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Fig. 2 | Genome Medicine

Fig. 2

From: Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies

Fig. 2

Cellular senescence and crisis. Telomeres protect chromosome ends from undergoing fusions and recombination by masking telomeric DNA with shelterin protein protective caps, preventing the ends from being recognized by the DNA damage surveillance pathways. 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

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