres were not shortened during senescence.
[38]
Exercise-induced lengthening
A 2013 pilot study from
UCSF
took 35 men with localized early-stage prostate cancer and had 10 of
them begin "lifestyle changes that included: a plant-based diet (high in
fruits, vegetables and unrefined grains, and low in fat and refined
carbohydrates); moderate exercise (walking 30 minutes a day, six days a
week); stress reduction (gentle yoga-based stretching, breathing,
meditation)" and also "weekly group support". When compared to the other
25 study participants, "The group that made the lifestyle changes
experienced a 'significant' increase in telomere length of approximately
10 percent. Further, the more people changed their behavior by adhering
to the recommended lifestyle program, the more dramatic their
improvements in telomere length."
[39]
A 2014 study entitled "Stand up for health – avoiding sedentary
behaviour might lengthen your telomeres: secondary outcomes from a
physical activity RCT in older people" indicated somewhat contradictory
results, stating, "In the intervention group, there was a negative
correlation between changes in time spent exercising and changes in
telomere length (rho=-0.39, p=0.07). On the other hand, in the
intervention group, telomere lengthening was significantly associated
with reduced sitting time (rho=-0.68, p=0.02).
[40]
Sequences
Known, up-to-date telomere
nucleotide sequences are listed in
Telomerase Database website.
Cancer
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Telomeres are critical for maintaining genomic integrity and studies
show that telomere dysfunction or shortening is commonly acquired during
the process of tumor development.
[43]
Short telomeres can lead to genomic instability, chromosome loss and
the formation of non-reciprocal translocations; and telomeres in tumor
cells and their precursor lesions are significantly shorter than
surrounding normal tissue.
[44][45]
Observational studies have found shortened telomeres in many cancers:
including pancreatic, bone, prostate, bladder, lung, kidney, and head
and neck. In addition, people with many types of cancer have been found
to possess shorter leukocyte telomeres than healthy controls.
[46] Recent meta-analyses suggest 1.4 to 3.0 fold increased risk of cancer for those with the shortest vs. longest telomeres.
[47][48] However the increase in risk varies by age, sex, tumor type and differences in lifestyle factors.
Some of the same lifestyle factors which increase risk of developing
cancer have also been associated with shortened telomeres: including
stress, smoking, physical inactivity and diet high in refined sugars
[48]
Diet and physical activity influence inflammation and oxidative stress.
These factors are thought to influence telomere maintenance.
[49]
Psychologic stress has also been linked to accelerated cell aging, as
reflected by decreased telomerase activity and short telomeres.
[50]
It has been suggested that a combination of lifestyle modifications,
including healthy diet, exercise and stress reduction, have the
potential to increase telomere length, reverse cellular aging, and
reduce the risk for aging-related diseases. In a recent clinical trial
for early-stage prostate cancer patients, comprehensive lifestyle
changes resulted in a short-term increase in telomerase activity and
long-term modification in telomere length.
[51][52]
Lifestyle modifications have the potential to naturally regulate
telomere maintenance without promoting tumorigenesis, as traditional
mechanisms of telomere lengthening involve the use of telomerase
activating agents.
[citation needed]
Cancer cells require a mechanism to maintain their telomeric DNA in
order to continue dividing indefinitely (immortalization). A mechanism
for telomere elongation or maintenance is one of the key steps in
cellular immortalization and can be used as a diagnostic marker in the
clinic. Telomerase, the enzyme complex responsible for elongating
telomeres through the addition of telomere repeats to the ends of
chromosomes, is activated in approximately 80% of tumors.
[53] However, a sizeable fraction of cancerous cells employ
alternative lengthening of telomeres (ALT),
[54] a non-conservative telomere lengthening pathway involving the transfer of telomere tandem repeats between sister-chromatids.
