Transcript Telomere Structure and Function

Telomeres and Telomerase
in Cancer Development
20 March 2008
Hannah Yin
(www.biovita.fi)
Telomere Structure and Function
Specialized chromosomal terminal structures – caps that guard the
chromosome from recognition as a product of DNA fragmentation
Regulate chromosomal integrity and cell life span
(Hahn, 2003)
DNA End Replication
and Telomere Shortening
(Wikipedia.com)
(universe-review.ca)
Telomerase Structure and Function
Reverse
transcriptase
heterotetramer
hTERC: RNA template portion
hTERT: DNA polymerase enzymatic portion
(Hahn, 2003)
Telomeres and Telomerase
in Normal vs. Immortal Cells
In normal presenescent human cells
- Telomerase activity is repressed
- Telomeres shorten with successive cell
divisions
- Limited proliferative capacity in culture
(Amazon.com)
Hayflick
Limit
In cancer cell lines
- Telomerase activity maintains
stable telomere lengths
- Unlimited replicative potential
IMMORTALIZATION
Cells must…
Overcome replicative senescence
AND
Escape regulation of the cell cycle
Telomerase activity is NECESSARY…
…but
NOT
SUFFICIENT
The Path to Immortality
(Hahn, 2003)
Paradigm: Telomerase and Cancer
(Hahn, 2003)
What happens if we Knock Out Telomerase?
(Blasco, et al, 1997)
Diagnostics
(Eiso Hiyama & Keiko Hiyama, 2002)
Therapeutics
– Small molecule inhibitors of telomerase reverse transcriptase
RTIs already exist for treatment of HIV!
– Specific inhibitors that target the active site of telomerase
BIBR1532, a synthetic, non-nucleosidic drug
(Pascolo et al, 2002)
– Cellular immunotherapy
“Data from both human and murine systems demonstrate
that cytotoxic T-lymphocytes (CTL) can recognize peptides derived
from TERT and kill TERT-positive tumor cells of multiple histologies.
Given the vast overexpression of hTERT in human tumors and its lowlevel expression in rare normal tissues, clinical trials have begun that
test the credentials of hTERT as a broadly applicable target for
immunotherapy of cancer.”
(Vonderheide, 2002)
Considerations
• Telomere lengths vary widely among different cancer cells,
and the mechanisms that control the length of telomeres in
cancer cells are not yet understood
• Selection of non-telomerase-based mechanisms of telomere
maintenance after prolonged treatment with telomerase
inhibitors (evidence of ALT pathways)
• Some normal cells, including those with stem cell-like
properties, retain the ability to activate telomerase
physiologically  side effects of long-term treatment with
telomerase inhibitor or immunotherapy??
Big Picture
“Increasing our understanding of telomere
biology will not only identify targets for drug
development but will also aid the efficient
design of clinical trials to identify effective
anti-telomere- and antitelomerase-based
therapies.” (Hahn, 2003)
(www.lbl.gov)
(GeneticsAndHealth.com)