ZOOHCC - 501: Molecular Biology (Theory)
Unit 2: DNA Replication
Telomeres
Telomeres are repeating sequences of nucleotides at the ends of chromosomes.
It is present on eukaryotic chromosomes. These are non-coding regions and do
not code for any protein.
Müller coined the term "telomere". Barbara McClintock showed that broken
chromosomes have sticky ends compared to natural chromosome ends, which are
stable and difficult to fuse. Telomeres keep chromosomes from sticking
together and protect them from deterioration.
Telomeres contain non-coding repetitive sequences rich in guanine
nucleotides. In humans, the repeat sequence is 5'-TTAGGG-3' and is repeated
multiple times.
Aging
Telomeres play a central role in cell fate and aging by adjusting the
cellular response to stress and growth stimulation on the basis of
previous cell divisions and DNA damage. At least a few hundred nucleotides
of telomere repeats must "cap" each chromosome end to avoid activation of
DNA repair pathways. Repair of critically short or "uncapped" telomeres by
telomerase or recombination is limited in most somatic cells and apoptosis
or cellular senescence is triggered when too many "uncapped" telomeres
accumulate. The chance of the latter increases as the average telomere
length decreases. The average telomere length is set and maintained in
cells of the germline which typically express high levels of telomerase.
In somatic cells, telomere length is very heterogeneous but typically
declines with age, posing a barrier to tumor growth but also contributing
to loss of cells with age. Loss of (stem) cells via telomere attrition
provides strong selection for abnormal and malignant cells, a process
facilitated by the genome instability and aneuploidy triggered by
dysfunctional telomeres. The crucial role of telomeres in cell turnover
and aging is highlighted by patients with 50% of normal telomerase levels
resulting from a mutation in one of the telomerase genes. Short telomeres
in such patients are implicated in a variety of disorders including
dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer.
Here the role of telomeres and telomerase in human aging and
aging-associated diseases is reviewed.
Structure
Telomeres are present at the ends of all eukaryotic chromosomes. It consists
of a short nucleotide sequence that is repeated several times. They do not
code for any proteins.
The order in which they are repeated depends on the species. The number of
copies of the repeat unit varies from chromosome to chromosome or even
within the same chromosome in different cells. A normal human cell has about
500 to 3000 repetitions, which gradually become shorter. In some cells, such
as germline cells and cancer cells, telomeres do not shorten with age.
The basic repeating unit pattern for most species is 5`-T1-4A0-1G1-8-3`.
Telomeres usually end with a guanine-rich single strand at the 3' end. In
humans, a T-loop is formed at the end of his 3′ single strand. The protein
shelterin protects telomeres from deterioration and alteration.
The human repeat is 5'-TTAGGG-3'. In the plant Arabidopsis thaliana it is
TTTAGGG. Additional sequences related to telomeres are found in most
species.
Telomeres containing tandem repeats of TTAGGG are very common in
vertebrates. It is found in over 100 species, including birds, reptiles,
amphibians, fish and mammals.
In most prokaryotes, the DNA is circular, so telomeres are not found.
Telomeres are found in some prokaryotes with linear DNA, but their structure
differs from eukaryotic cells. They are in the form of hairpin loops, formed
from single strands or attached to proteins.
Function
Telomeres arise from imperfect replication at the ends of chromosomes. With
each replication cycle, a piece of DNA is lost. These protective end caps
ensure that genetic information is preserved and not lost in the process.
They play an important role in aging. They are essential for attracting the
telomerase replication machinery to the ends of chromosomes and regulating
its function there. In addition, telomeres are required to stabilize
eukaryotic chromosomes in a variety of ways. Telomeres protect chromosome
ends from recognition by the cell's DNA damage response system. It seals the
ends of chromosomes to prevent degradation and fusion. The fused chromosome
may have segregated incorrectly in meiosis or mitosis. Telomeres are often
located beneath the nuclear membrane, and their unique association with the
spindle pole body of fission yeast is essential for normal conduction of
meiotic recombination.
Role in aging and cancer
Telomeres play an important role in cellular aging. Telomeres shorten with
each replication, and when they become too short, cells stop replicating,
leading to senescence and apoptosis. Therefore, it acts as a biological
clock for cellular aging. It also causes oncogenic transformation of cells.
The rate of telomere shortening can be reduced with a better lifestyle,
diet, and activity. It delays the onset of age-related diseases and prolongs
life.
A special enzyme called "telomerase" can extend the length of telomeres. It
exists in infinitely dividing cells. Unicellular eukaryotes, egg and sperm
cells, blood cells and even cancer cells.
Scientists have observed that in cancer cells, telomeres are too short, and
when they reach a critical point, telomerase is reactivated, causing cancer
cells to grow out of control. Most cancer cells such as breast cancer,
prostate cancer, lung cancer, pancreatic cancer Contains telomerase, which
maintains telomere length and prevents apoptosis. Research into anticancer
drugs that target telomerase is underway.
telomere duplication/ replication
Telomeres are the ends of linear chromosomes. They are repetitive
sequences that do not code for specific genes. Telomeres are involved in
protecting critical genes from deletion during cell division and
shortening of DNA strands during replication.
Some telomeric sequences are lost after each round of replication at her
5' end of the synthetic strand of each daughter DNA. Since these are
non-coding sequences, their loss does not severely affect the cell.
However, these sequences are not unlimited. After a sufficient number of
replications, the telomere repeats are lost. There is a risk that the DNA
will lose the coding sequence in the next round.
Therefore, telomeres play an important role in maintaining DNA and genes
involved in cellular aging. It protects the genome from degradation,
unwanted repair, recombination, and fusion between two chromosomes.
Importance
Serves as the cell's mitotic clock as it shortens with each round of cell
division
In humans, these are distinct chromosomal terminal structures containing
repetitive sequences.
Essential for maintaining chromosomal integrity. Its excessive shortening
is associated with DNA instability