Senescence and Immortalization: Relationships to Telomeres and Telomerase

Cellular senescence is a general stress‐response program that restrains cellular proliferation. Under optimal growth conditions, the onset of senescence depends on telomere status. There is not a sentinel short human telomere that triggers senescence but a group of about 10% of the shortest telomeres that are involved. When a few telomeres are sufficiently short (uncapped), a DNA damage response‐induced growth arrest occurs. The senescence pathway involves the formation of telomere dysfunction induced foci that contain DNA damage response factors, such as 53BP1, gamma‐H2AX, and the Mre11complex. The signaling pathway responsible for establishing a senescent state in such cells involves primarily ATM, Chk1/Chk2 and p53, leading to a G1 phase arrest. Importantly, the DNA‐damage response observed in senescent cells is not a transient phenomenon, but consists of a permanent activation of the DNA damage checkpoint machinery. The long‐term growth arrest at senescence may be thought of as an initial anti‐tumor protection mechanism. In situations where normal cell cycle checkpoints are altered, cells can bypass the normal senescence signaling pathway and continue to grow until they reach a second growth arrest state known as crisis. In crisis, telomeres are terminally short and, in the presence of other genetic and epigenetic changes, can result in telomeric fusions, subsequent breakage‐fusion‐bridge cycles and in rare cells, up‐regulation or reactivation of telomerase, the cellular RNP that is able to add telomeric repeats to the ends of chromosomes and thus prevent their shortening. In both senescence and crisis ectopic expression of the catalytic subunit of telomerase (hTERT) leads directly to an immortal state demonstrating that telomeres are important in both replicative senescence and crisis.