Life at the End of Chromosomes

1. By,
PALUVAI HARIKRISHNAREDDY

2. Contents
1.INTRODUCTION.
2. Telomere biology and cancer
2.1 Link between telomere and telomerase
2.2 Telomeres, a multi protein complex
2.3 End-replication problem.
2.4 Telomerase
2.5 Telomerase and Cancer
3. Role of telomere in Aging.
4.Conclusion.

3.  The major function of telomere is to cap the ends of
chromosomes and protect the chromosomes from RED
mechanism.
 As cells divide, telomeres continuously shorten with each
successive cell division.
 Telomerase provides the necessary enzymatic activity to
restore and maintain the telomere length.
 The vast majority of tumour's activate telomerase , and only
few maintain telomeres by ALT mechanism relying on
recombination.
 Telomere and telomerase are the attractive targets for anti-
cancer therapeutics.

4. TELOMERE BIOLOGY

5. Why senescence occurs in eukaryotic
organisms…?

6.  Our bodies are composed of more than a billion cells. Cells are
continually dying and new cells are continually being formed
 Inside the nucleus of a cell, our genes are located on twisted,
double-stranded molecules of DNA called chromosomes.
 Unique structures at the end of chromosomes are necessary for
chromosomal integrity and overall genomic stability called as
telomeres which protect our genetic data, make it possible for
cells to divide, and hold some secrets to how we grow old and
get cancer.
 An entire chromosome has about 150 million base pairs. Each
time a cell divides, an average person loses 30 to 200 base
pairs from the ends of that cell's telomeres

8.  This is because enzymes that duplicate DNA cannot
continue their duplication all the way to the end of
chromosomes. If cells divided without telomeres, they
would lose their ends of chromosomes and necessary
information they contain.
 Cells normally can divide only about 50 to 70 times, with
telomeres getting progressively shorter until the cells
become senescent, die or sustain genetic damage that can
cause cancer.
 Example:
In human blood cells, the length of telomeres ranges from
8,000 base pairs at birth to 3,000 base pairs as people age
and as low as 1,500 in elderly people.
 Telomeres do not shorten with age in tissues such as heart
muscle in which cells do not continually divide.

9. People who are older have chromosomes
that have replicated more times

10. Number of cell division Vs Number of nucleotides
lost in normal cell :
0
2000
4000
6000
8000
10000
12000
14000
16000
No.of nucleotides
No.of
cell
divisions

11.  Telomere structure:
Telomeres are comprised of repeat sequences and bound by
multiple telomeric interacting proteins. In mammalian cells,
telomere DNA contains double-stranded tandem repeats of
TTAGGG followed by terminal3¹ G-rich single-stranded over-
hangs. Telomere DNA is thought to adopt the T-loop structure,
where the telomere end folds back on itself and the3¹ G strand
overhang invades into the double-stranded DNA(these-called
D- loop)

13. Telomeric DNA strucutre:

14. 14
Telomere s, a multi protein complex
• Mammalian telomeres have a SIX PROTEIN complex called
“SHELTERIN”.
• TRF1 and TRF2 bind to the TTAGGG sequences in the double
strand telomeric DNA.
• POT1 binds to the sequences in single strand form
• TIN2 and TPP1 proteins keep TRF1, TRF2 and POP1 together.
• This six protein complex, SHELTERIN prevents the activation
of the DNA damage response.
• SHELTERIN is required for the recruitment of telomerase.

15. 15
AN OVERVIEW OF TELOMERE CHEMISTRY.

16. Telomere function
CappingReplication
Recombination
End to end joining
Degradation
(RED)

17. A) The telomeres are seen as the bright
red signals on the chromosome ends.
B) Fusions between the chromosomes are
indicated by the arrows, no telomeric
DNA is observed at these points.

18.  Before a cell can divide, the chromosomes within it are
duplicated so that each of the two new cells contains identical
genetic material. A chromosome's two strands of DNA must
unwind and separate.
 While replicating DNA, the eukaryotic DNA replicating
enzymes, cannot replicate the sequences present at the end of
chromosomes. Hence these sequences and the information
they carry may get lost.
 They cap the end sequences and themselves get lost in the
process of DNA replication.
 In 1972, James Watson called this as End-replication problem.

19.  The first step is to unwind their double helices into separate
strands. As the double helix of DNA unwinds into two parent
strands, the ends of the different bases are exposed. Due to the
obligatory pairing of A-T and G-C, each parent strand becomes
a template for copying a whole new DNA helix.
 Since the DNA structure can be rebuilt on both parent strands,
two identical DNA helices are produced, each containing one
original parent strand and one newly synthesized strand, called
a complementary strand.
 Due to the nature of the mechanism via which DNA is
replicated, one strand of the DNA is left with an incompletely
replicated end. Without specialized means of
maintaining chromosomes, this causes chromosome ends to
shrink with each successive cell division.

