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.