Introduction in (Fig 1.B) . This is because

Introduction

        
Telomeres are the part of chromosomes which are present at the ends of
eukaryotic chromosomes. Telomeres have the properties to maintain genome
stability for long duration. Telomeres protect the ends of chromosomes by
covering them to prevent DNA breaks or fusion or degradation. These telomeres
are actually consists of G-rich simple sequence repeats. These repeats varies
such as tens of base pairs to 150 kilo base pairs from organism to organism and
also varies in the sequences shown in below

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In
vertebrates- TTAGGG

In
majority of plants with many exceptions – TTTAGGG

In
model algae Chlamydomonas
– TTTTAGGG

Human – TTAGGG

There should minimum length of telomere DNA to prevent
end-end fusion. Role of plant telomerase enzyme is almost same as that of
vertebrate telomerase (Watson et al. 2010)

Telomere Replication

        The DNA
replication occurs with the help of primers and polymerases etc., produces
daughter strands from lagging strand and leading strands of parental DNA. But
in the case of formation of daughter strands from lagging strand produces
okazaki fragments, end of 3′ parental DNA is not replicated onto the daughter
strand as shown in the below (Fig 1.A) due to the presence of primer of last
okazaki fragment at the same place to form the daughter strands as shown in (Fig
1.B) . This is because of absence of a place to be attached by a primer which
reads the last part of 3′ parental DNA. When this daughter strand is
replicated, results in the formation of shortened granddaughter molecule (Brown,
2002). So in
this case if multiple replications is done, daughter DNA’s become shorter and
shorter, and finally leads to cellular senescence (Eric Gilson et al.
2007).

 

 

 

 

 

 

Fig 1.B during DNA replication, showing reduction in the
length of granddaughter molecule due to presence of primer of last Okazaki
fragment at 3′ end (Brown, 2002)
 

 

Fig 1.A during DNA replication, showing missing of last Okazaki
fragment from the lagging strand (Brown, 2002)
 

Fig 3. Showing how telomere ends are extended using
telomerase enzyme (Alberts et al. 2002)

Fig 2 showing the structure of telomerase enzyme (Alberts et al. 2002)

              End-replication problem can be
solved with help of an enzyme called telomerase, a reverse transcriptase enzyme
which produces DNA with help of RNA. Telomerase is a protein-RNA complex which
contain a simple RNA template in itself as shown (Fig 2) useful to extend the
DNA in the form of high G-rich sequence to form telomere regions. Telomerase enzyme recognizes the 3′ end of
parental DNA and attaches to it and extend the parental 3′ end DNA with help of
RNA-template. After extension of parental DNA, primers are attached to extended
parental DNA and parental DNA strand can be completely replicated to form
daughter strands (Fig 3) without any reduction in the length (Alberts
et al. 2002).

               Hence
G-strand is longer than C-strand leads to the formation of 3′ G-overhang. This
G-overhang folds back and forms T-loops which will protect the ends of chromosome (Fig 4.A). T-Loops have been observed in humans,
protozoans, and plants (Watson et al. 2010).

              
Actually telomere sequence protects chromosomal ends with six-telomere
specific proteins. The telomeric sequence with six proteins forms a complex
known as shelterin. The six proteins in the shelterin complex are TRF1, TRF2,
POT1, TIN, TPP1 and RAP1. This complex along with several DNA repair factors
will remodel the telomeric sequence, results in the formation of T-loop and
protect the chromosomal ends (de Lange,
2005).

                Among
those six proteins, TRF1 and TRF2 connects with telomeric DNA, while TIN2
connects with both TRF1 and TRF2, TPP1 attaches to both POT1 and TIN2 on
opposite edges or sides. POT1 protein interacts with telomeric DNA in two
different ways 1) attaches to end of chromosomal DNA in the case of open
configuration and 2) attaches to the single stranded telomeric DNA results in
the formation of T-loop as shown (fig 4.B) (Cesare et al. 2013)

 

 

 

 

 

 

Fig 4.A showing 3′ overhang in open configuration of
telomere and in form of T-loop, 4.B showing shelterin complex in open
configuration form and in T-loop form (Cesare et al. 2013)       

 

Implications of telomeres

           The telomere sequence is shortened
at fast rate in the cells of blood, gastrointestinal system and skin. There is
a correlation between telomere length and ageing. As time progress each cell
divides and produces daughter cells and with division the telomere length is reduced
in the respective daughter cells. And at a certain time these cells are with
critically shortened telomere length which results in cellular senescence.
These senescent cells will produce a different kinds of proteins which are not
the same proteins which are produced by the non-senescent cells. This will
leads to change in the stable condition of cells or tissue or body which
results in ageing. By this many studies have been conducted to measure the
length of telomere in my different kinds of tissues, and observed in the blood
cells that there is a relationship between telomere length and many age-related
diseases. So when the telomere length is measured from cells of individuals
with a disease, results in the shortened telomeres (Shay et al. 2007).

