Figure 2.

Graphical representation of the different telomere states, characterized by different levels of telomeric proteins and post-translational modifications. Protected state: telomere is in a closed form, probably the t-loop, maintained by the binding with the shelterin proteins; the presence of trimethylation of histones H3 and H4, typical heterochromatic markers, induces a compacted state. This state inhibits the DNA damage response. Deprotected state: telomere shortening could disrupt the closed structure leading to an open state, characterized by a decrease of heterochromatic marks. Telomeres are recognized as DNA damage, signaled by phosphorylation of H2AX, but retain enough shelterin proteins (mainly TRF2) to prevent NHEJ and thus telomeric fusion. DNA damage signaling leads to replicative senescence. Dysfunctional state: if growth arrest checkpoint is inactivated, telomeres continue to shorten leading to a fully uncapped form, deriving from the depletion of shelterin proteins such as TRF2 or POT1. Telomere dysfunctions are signaled by phosphorylation of H2AX and the ubiquitylation of H2A and H2AX. Telomeres are not protected from the DNA damage response machinery, giving rise to extensive telomere fusions.