Telomere Terminal Transferase and its Role in Cancer Brian R. Keppler February 27, 2003.
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Transcript of Telomere Terminal Transferase and its Role in Cancer Brian R. Keppler February 27, 2003.
![Page 1: Telomere Terminal Transferase and its Role in Cancer Brian R. Keppler February 27, 2003.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649eb55503460f94bbe136/html5/thumbnails/1.jpg)
Telomere Terminal Transferase and its Role in Cancer
Brian R. Keppler
February 27, 2003
![Page 2: Telomere Terminal Transferase and its Role in Cancer Brian R. Keppler February 27, 2003.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649eb55503460f94bbe136/html5/thumbnails/2.jpg)
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.
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DNA Replication
Semi-conservative
Bi-directional
Occurs in the 5’ to 3’ direction only
Leading strand is synthesized continuously
Lagging strand is synthesized discontinuously
- Can’t replicate to entirety- Gradually shortens
Lodish, H. et al., Molecular Cell Biolgy, 4th Ed., Freeman Publishing, 2000, p.461.
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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.
Organism Telomeric DNA sequence RNA template 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
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Proposed “Rough” Model of Telomerase
Alberts, B. et al., Molecular Biology of the Cell, 4th Ed., Garland Science, 2002, p. 264.
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Mechanism of Telomerase Action
Lodish, H. et al., Molecular Cell Biolgy, 4th Ed., Freeman Publishing, 2000, p.466.
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Telomerase and Cancer
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
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.
Artandi, SE et al., Proc Natl Acad Sci U S A 2002 May 28
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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.
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Targeting Telomerase as an Anticancer Drug Approach
Targeting the protein/RNA subunit
Mouse models
Specificity?