Figure 3. Telomere crisis.

Loss of the RB and p53 tumour suppressor pathways disables the ability of cells to respond with cell cycle arrest to ATR and ATM signalling. As the cells continue to divide, their telomeres continue to shorten. Once many telomeres become too short to function, the unprotected chromosome ends generate end-to-end fusions and dicentric chromosomes, leading to many forms of genome instability. Ultimately, telomerase reactivation provides a route out of telomere crisis by healing critically shortened telomeres and improving genomic stability, thereby increasing cell viability. The resulting tumour will have active telomerase and a heavily rearranged genome.