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Blockade of telomerase function by nucleoside analogs
Y E Yegorov1, D N Chernov, S S Akimov
1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia. yegorov@genome.eimb.rssi.ru
Biochemistry. Biokhimiia
|February 19, 1998
Summary
Senescent cells can become immortal through telomerase activation, even when treated with reverse transcriptase inhibitors. This study explores the mechanisms of cellular senescence and immortalization in fibroblasts and myoblasts.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Cellular senescence is a state of irreversible growth arrest.
- Telomeres, protective caps at the ends of chromosomes, shorten with each cell division.
- Telomerase is an enzyme that can maintain telomere length.
Purpose of the Study:
- To investigate the mechanisms of spontaneous cellular transformation and immortalization in mouse embryonic fibroblasts.
- To examine the role of telomerase activity in overcoming senescence.
- To explore the effects of reverse transcriptase inhibitors on senescence and telomere length.
Main Methods:
- Culture of senescent mouse embryonic fibroblasts and rat myoblasts.
- Treatment with reverse transcriptase inhibitors (azidothymidine, carbovir).
- Analysis of cell proliferation, senescence, telomerase activity, and telomere length.
Main Results:
- Two types of transformed cells emerged: limited proliferative potential and immortalized cells.
- Telomerase-free clones were generated in the presence of inhibitors.
- A fraction of clones overcame senescence by acquiring high telomerase activity, becoming resistant to inhibitors.
- Azidothymidine induced senescence in rat myoblasts with morphological changes.
- In human cells, telomere shortening occurred without senescence.
Conclusions:
- Cellular senescence can be overcome by acquiring telomerase activity, leading to immortalization.
- Telomerase-independent senescence may involve changes in telomeric chromatin structure.
- The response to telomere shortening and senescence induction varies across cell types.