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Telomerase

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Telomere Terminal Transferase and its Role in Cancer Brian R. Keppler February 27, 2003 The Telomere Found on the ends of eukaryotic chromosomes. – PowerPoint PPT presentation

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Title: Telomerase


1
Telomerase
Telomere Terminal Transferase and its Role in
Cancer
Brian R. Keppler
February 27, 2003
2
The Telomere
  • Found on the ends of eukaryotic chromosomes.
  • Characterized by a 3-overhang of
    single-stranded DNA.
  • Forms a T-loop with the help of specialized
    proteins to protect
  • itself from exonuclease activity.
  • Shortening of telomeres results in the loss of
    genetic information
  • and ultimately cell death.

3
DNA Replication
  • Semi-conservative
  • Bi-directional
  • Occurs in the 5 to 3 direction only
  • Leading strand is synthesized
  • continuously
  • Lagging strand is synthesized
  • discontinuously
  • - Cant replicate to entirety
  • - Gradually shortens

Lodish, H. et al., Molecular Cell Biolgy, 4th
Ed., Freeman Publishing, 2000, p.461.
4
Telomerase
  • A specialized form of reverse transcriptase that
    carries its own
  • internal RNA template to direct DNA
    synthesis.
  • Elongates the lagging strand template from its
    3-OH end.
  • Adds short, repeated, guanosine-rich sequences
    to the ends of
  • chromosomes.

______________________________________________
RNA template sequence
Organism
Telomeric DNA sequence
H. sapien
5-T2AG3
3-UCCCAAUC T. thermophila
5-T2G4
3-AACCCCAA O. bifaria
5-T4G4
3-CCAAAACCCC A. thaliana
5-T3AG3
unidentified
E. aediculatus
5-T4G4
3-CCAAAACCCCAAAAC S. cerevisiae
5-T1-6GTG2-3
3-CACACACCCACACCAC
5
Proposed Rough Model of Telomerase
Alberts, B. et al., Molecular Biology of the
Cell, 4th Ed., Garland Science, 2002, p. 264.
6
Mechanism of Telomerase Action
Lodish, H. et al., Molecular Cell Biolgy, 4th
Ed., Freeman Publishing, 2000, p.466.
7
Telomerase and Cancer
  • Telomerase is up-regulated in the vast majority
    of human cancers and
  • serves to halt the progressive telomere
    shortening that ultimately blocks
  • would-be cancer cells from achieving a full
    malignant phenotype.
  • Telomerase is active in the germ line and in
    renewable cells (e.g. bone
  • marrow).
  • Most human somatic cells lack telomerase
    activity.
  • Telomere shortening
  • Senescence
  • End-to-end chromosome fusion and cell death
  • Most tumors regain the ability to produce
    telomerase.
  • - Cells become immortal

Artandi, SE et al., Proc Natl Acad Sci U S A 2002
May 28
8
How Do Cancer Cells Activate Telomerase Activity?
  • Some cancer cells with telomerase activity arise
    from mutant precursor
  • cells that have avoided telomere shortening.
  • - These cells have never encountered a
    telomeric limit to cell division.
  • Telomerase can be activated after a genetic
    catastrophe (e.g. p53 loss).
  • - Loss of checkpoint controls, uncontrolled
    proliferation, accumulation
  • of mutations, chromosomal instability...But,
    telomeres are also
  • shortening with each successive generation of
    cells.
  • - The cell up-regulates telomerase expression in
    order to regain
  • stability and survive.

Alberts, B. et al., Molecular Biology of the
Cell, 4th Ed., Garland Science, 2002, p. 1348.
9
Targeting Telomerase as an Anticancer Drug
Approach
  • Targeting the protein/RNA subunit
  • Mouse models
  • Specificity?

10
Alberts, B. et al., Molecular Biology of the
Cell, 4th Ed., Garland Science, 2002, p. 264.
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