Figure 7.

A multistep model defining entry into telomere-mediated senescence. The top panel highlights that telomere shortening leads to uncapping and the apparition of TIF (red star). Cells with TU are susceptible for sporadic sister chromatid fusions mediated by HR. As cells sustain and tolerate TIF, additional divisions with dysfunctional and potentially fused telomeres lead to abnormal chromosomal segregation, genomic instability and random secondary non-TIF DSBs (green star), which are the true inducers of a strong DDR and a stable senescence-associated proliferation arrest. The bottom panel represent an alignment between the time course of EdU proliferation and the timeline of 53BP1 DDF formation. We conclude that telomere-induced senescence initiates with a weak and transient DDR via TIF formation eventually followed by a stable senescence arrest associated with secondary non-telomeric (non-TIF) DNA lesions.