TELOMERES F O U D H O U R A N I

S I A M A K R E Z A E I

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Martinez, P., and Blasco, M., 2011. Telomeric and extra-telomeric roles

for telomere-binding proteins. Nature Reviews Cancer. (3) 161-176

Telomeres

• The ends of chromosomes.

• Functions:

o Protect chromosome from degradation.

o Regulate telomerase activity at chromosome

ends.

o Essential for chromosome stability

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INTRODUCTION

• Structure

o Formed by tandem repeats of

TTAGGG sequence.

o Bounded by a specialized six-

proteins complex known as

shelterin.

o Elongated by telomerase

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subunits of shelterin

Protection of telomeres protein 1

Telomeric repeat binding factors 1&2 Repressor-activator protein 1

(Transcriptional regulation)

Organizing protein

• Telomeric roles of shelterin:

Protection and recombination (TRF1, TRF2, TIN2,

TPP1, and RAP1)

Length regulation (TRF1, TRF2, TIN2, TPP1 and

RAP1).

Inhibition DDR (POT1, RAP1, TRF1, and TRF2).

Telomere replication (TRF1)

TRF1-interacting protein 2

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Is a two partner enzyme, the reverse

transcriptase catalytic subunit (TERT)

and the RNA component (TERC), which

recognizes the hydroxyl group at the 3’

end of G-strand overhang and

elongates the telomere

Telomerase

• Structure

• Function

o Telomere dysfunction causes ageing or cancer depending on

the DNA damage response.

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OBJECTIVE

The present paper discusses the role of

telomeric proteins in cancer and ageing

through modulating telomere length and

protection.

And regulating gene expression by binding

to non-telomeric sites.

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DISCUSSION

Factors that influence telomere function

• Telomerase

• The telomeric chromatin

• The shelterin complex

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• Telomerase

o During each cell division cycle, telomeres shorten

as a result of the incomplete replication of linear

DNA molecules by conventional DNA polymerase.

o Telomerase compensates for telomere attrition

through addition of TTAGGG repeats by TERT onto

the chromosome ends by using an associated

RNA component as a template TERC

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o But this is not sufficient mechanism to maintain the telomere

length.

o Indeed, there are some conditions may lead to accelerate the rate

of telomere shortening such as:

age in most tissues.

Some cases of aplastic anaemia and idiopathic pulmonary

fibrosis are linked to germline mutations in TERC and TERT

some diseases are characterized by the premature loss of

tissue renewal and premature death (dyskeratosis congenita)

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• The telomeric chromatin

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o TERRA:Telomere repeat containing RNAs

o TelRNA: telomeric RNAs.

• The shelterin complex

RAP1 is dispensable for

telomere capping but prevents

telomere recombination and

fragility. Thus, RAP1 is not a

telomere protective protein, in

contrast to the rest of proteins.

So the role of RAP1 is

telomerase regulation

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Extra-telomeric roles for a telomeric protein

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• Genomic instability is a prominent

characteristic of most cancer types that

has an essential role in tumorigenesis

by accelerating the accumulation of

genetic changes that are responsible

for cancer cell evolution.

Telomere dysfunction and genomic instability

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• One of the important source of genomic instability is telomere

shortening.

• Telomere dysfunction can causes by deficient of telomerase

and/or the shelterin proteins, either owing to the loss of

telomeric repeats or owing to the loss of the telomere

protective structure, causes genome instability and thereby

affects tumorigenesis.

• The molecular mechanisms that related to telomere defects

are:

o Breakage-fusion-bridge cycles.

o Defects in telomeric DNA replication.

o The susceptibility of telomeric DNA to genotoxic damage.

o Cell cycle control and endoreduplication.

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o Breakage-fusion-bridge cycles

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o Defects in telomeric DNA replication

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o The susceptibility of telomeric DNA to genotoxic damage

T A

T A

G C

G C

G C

G C

T A

T A

G C

G C

G C

G C

UV

Replication

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o Cell cycle control and endoreduplication

Limiting genome replication to once per cell cycle is

essential for maintaining genomic stability.

Cancer cells are usually aneuploid, with highly variable

chromosome numbers, ranging from hypodiploidy and

hypertetraploidy.

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Telomere shortining and telomere dysfunction have

been shown to trigger polyploidization.

example

Mitosis Tetraploid

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Telomerase and anticancer treatment

o The link between the inability to maintain telomeres with

age and consequent declining health, including the

increased risk of degenerative diseases and cancer, has

suggested that telomerase is appealing target for the

treatment of these diseases.

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o Several factors make telomerase inhibition as an anticancer

treatment a safe and rather specific therapy:

Telomerase is expressed in 85% of tumours from all types

of cancers and so it would be widely applicable.

The likelihood of developing resistance mechanisms is low.

The different telomerase expression levels in healthy cells

versus tumour cells, suggest a high degree of tumour

specifity and a low risk of toxicity to normal tissues.

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o Telomerase inhibitor

Drugs; inhibit telomerase enzymatic activity.

Active immunotherapy.

Gene therapy.

Agent that block telomerase biogenesis

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Conclusion

Telomeres are still fertile field, and it needs to identify new interacting

factors between telomerase and shelterin components, and to understand their

biological function and how their activities are controlled in more detail.

“Such knowledge would not only enhance our appreciation of the molecular

mechanisms underlying telomere maintenance but would also provide valuable

insights into human genetic disease, ageing and cancer, and thereby provide

opportunities for the better management of human health and disease”.

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Q & A

Thank you