Telomeres to fill the gap left by the

Telomeres are the repeatedly shortening and lengthening tips
of chromosomes which enable cell division (1), while telomerase is the enzyme
which catalyses the synthesis of telomeres. However, not all cell types contain
telomerase; different cell types contain different levels of telomerase
according to their function, for example, cancer cells contain high levels while
normal somatic cells usually contain unexpressed telomerase (2). Understanding
the role of telomerase in cancer and somatic cells is essential for our
understanding of cellular aging (6), as well as for the possible discovery of
anti-cancer drugs based on telomerase and its effect on cancer cells (1). This mini-review will discuss the
structure and function of telomeres and telomerase, how telomerase affects
somatic and cancer cells and finally, the influence of telomerase on cellular
aging.

The structure of telomeres and
telomerase:

The precise structure of telomeres was
discovered in the 1970s, where scientists Blackburn and Gall found that
telomeres in the unicellular organism Tetrahymena
contained the repeated short nucleotide TTAGGG (1). Telomerase was
identified 15 years ago, and is made of protein, but uniquely contains a single
strand of RNA, containing the nucleotide template for the synthesis of
telomeric subunits. (1).

As shown in Figure 1, telomerase synthesises telomeres by
placing the end of one strand of DNA in line with the template RNA strand, then
adding one DNA nucleotide at a time until a telomeric subunit is formed (1).
When the 3′ overhang (7) is long enough, normal DNA replication mechanisms take
place to produce double stranded DNA (7). Thus, telomerase provides a solution
to the ‘End-replication problem’, which states that DNA polymerase is unable to
replicate (1) the lagging strand of DNA (7) to the tip of the chromosome due to
its inability to fill the gap left by the removal of the primer at the 5′ end
of each strand (1). If cells had no way to overcome this, eventually their
chromosomes would diminish as they shorten with each division (1). Telomerase
finishes this replication and so ensures the chromosomes will not shrink (1).  

Telomerase in cancer cells:

There are
different levels of telomerase in different cell types (1). In somatic cells, scientists
suggest there is a lack of telomerase in order to help avoid cancer (1); with
each cell division, the length of telomeres shorten and so eventually, when the
chromosome reaches a critical length, the cell stops dividing. If telomerase
was present in abundance in these cells, they would continue to lengthen the
telomeres and so induce cell division, possibly resulting in uncontrolled cell
division identifiable to that of cancer cells (2). However, cancer cells have
high levels of telomerase, thus promoting cell division and causing the cancer
to grow (2). It has been found that telomeres in cancer cells are shorter than
in normal cells (1). Scientists believe this is because cells only synthesise
telomerase after uncontrollable replication has taken place (1). The cell will
not stop dividing as the reactivated telomerase causes the shortened telomeres
to be maintained, and so the genetically altered cells will become immortal (1).

Scientists
are researching anti-cancer drugs (1) with relation to telomerase (2). As
telomerase is found in cancer cells and is absent in normal somatic cells,
scientists believe it can be used as a target for anti-cancer drugs (1). An
example of this is telomerase-inhibiting drugs, which would cause cancer cells
to die (1). However, some normal somatic cells contain telomerase, and so the
drug targeting it could harm these cells as well (1). Scientists therefore need
to find out which cell types contain telomerase (1), for example in stem cells
(2), and decide whether the advantages of destroying the cancer cells outweigh
the disadvantages (1) (in the case of stem cells, this could be deadly as stem
cells need to be able to divide in order to differentiate) (2).

The role of telomerase in cellular
aging

Cellular aging (senescence) occurs
when telomeres shorten to a critical length after numerous divisions (3). As
shown in Figure 2, a DNA damage signal is instigated when the telomeres are
very short (2). If a cell has passed the M1 senescent state, the cell ignores
this signal and divides until the telomeres length is critical, when M2 (crisis
state) begins and apoptosis occurs (2). In rare cells, the cell may become
immortal (2).

Understanding the role of telomerase in cellular aging is
crucial for research into age-related diseases (4), for example, Progeroid
syndromes (5). These are diseases which mimic physiological aging, making
sufferers look older than they actually are (5). Scientists believe telomeres
are involved with such diseases, as the damage in the DNA causes telomeres to
shorten and leads to increased cell death (4). Thus, telomere length seems to
act as a standard against which the lifespan of a cell and organism can be
determined (6).  To prove that telomeres
shorten with age, transgenic introduction of a telomerase gene into a normal
human cell was performed and shown to extend the cell’s lifespan (6). Thus, it
seems, most age-related diseases are associated with the shortening of
telomeres, as shown by the observation that individuals with shorter telomeres
died more than those with longer telomeres due to infection and cardiac
diseases (6), e.g. atherosclerosis (1).

Conclusion:

Overall, it
can be determined that telomerase plays a crucial role in the process of
cellular aging. Without the presence of telomerase, telomeres shorten to a
critical length, resulting in the aging of cells and their eventual death (3),
as well as leading to age-related diseases such as heart disease (6). Although
there is still a gap in the research regarding the role telomerase could play
in anti-aging treatments (6), it is clear that telomerase is essential to DNA
replication (1, 7), and so to life itself. 

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