FIGURE 2. Telomere shortening, senescence and cancer.

Primary cells divide exponentially, and telomeres shorten from 15 kilobases (kb) until they reach a critical length, 4–6 kb. Irreversible cell-cycle arrest then occurs (blue). Activation of telomerase before senescence allows cells to divide indefinitely and maintain a stable genome (green). If, instead, the p53 and RB1 pathways are suppressed, cells continue dividing (orange) until end protection is completely lost, resulting in telomeric crisis, cell death and massive genomic instability (dark pink). If telomerase is activated before erosion is complete, this rescues the genome from instability by re-establishing telomere maintenance (light pink). Activation of telomerase after the accumulation of mutations results in an unstable genome, allowing clones that carry multiple mutations to escape cell death (that is, to become immortal). Such cells are predisposed to oncogenic transformation (brown). PD, population doublings.