21.  An enzyme named telomerase adds bases to the ends of
telomeres. In young cells, telomerase keeps telomeres from
wearing down too much. But as cells divide repeatedly, there is
not enough telomerase, so the telomeres grow shorter and the
cells age.
 Telomerase is turned off in somatic cells but remains active in
sperm and eggs, which are passed from one generation to the
next. If reproductive cells did not have telomerase to maintain
the length of their telomeres, any organism with such cells soon
would go extinct.
 Telomerase activity is low or absent in normal cells, when
compared to cancer cell.
 Telomerase is composed of catalytic subunits htert and htr.

22.  Telomerase is a ribonucleoprotein complex whose principal
role is the maintenance of telomeres, the heterochromatic
structures made of G-rich repeated sequences that cap and
protect the ends of chromosomes.
 Human telomerase is composed of two main subunits: the
human telomerase RNA (hTR), which harbors an 11
nucleotide long sequence acting as a template for synthesis of
telomeric repeats, and the human telomerase reverse
transcriptase (hTERT), which is the core catalytic subunit of
the enzyme.
 When correctly assembled, telomerase contributes to lengthen
chromosome termini, thus counteracting telomere erosion that
occurs at each round of cell division.
 In the absence of telomerase, the extreme ends of
chromosomes is not replicated and the telomeres progressively
shorten with every cell division.

24.  Telomeres were first discovered in cancer cells because, cancer cells are
saturated with an enzyme called telomerase.
 Telomerase is the key enzyme for human cells to accquire immortality.
 As a cell begins to cancerous, it divides more often and its telomere
becomes very short. If its telomeres get too short, the cell may die,
whereas normal cell is devoid of telomerase activity.
 It can escape this fate by becoming cancerous cell by activating
telomerase (or) ALT pathway is activated, resulting in abnormal
telomere lengthing & proliferative growth
 Telomerase is over expressed in many cancers cells.
 When cells lose the function of P53 pathway, they can no longer arrest
cells in G1 an important point in cell cycle for repairing DNA damage
response. Cells without P53 are able to divide with deprotected telomeres,
which cause genomic instability a common feature of malignant cells.

26. 0
2000
4000
6000
8000
10000
12000
14000
16000
No.of nucleotides in base pairs
No.of cell divisions

29. Aging is a degenerative process that is associated with
progressive accumulation of deleterious changes with time,
reduction of physiological function and increase in the chance of
disease and death.
 Some long lived species like human have telomeres that are
much shorter than species like mice, which live only few
years.
 But its evidence shows that telomeres alone, do not reduce the
life span, but there are some factors which also plays an
important role in aging.
 Cawthon´s study, found that, when people are divided into 2
groups based on telomere length, the half with longer telomere
lives five years longer than the shorter telomeres. That
suggests lifespan could be increased five years by increasing

30. the length of telomeres in shorter one.
 Short telomeres are linked to higher risk of age related
diseases.
 Stressful life experiences in childhood and adulthood
have been linked to accelerate telomere shortening.
 Long term unemployment may accelerate aging in men.

31.  The major cause of aging is ʻʻOxidative stressʼʼ and ʻʻGlycationʼʼ.
 Mitochondrial dysfunction also plays an important role in aging and
age related diseases.
 Protein misfolding can also cause age related disease as we grow
old.
 The below graphs shows human life span has increased from1700ˊS
with an average of 5years

32. 1770 56.8
1800 59.61
1990 65.42
2000 72.50
2010 Projected 78.5
0
20
40
60
80
1770 1800 1990 2000 2010
Life
span
Centuries

33. CONCLUSION:
 Measuring telomerase may be a new way to detect cancer.
 If scientists can learn how to stop telomerase, they might be
able to fight with cancer by making cancer cells age and die.
 Some of the drugs are showed positive results by inhibiting
telomerase and associated proteins and finding the way to
shortening of telomere which results in cell death/apoptosis.
 Most of anti-telomerase drugs are still in Clinical phases I and
II.

34.  Role of telomere and telomerase — Elizabeth Blackburn.
 Telomeres—structure, function, and regulation—Weisi Lua,
YiZhangb, DanLiub, ZhouSongyanga,b,c,n, MaWanb,
 Telomeres and telomerase as targets for anticancer drug
development—Ken André Olaussen a, Karine Dubrana a, Julien
Domonta, Jean-Philippe Spano b,
 Control of Telomeric DNA Replication:Genetics, Molecular
Biology, and Physiology— Akira Matsuura and Aiko Matsui
 Telomerase: a therapeutic target for the third millennium? Franc¸ois
Lavelle *, Jean-Franc
 Structure and function of telomere: -www.sciencedaily.com
www.the-scientist.com
www.researchgate.net
www.nature.com
www.sciencedirect.com

35. QUERIES….?

36. THANK YOU