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Notes On Telomeres

Telomeres are repetitive DNA sequences at the ends of chromosomes that allow cells to distinguish chromosome ends from broken DNA. Telomeres prevent chromosome fusions and ensure chromosome stability but shorten with each cell division due to the end replication problem. When telomeres reach a critical short length, cellular senescence is triggered. Immortal cells avoid telomere shortening and senescence through the enzyme telomerase, which adds telomeric repeats. While telomerase prevents replicative senescence, it does not prevent other forms of cellular senescence.

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252 views

Notes On Telomeres

Telomeres are repetitive DNA sequences at the ends of chromosomes that allow cells to distinguish chromosome ends from broken DNA. Telomeres prevent chromosome fusions and ensure chromosome stability but shorten with each cell division due to the end replication problem. When telomeres reach a critical short length, cellular senescence is triggered. Immortal cells avoid telomere shortening and senescence through the enzyme telomerase, which adds telomeric repeats. While telomerase prevents replicative senescence, it does not prevent other forms of cellular senescence.

Uploaded by

malakmounir
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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Telomeres

2/21/16, 12:30 PM

Telomeres
What are they?
Ends of linear chromosomes
Repetitive DNA sequence: TTAGGG in vertebrates
Specialized proteins
Form a "capped" end structure

Why are telomeres important?


Telomeres allow cells to distinguish chromosome ends from broken DNA
If DNA is broken there are two options after the cell cycle is stopped: Repair or Death
Repair can occur in two ways:
Homologous Recombination (HR) -- Error-free but need homologue nearby
Non-homologous end-joining (NHEJ) -- Error-prone but saves chromosome from
degradation
Telomeres prevent chromosome fusions by NHEJ
Fusion-bridge-breakage cycles leads to genomic instability which in turn can result in cell
death or neoplastic transformation
Telomeres are specialized structures that are essential for protecting chromosome ends and ensuring
chromosome stability
Telomeres also provide a mechanism for "counting" cell divisions

Telomere shortening - the end replication problem


Telomeres shorten with each cell division (S phase)
The "end replication" problem:
DNA replication is bidirectional
DNA polymerases are unidirectional
DNA polymerases must initiate replication from a primer
Therefore: each round of DNA replication leaves 50-200 bp DNA unreplicated at the 3' end
Cells with telomeres that are 10-12 kb in length (average) divide 50-60 times
Telomeres are 4-6 kb [5-7 kb] in length (average)
Cellular senescence is triggeredwhen telomeres are on average 4-6 kb

How do immortal cells avoid telomere loss (i.e. solve the end
replication problem)?
Telomerase = the key to replicative immortality
Enzyme (reverse transcriptase) with protein + RNA subunits
Adds telomeric repeats directly to 3' overhang (uses its own RNA component as a template)
http://mcb.berkeley.edu/courses/mcb135k/telomeres.html

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Telomeres

2/21/16, 12:30 PM

Vertebrate telomere repeat: TTAGGG


Vertebrate telomerase RNA template: AATCCC
Overcomes telomere shortening/end replication problem
Added back to somatic cells
1. Prevemts telomere shortening
2. Prevents replicative senescence
However cells that express telomerase still undergo cellular senescence in response to DNA
damage, oncogenes, etc.
Expressed by germ cells and early embryonic cells
NOT expressed by most somatic cells (human)
Expressed by certain stem cells, but highly regulated
Expressed by 80-90% of tumor cells!
remaining 10-20% still need to overcome end replication problem -- do so by alternative
telomere lengthening mechanism (ALT), probably recombination

Telomere Hypothesis of Aging


Hypothesis: Telomeres shorten with age (T cells, tissue with high cell turnover)
Therefore, telomere shortening is a cause of aging
What is wrong with this hypothesis?
Telomere contributes to aging ONLY IF replicative senescence contributes to aging
Therefore, telomerase will prevent aging and/or restore youthfulness
Telomerase protects against replicative, but not other forms of cellular senescence
Telomerase: Useful for expanding cells for medical use
Telomerase Inhibitors: Useful for inhibiting or killing tumor cells

Summary
Telomeres are essential for chromosome stability
Telomere shortening causes replicative senescence. Other inducers of cellular senescence are
telomere - independent
Telomerase prevents telomere shortening and replicative senescence
The telomere hypothesis of aging hinges on the cellular/replicative senescence hypothesis of aging
Dr. Campisi's diagrams from last year's lecture: Campisi diagrams from February 2000

http://mcb.berkeley.edu/courses/mcb135k/telomeres.html

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