Chromosome telomeres and activity of telomerase in various human stem cells. End replication problem, telomere and ageing

1. TELOMERES
AND
TELOMERASES
Presented By,
KARAN N
21L10714
MSc Biotechnology
Department of Biotechnology and
Bioinformatics
JSSAHER

2. ● Chromosomes are thread-like structures present in the nucleus, which
carries genetic information from one generation to another. They play a
vital role in cell division, heredity, variation, mutation, repair and
regeneration.
● In Eukaryotic cells, genetic material is present in the nucleus in
chromosomes, which is made up of highly organized DNA molecules with
histone proteins supporting its structure.
● Each cell has a pair of each kind of chromosome known as a Homologous
chromosome.
● Chromosomes are made up of chromatin, which contains a single molecule
of DNA and associated proteins. Each chromosome contains hundreds and
thousands of genes that can precisely code for several proteins in the cell.
Structure of a chromosome can be best seen during cell division.
BACKGROUND-CHROMOSOMES

3. ● A Telomere is a region of repetitive nucleotide sequences associated with
specialized proteins at the ends of linear chromosomes.
● Although there are different architectures, telomeres, in a broad sense, are a
widespread genetic feature most commonly found in eukaryotes.
● In most, if not all species possessing them, they protect the terminal
regions of chromosomal DNA from progressive degradation and ensure
the integrity of linear chromosomes by preventing DNA repair systems from
mistaking the very ends of the DNA strand for a double strand break.
● Telomere length varies greatly between species, from approximately 300
base pairs in yeast to many kilobases in humans, and usually is composed of
arrays of guanine-rich, six- to eight-base-pair-long repeats.
● 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.
TELOMERES

4. ● As is known the DNA in eukaryotic chromosomes is a linear molecule, the
termination in eukaryotic DNA also involve completing replication at the ends
of chromosomes known as Telomeres.
● During the synthesis of Okazaki fragments, RNA primer provide 3′-OH group
for 5′ to 3′ replication. On the removal of RNA primer, from the lagging strand
at the chromosome end, the end remains unreplicated and the newly
synthesized strand is shortened which is called End Replication problem.
● This shortening of the chromosome is prevented by the presence of special
repeats of sequences called telomeres (and telomere-associated proteins) at
the ends of DNA in chromosomes contain.
● Human Chromosomes are protected by telomeres having repeated sequences
of (TTAGGG)n of about 15–20 kb at birth. These structures protect the ends
of chromosomes from being mistakenly considered as DNA double strand
breaks (DSB).
END REPLICATION PROBLEM

5. END REPLICATION PROBLEM
AND TELOMERES

6. ● In normal somatic cells, the telomeric region of eukaryotic chromosomes are shortened with each round of
DNA replication. After certain number of DNA replications, and hence cell divisions, the telomeres are
shortened to an extent that it leads to replicative cell senescence or apoptosis.
● Some cells like germ cells, cancer cells and some adult stem cells have the ability to reverse telomere
shortening by expressing telomerase, an enzyme that extends the telomeres of chromosomes.
● Telomerase is a reverse transcriptase which has a RNA template, known as template-encoding RNA molecule
(TER) for extension of the telomeric DNA. The basic protein component of telomerase is known as TERT
(Telomerase Reverse Transcriptase).
● The enzyme binds to a special RNA molecule that contains a sequence complementary to the telomeric repeat.
● It extends (adds nucleotides to) the overhanging strand of the telomere DNA using this complementary RNA
as a template. When the overhang is long enough, a matching strand can be made by the normal DNA
replication machinery (that is, using an RNA primer and DNA polymerase), producing double-stranded DNA.
● The primer may not be positioned right at the chromosome end and cannot be replaced with DNA, so an
overhang will still be present. However, the overall length of the telomere will be greater.
TELOMERASE

7. TELOMERASE SHORTENING AND
TELOMERASE

8. TELOMERASE FUNCTION

9. TELOMERASE FUNCTION

10. TELOMERASE FUNCTION

11. ● In somatic cells, the activity of telomerase, a reverse transcriptase that can elongate telomeric repeats, is
usually diminished after birth so that the telomere length is gradually shortened with cell divisions, and
triggers cellular senescence.
● In embryonic stem cells, telomerase is activated and maintains telomere length and cellular immortality;
however, the level of telomerase activity is low or absent in the majority of stem cells regardless of their
proliferative capacity.
● Thus, even in stem cells, except for embryonal stem cells and cancer stem cells, telomere shortening occurs
during replicative ageing, possibly at a slower rate than that in normal somatic cells.
● low levels of telomerase activity have been found in human adult stem cells including hematopoietic and non-
hematopoietic stem cells such as neuronal, skin, intestinal crypt, mammary epithelial, pancreas, adrenal cortex,
kidney, and mesenchymal stem cells (MSCs).
● The level of telomerase is low in the majority of human stem cells, whereas it is upregulated in cells that
undergo rapid expansion, such as committed hematopoietic progenitor cells, activated lymphocytes, or
keratinocytes, even within tissues with a low cell turnover such as the brain
TELOMERES AND TELOMERASE IN
STEM CELLS

12. TELOMERASE ACTIVITY IN
DIFFERENT STEM CELLS

13. TELOMERASE AND TELOMERES
IN DIFFERENT STEM CELLS

14. DYSKERATOSIS CONGENITA
The critical importance of telomerase activity in human stem cells has been
recently highlighted as the aetiology of DKC. In this disease, a defect of the
telomerase RNA template gene results in the absence of telomerase activity and
premature telomere shortening, developing bone marrow failure, intestinal
disorder, or malignancy, typically under 50 years old.
APLASTIC ANAEMIA
Aplastic Anaemia results from the failure of bone marrow to produce sufficient
quantities of all hematopoietic lineages. The aetiology of this disease is unclear
in most cases, but is generally thought to be the result of HSC damage or loss.
Telomere length in peripheral blood granulocytes and monocytes in patients
with aplastic anaemia or related disorders was significantly shorter than that in
age-matched controls, and correlated with disease duration
DISEASES DUE TO LACK OF
TELOMERASE IN STEM CELLS

15. ● Hiyama E, Hiyama K. Telomere and telomerase in stem cells. Br J Cancer.
2007 Apr 10;96(7):1020-4. doi: 10.1038/sj.bjc.6603671. Epub 2007 Mar 13. PMID:
17353922; PMCID: PMC2360127.
● https://www.khanacademy.org/science/biology/dna-as-the-genetic-
material/dna-replication/a/telomeres-telomerase
● REVIEW: Telomerase: Structure, Functions, and Activity Regulation M. I.
Zvereva*, D. M. Shcherbakova, and O. A. Dontsova
● https://thebiotechnotes.com/2019/07/26/dna-replication-in-eukaryotes-
elongation-and-termination/
● Pictures from google images
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