Telomere dysfunction and tumour suppression: the senescence connection

Key Points Telomeres are TTAGGG repetitive sequences that cap the ends of eukaryotic chromosomes. A core of telomere binding proteins, termed the shelterin complex, serve to protect telomeric ends. Critical telomere shortening or uncapping of telomere binding proteins results in telomere dysfunction. Dysfunctional telomeres activate a DNA damage response. In the setting of a competent p53 pathway, this initiates senescence and apoptotic programmes to inhibit tumorigenesis. In cells with mutant p53, dysfunctional telomeres promote genome instability and progression to cancer. Cellular senescence is as potent as apoptosis in suppressing spontaneous tumorigenesis in mouse models of telomere dysfunction. Using recent evidence from mouse models, this Review discusses whether p53-dependent senescence induced by dysfunctional telomeres is as potent as apoptosis in suppressing tumorigenesis in vivo . Long-lived organisms such as humans have evolved several intrinsic tumour suppressor mechanisms to combat the slew of oncogenic somatic mutations that constantly arise in proliferating stem-cell compartments. One of these anticancer barriers is the telomere, a specialized nucleoprotein complex that caps the ends of eukaryotic chromosome. Impaired telomere function activates the canonical DNA damage response pathway that engages p53 to initiate apoptosis or replicative senescence. Here, we discuss how p53-dependent senescence induced by dysfunctional telomeres may be as potent as apoptosis in suppressing tumorigenesis in vivo .