Fig. 1

Schematic representation of different healthy and pathological telomeric states. The figure shows the changes of the telomere structure from a capped telomere to neoplastic transformations (from top to bottom). The t-loop structure, as several proteins that play a role at telomeres, are not shown for sake of clarity. Capped telomere: the shelterin complex protect telomeres from DNA damage response and from DNA repair pathways. Telomeric chromatin is maintained in a hypoacetylated, heterochromatic form by the action of the deacetylase SIRT6, ATRX promotes the incorporation of histone H3.3 and resolves G-quadruplex structures and R-loops. Deprotected telomere: telomere shortening leads to the disruption of the closed conformation and to the activation of DDR signaling. Cells undergo a growth arrest named replicative senescence or M1 (mortality stage 1). There is still enough shelterin proteins to block non-homologous end joining (NHEJ) and homologous recombination (HR) pathways. Uncapped state: Inactivation of growth arrest checkpoint (p53) allows cells to bypass M1. This leads to excessive telomere shortening, until cells reach a state termed crisis (or M2) characterized by extensive cell death. Telomeres are fully uncapped, loss of shelterin leads to activation of DNA repair pathways, resulting in telomeric fusions. Rarely, premalignant cells escape from crisis acquiring a telomere maintenance mechanism that permits unlimited proliferation. In most cases, by reactivating telomerase (on the left); 10–15% tumors develop an alternative mechanism named ALT (on the right), characterized by high TERRA levels, R-loops, DDR, and maintenance of telomere length by homologous recombination