01The end-replication problem
DNA polymerase can't fully copy the very ends of linear chromosomes, so each division shortens the telomeres — repetitive TTAGGG caps. After roughly 50 divisions (the Hayflick limit), short telomeres trigger p53-dependent senescence, a permanent arrest.
If p53 and Rb are disabled, cells keep dividing until telomeres become critically short and chromosomes fuse — a crisis that kills most cells but scrambles the genome of survivors.
02Telomerase reactivation
About 85–90% of cancers escape by reactivating telomerase, an enzyme with a protein subunit (TERT) and an RNA template that rebuilds telomere repeats. TERT promoter mutations are among the most common noncoding mutations in cancer (melanoma, glioblastoma, bladder).
The remaining 10–15% use ALT (alternative lengthening of telomeres), copying telomere sequence by recombination.