            In the embryonic cells and in male
germ line cells, we can find telomerase but not in normal somatic cells. Even
if there is identifiable amounts of telomerase in normal somatic cells, there
is shortening of telomeres for each division. As telomerase is mainly comprised
of telomerase reverse transcriptase subunit (TERT) and telomerase RNA (TR or
TERC), when TERT is introduced into the cells which do not show telomerase
activity, it will activate telomerase and elongates the telomeres        (fig 6). Thus cellular senescence can
be initiated based on telomere length via number of cell divisions, as telomere
length is decreased per cell division. Due to the telomere dysfunction many
diseases have been identified and also when individuals born without efficient
levels of telomerase will have shorter telomeres and this leads to telomere
dysfunction and also will have high chance of development of cancer (Shay et
al. 2007).

Fig 5. Showing the telomere length with accordance of
cell divisions in Germline cells/ embryonic stem cells, Pluripotent cells
and normal somatic cells and formation of cancer cells from normal cells.
Also showing stages of formation of cancer cells (shay et al. 2011)
 

             The telomere length of Male
reproductive cells and embryonic stem cells will never decreases due to the
presence telomerase activity. In the pluripotent cells the length of telomeres
is reduced throughout life but occurs at very slower rate. Whereas the somatic
cells will reduce their telomere length for each cell division and at a particular
time reaches senescence and when some of these senescent cells pass through
senescence and reach crisis where telomere lengths are so short and there is no
capping of chromosomal ends leads to genomic instability in which fusions or
breaks of chromosomal ends occurs. The cells which escapes this crisis will
activate telomerase which results in cancer cells (fig 5) (Shay et al. 2011).

Fig 6. Showing production of normal cells having
extended life span without any malignant by using TERT component of
telomerase enzyme (Shay et al. 2007)

              In the case of cancer, there is
high levels of telomerase enzyme. This can used for diagnosing of different
kinds cancer. For the cancer patients it is best to use telomerase inhibitors
as for cancer treatment. As telomerase inhibitors will reduce the length of
telomeres and finally stop the cancer cells to divide or make cancer cells to
be in senescent stage. Senescence of cancer cells is to be reached before there
is telomere dysfunction due to reduced length of telomeres in the reproductive
and somatic cells which have telomerase positive effect. As most of the somatic
cells do not express telomerase, use of telomerase inhibitors will not effect
on these normal somatic cells. So usage of these telomerase inhibitors will
result in low side effects. So this anti-telomerase therapy for cancer can be
stopped when the cancer cells undergo senescence and telomerase activity in
reproductive and stem cells can be reactivated. (Shay et al. 2007).       

               When TERT is used to activate
telomerase in different kinds of cells, it increases the life span of these
cells and does not inhibit normal functions of these cells and also increase
the telomere length (fig 6). So this principle can be used to deal with
age-related diseases. First of all collect the effected cells of disease and
grow them in-vivo along with TERT, by using engineering methods, so that
telomerase is activated in these cells, so when these dividing cells reach with
certain length of telomeres, returned to the same patient, absolutely there
will not be any rejection because these cells originally obtained from the same
patient, leads to improved longevity and health of the patient. This approach can be done in the case of dyskeratosis congenita (DKC) patients. So as it is
worked well in this case, it can be used as a treatment for telomere based or
age-related diseases (Shay et al. 2007).

Conclusions:-

           Telomeres
are G-rich simple sequence repeats and vary in length and sequence from
organism to organism. Telomerase enzyme prevents the loss of genetic data and
maintains genomic stability. Telomere sequence contains mainly six proteins and
together with these proteins forms T-loop and protect chromosomal ends. There
is a correlation between telomere length and ageing. In blood cells there is a
relationship between telomere length and age-related diseases. Based on
telomere length and telomerase, cancer cells are formed. The high levels of
telomerase enzyme can be used to diagnose cancer. Telomere inhibitors can be
used as telomerase therapy for cancer. 

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