By, PALUVAI HARIKRISHNAREDDY

Life at the End of Chromosomes

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.

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.

Introduction:

TELOMERE BIOLOGY

Why senescence occurs in eukaryotic organisms…?

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

What are telomeres.

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.

People who are older have chromosomes that have replicated more times

Number of cell division Vs Number of nucleotides lost in normal cell :

cell

division

1

cell

division

10

cell

division

20

cell

division

30

cell

division

40

cell

division

500

5000

10000

15000

20000

No.of nucleotides

No.of cell divisions

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)

Telomeric DNA strucutre:

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.

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AN OVERVIEW OF TELOMERE CHEMISTRY.

Telomere function

Telomere function

CappingReplication

RecombinationEnd to end joiningDegradation

(RED)

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.

Why do telomeres get shorter each time a cell divides? 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.

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.

End of replication problem

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.

Does anything counteract telomere shortening?

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.

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.

What role do telomeres play in cancer?

cell

division

1

cell

division

10

cell

division

20

cell

division

30

cell

division

40

cell

division

50

cell

division

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cell

division

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cell

division

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cell

division

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cell

division

100

02000400060008000

10000120001400016000

No.of nucleotides in base pairs

Graphical representation of telomere length extension in cancer cell:

No.of cell divisions

Role of telomeres in aging:

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

What is aging:

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.

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

1770 56.8

1800 59.61

1990 65.42

2000 72.50

2010 Projected 78.5

1770 1800 1990 2000 20100

10

20

30

40

50

60

70

80

Life span

Centuries

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.

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

References:

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