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TELOMERES What are they? Why are they important? Telomere shortening and the end-replication problem Telomerase Telomere PowerPoint Presentation
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TELOMERES What are they? Why are they important? Telomere shortening and the end-replication problem Telomerase Telomere hypothesis of aging. Telomeres Ends of linear chromosomes. Centromere. Telomere. Telomere. Repetitive DNA sequence (TTAGGG in vertebrates) Specialized proteins

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Presentation Transcript
slide1

TELOMERES

What are they?

Why are they important?

Telomere shortening and the end-replication problem

Telomerase

Telomere hypothesis of aging

slide2

Telomeres

Ends of linear chromosomes

Centromere

Telomere

Telomere

Repetitive DNA sequence

(TTAGGG in vertebrates)

Specialized proteins

Form a 'capped' end structure

slide4

TELOMERE STRUCTURE

5’

3’

Telomeric

t loop

Telomeric

proteins:

TRF1

TRF2

TIN2

RAP1

TANKS 1,2

POT1

etc

5'

3'

NUCLEAR

MATRIX

slide5

Why are telomeres important?

Telomeres allow cells to distinguish chromosomes

ends from broken DNA

Stop cell cycle!

Repair or die!!

Homologous recombination

(error free, but need nearby homologue)

Non-homologous end joining

(any time, but error-prone)

slide6

Why are telomeres important?

Prevent chromosome fusions by NHEJ (non-homologous end joining)

NHEJ

FUSION

BRIDGE

BREAKAGE

Mitosis

Fusion-bridge-breakage cycles

Genomic instability

Cell death OR neoplastic transformation

slide7

Telomere also provide a means for

"counting" cell division

Finite

Replicative

Life Span

"Mortal"

Infinite

Replicative

Life Span

"Immortal"

Proliferative capacity

Number of cell divisions

How do cells "know" how many

divisions they have completed??

slide8

The End Replication Problem:

Telomeres shorten with each S phase

5'

3'

3'

5'

3'

5'

5'

5'

3'

Ori

DNA replication is bidirectional

Polymerases move 5' to 3'

Requires a labile primer

Each round of DNA

replication leaves

50-200 bp DNA unreplicated

at the 3' end

slide9

Telomere also provide a means for "counting"

cell division: telomeres shorten with each cycle

Telomeres shorten from 10-15 kb

(germ line) to 3-5 kb after 50-60 doublings

(average lengths of TRFs)

Cellular senescence is triggered when

cells acquire one or a few

critically short telomeres.

20

Normal

Somatic

Cells

Telomere Length (humans)

10

(Telomerase

Negative)

Cellular (Replicative) Senescence

Number of Doublings

slide10

How do replicatively immortal cells

avoid complete loss of telomeres

(how do they solve the end-replication problem)?

slide11

TELOMERASE:

Key to replicative immortality

Enzyme (reverse transcriptase) with

RNA and protein components

Adds telomeric repeat DNA directly to

3' overhang (uses its own RNA as a template)

Vertebrate repeat DNA on 3' end:

TTAGGG

Telomerase RNA template:

AAUCCC

slide12

TELOMERASE:

Key to replicative immortality

+ TELOMERASE

Overcomes telomere shortening and the end-

replication problem

Expressed by germ cells, early embryonic cells

Not expressed by most somatic cells (human)

May be expressed by some stem cells, but highly controlled

Expressed by 80-90% of cancer cells

Remaining still need to overcome the end replication problem;

do so by recombinational mechanisms --

ALT (alternative lengthening of telomeres) mechanisms

slide13

Telomere Length and Cell Division Potential

Germ Cells (Telomerase Positive)

20

Normal

Somatic

Cells

Telomere Length (humans)

+ Telomerase

10

(Telomerase

Negative)

Cellular (Replicative) Senescence

Number of Doublings

slide14

HOWEVER,

CELLS THAT EXPRESS TELOMERASE

STILL UNDERGO SENESCENCE

(E.G., IN RESPONSE TO DNA

DAMAGE, ONCOGENES, ETC.)

Inducers of cellular senescence

Strong mitogens/

stress

Cell proliferation

(short telomeres)

DNA damage

Oncogenes

Potential Cancer Causing Events

slide15

Telomerase:

Biomedical uses

Expand cells for replacement therapies

(burns, joint replacements, etc)

Telomerase inhibitors to selectively kill cancer cells

slide16

The telomere hypothesis of aging

Telomeres shorten with each cell division

and therefore with age

TRUE

Short telomeres cause cell senescence and

senescent cells may contribute to aging

TRUE

HYPOTHESIS:

Telomere shortening causes aging and

telomerase will prevent aging

TRUE OR FALSE?

slide17

The telomere hypothesis of aging

Telomere length is not related to life span

(mice vs human; M musculus vs M spretus)

Telomeres contribute to aging ONLY if

senescent cells contribute to aging

Telomerase protects against replicative

senescence but not senescence induce by

other causes

slide18

SUMMARY

Telomeres are essential for chromosome stability

Telomere shortening occurs owing to the biochemistry of

DNA replication

Short telomeres cause replicative senescence

(other senescence causes are telomere-independent)

Telomerase prevents telomere shortening and

replicative senescence

The telomere hypothesis of aging depends on the

cellular senescence hypothesis of aging