2. Pre-requisites
◦ Normal animal cells undergo Replicative senescence after about 50 cycles of cell division when
examined on plate.
◦ This is due to the shortening of telomeres.
◦ Young cells have longer telomeres than older cells.
◦ Telomeres = 5000-15000 base pair repeats of : TTAGGG
◦ With each cell division 50-100 bp are lost, multiplied by 50(ie., 50 cycles)
REPLICATIVE SENESCENCE
3. INTRODUCTION
◦ In vivo, telomere length is maintained by telomerase.
◦ Telomerase = Ribonucleoprotein = Protein(Reverse transcriptase) + RNA
◦ This reverse transcriptase is called; hTERT
◦ hTERT reads RNA template and adds TTAGGG repeats to make the ends of
chromosomes(Telomeres).
◦ Telomerase activity is prevalent in pluripotent cells.
◦ Telomerase activity is turned off in differentiated cells.
4. Telomerase in cancer cells
◦ Gets reactivated
Activating proliferative capacity
◦ This happens 85-90% of the times
◦ 10-15% of times, telomerase activity remains undetected.
◦ Mechanism of cancer development from normal cells is explained on next slide.
5.
6. Telomerase as target for
chemotherapeutic agents
◦ Telomerase has the potential to be the target for cancer treatment.
◦ But, the research is in infancy.
◦ Chemotherapeutic agents, so far found are not specific for only cancer cell telomerase.
◦ They also affect the telomerase of hematopoietic and other pluripotent essential cells,
Negatively.
Telomere shortening is a natural consequence of cell division due to the “end replication problem” whereby lagging strand DNA synthesis cannot be completed all the way to the very end, and increased cell divisions lead to critically shortened telomeres which elicit DNA damage responses that trigger cellular senescence. In the cells undergoing replicative senescence, the p53 and p16–RB pathways are often activated leading to essentially irreversible growth arrest. Cells that gain additional oncogenic changes (p53 loss) can bypass senescence and continue to divide until multiple critically shortened telomeres initiate crisis, a period of increased chromosome end-to-end fusions and extensive cell death. Only a rare human cell (one in 105 to 107) can engage a mechanism to bypass crisis and become immortal. This is almost universally accomplished by the upregulation or reactivation of telomerase. A rarer telomerase negative immortalization pathway, termed ALT (alternative lengthening of telomeres), involves DNA recombination to maintain telomeres