[55]
Telomerase and cancer
Telomerase is the natural enzyme that promotes telomere lengthening. It is active in
stem cells,
germ cells,
hair follicles, and 90 percent of cancer cells, but its expression is
low or absent in somatic cells. Telomerase functions by adding bases to
the ends of the telomeres. Cells with sufficient telomerase activity are
considered immortal in the sense that they can divide past the
Hayflick limit without entering
senescence or
apoptosis. For this reason, telomerase is viewed as a potential target for anti-cancer drugs (such as
Geron's Imetelstat currently in human clinical trials and
telomestatin).
[56]
Studies using
knockout mice
have demonstrated that the role of telomeres in cancer can both be
limiting to tumor growth, as well as promote tumorigenesis, depending on
the cell type and genomic context.
[57][58]
Telomerase
is a "ribonucleoprotein complex" composed of a protein component and an
RNA primer sequence that acts to protect the terminal ends of
chromosomes from being broken down by enzymes. The telomeres (and the
actions of telomerase) are necessary because, during replication,
DNA polymerase
can synthesize DNA in only a 5' to 3' direction (each DNA strand having
a polarity that is determined by the precise manner in which sugar
molecules of the strand's "backbone" are linked together) and can do so
only by adding nucleotides to RNA primers (that have already been placed
at various points along the length of the DNA). The RNA strands are
replaced with newly synthesized DNA, but DNA polymerase can only
"backfill"
deoxyribonucleotides
if there is already DNA "upstream" from (i.e., located 5' to) the RNA
primer. At the chromosome terminal, however, there is no nucleotide
sequence in the 5' direction (and therefore no upstream RNA primer or
DNA), so DNA polymerase cannot function and genetic sequence might be
lost through chromosomal fraying. Chromosomal ends might also be
processed as breaks in double-strand DNA with chromosome-to-chromosome
telomere fusions resulting.
Telomeres at the end of DNA prevent the chromosome from growing
shorter during replications (with loss of genetic information) by
employing "
telomerases" to synthesize DNA at the chromosome terminal. These include a protein subgroup of specialized
reverse transcriptase enzymes known as
TERT (
telomerase
reverse
transcriptases)
and are involved in synthesis of telomeres in humans and many other,
but not all, organisms. Because DNA replication mechanisms are affected
by oxidative stress and because TERT expression is very low in most
types of human cell, telomeres shorten every time a cell divides. Among
cell types characterized by extensive cell division (such as
stem cells and certain
white blood cells), however, TERT is expressed at higher levels and telomere shortening is partially or fully prevented.
In addition to its TERT protein component, telomerase also contains a piece of template RNA known as the TERC (
telomerase
RNA
component) or TR (
telomerase
RNA). In humans, this TERC telomere sequence is a repeating string of TTAGGG, between 3 and 20
kilobases
in length. There are an additional 100-300 kilobases of
telomere-associated repeats between the telomere and the rest of the
chromosome. Telomere sequences vary from species to species, but, in
general, one strand is rich in G with fewer Cs. These G-rich sequences
can form four-stranded structures (
G-quadruplexes),
with sets of four bases held in plane and then stacked on top of each
other, with either a sodium or a potassium ion between the planar
quadruplexes.
Mammalian (and other) somatic cells without telomerase gradually lose
telomeric sequences as a result of incomplete replication (Counter
et al., 1992). As mammalian telomeres shorten, eventually cells reach their
replicative limit and progress into
senescence or old age. Senescence involves
p53 and
pRb pathways and leads to the halting of
cell proliferation
(Campisi, 2005). Senescence may play an important role in suppression
of cancer emergence, although inheriting shorter telomeres probably does
not protect against cancer.
[23]
With critically shortened telomeres, further cell proliferation can be
achieved by inactivation of p53 and pRb pathways. Cells entering
proliferation after inactivation of p53 and pRb pathways undergo crisis.
Crisis is characterized by gross chromosomal rearrangements and
genome instability, and almost all cells die.
ALT (Alternative Lengthening of Telomeres) and cancer
About 5–10% of human cancers activate the alternative lengthening of
telomeres (ALT) pathway, which relies on recombination-mediated
elongation.
