Telomere uncapping at senescence. The nucleoprotein structure at the end of telomeres presumably forms a protective cap. This structure may be composed of the T-loop (a), which is formed by the invasion of the single-stranded overhang into an upstream double-stranded region of the telomere, and of protective telomere-binding proteins such as TRF1, TRF2, and POT1. As cells approach replicative senescence, the double-stranded portion of the telomere shortens, and the single-stranded overhang is eroded (b). This may cause the collapse of the telomere cap and the exposure of the telomere end, which is detected by the DNA damage machinery and leads to the activation of the senescence program (c). Telomerase activity, apart from stabilizing overall telomere length, can prevent overhang erosion and protect the telomere cap, thereby circumventing senescence (d). TERT, telomerase enzyme reverse transcriprase.