Telomeres and Cell Senescence - Size Matters Not

Abstract

Telomeres are protective structures present at the ends of linear chromosomes that are important in preventing genome instability. Telomeres shorten as a result of cellular replication, leading to a permanent cell cycle arrest, also known as replicative senescence. Senescent cells have been shown to accumulate in mammalian tissue with age and in a number of age-related diseases, suggesting that they might contribute to the loss of tissue function observed with age. In this review, we will first describe evidence suggesting a key role for senescence in the ageing process and elaborate on some of the mechanisms by which telomeres can induce cellular senescence. Furthermore, we will present multiple lines of evidence suggesting that telomeres can act as sensors of both intrinsic and extrinsic stress as well as recent data indicating that telomere-induced senescence may occur irrespectively of the length of telomeres.

Keywords: Ageing; DNA damage; Senescence; Stress; Telomeres.

Fig. 1

Length-independent telomere damage. Telomere shortening that occurs naturally with each round of cell division ultimately leads to chromosome ends becoming exposed and activating a DNA damage response, which results in a permanent arrest known as replicative senescence. However, recent evidence suggests that telomeres may serve as highly sensitive sensors of stress. It is known that mild oxidative stress causes single-stranded breaks to accumulate at telomeres, leading to accelerate shortening and premature cell cycle arrest. However, it is possible that acute stresses induce telomeric double-stranded breaks which are not efficiently repaired. This results in a persistent DDR signaling, preventing cells from undergoing further rounds of replication irrespective of their telomere length, a state which can also be called “telomere length-independent senescence”.