[59]
Rarely, cells emerge from crisis immortalized through telomere
lengthening by either activated telomerase or ALT (Colgina and Reddel,
1999; Reddel and Bryan, 2003). The first description of an ALT cell line
demonstrated that their telomeres are highly heterogeneous in length
and predicted a mechanism involving recombination (Murnane et al.,
1994). Subsequent studies have confirmed a role for recombination in
telomere maintenance by ALT (Dunham et al., 2000), however the exact
mechanism of this pathway is yet to be determined. ALT cells produce
abundant T-circles, possible products of intratelomeric recombination
and T-loop resolution (Tomaska
et al., 2000; 2009; Cesare and Griffith, 2004; Wang
et al., 2004).
Evolutionary aspects
Since
shorter telomeres are thought by some to be a cause of aging, this
raises the question of why longer telomeres are not selected for to
ameliorate these effects. A prominent explanation suggests that
inheriting longer telomeres would cause increased cancer rates (e.g.
Weinstein and Ciszek, 2002). However, a recent literature review and
analysis
[23] suggests this is unlikely, because shorter telomeres and
telomerase
inactivation is more often associated with increased cancer rates, and
the mortality from cancer occurs late in life when the force of
natural selection
is very low. An alternative explanation to the hypothesis that long
telomeres are selected against due to their cancer promoting effects is
the "thrifty telomere" hypothesis, which suggests that the cellular
proliferation effects of longer telomeres causes increased energy
expenditures.
[23] In environments of energetic limitation, shorter telomeres might be an energy sparing mechanism.
Relation to breast cancer
In a healthy female breast, a proportion of cells called
luminal progenitors
that line the milk ducts have proliferative and differentiation
potential and most of them contain critically short telomeres with DNA
damage foci. These cells are believed to be the possible common cellular
loci where cancers of the breast involving telomere dysregulation may
arise.
[60]
The telomere shortening in these progenitors is not age dependent but
is speculated to be basal to luminal epithelial differentiation
program-dependent. Also, the telomerase activity is unusually high in
these cells when isolated from younger women, but declines with age.
[61]
Measurement
Several techniques are currently employed to assess average telomere
length in eukaryotic cells. One method is the Terminal Restriction
Fragment (TRF) southern blot,
[62]
which involves hybridization of a radioactive 32P-(TTAGGG)n
oligonucleotide probe to Hinf / Rsa I digested genomic DNA embedded on a
nylon membrane and subsequently exposed to autoradiographic film or
phosphoimager screen. Another histochemical method, termed Q-FISH,
involves fluorescent in situ hybridization (FISH).
[63]
Q-FISH, however, requires significant amounts of genomic DNA (2-20
micrograms) and labor that renders its use limited in large
epidemiological studies. Some of these impediments have been overcome
with a Real-Time PCR assay for telomere length and
Flow-FISH. Real-time PCR assay involves determining the Telomere-to-Single Copy Gene (T/S)ratio,
[64] which is demonstrated to be proportional to the average telomere length in a cell.
Another technique, referred to as single telomere elongation length
analysis (STELA), was developed in 2003 by Duncan Baird. This technique
allows investigations that can target specific telomere ends, which is
not possible with TRF analysis. However, due to this technique's being
PCR-based, telomeres larger than 25Kb cannot be amplified and there is a
bias towards shorter telomeres.
While multiple companies offer telomere length measurement services,
[65][66][67]
the utility of these measurements for widespread clinical or personal
use has been questioned by prominent scientists without financial
interests in these companies.
[68][69]
Nobel Prize winner Elizabeth Blackburn, who was the co-founder of one
of these companies and has prominently promoted the clinical utility of
telomere length measures,
[70] resigned from the company in June 2013 "owing to an impending change in the control of Telome Health".
[71]
In popular culture
The opening track of the 2016 album, Curve of the Earth, by the
UK,
indie rock band,
Mystery Jets, is named Telomere and contains the following stanza:
In the telomere that lives inside us
And the people walking down below
Crawling home alone like spiders
As the cancer slowly starts to grow.
[72]
See also
References
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