The replicometer is broken: telomeres activate cellular senescence in response to genotoxic stresses

Abstract

Telomeres, the ends of our linear chromosomes, can function as 'replicometers', capable of counting cell division cycles as they progressively erode with every round of DNA replication. Once they are critically short, telomeres become dysfunctional and consequently activate a proliferative arrest called replicative senescence. For many years, telomeres were thought to be autonomous structures, largely isolated from cell intrinsic and extrinsic signals, whose function is to prevent limitless cellular proliferation, a characteristic of most cancer cells. It is becoming increasingly evident, however, that telomeres not only count cell divisions, but also function as sensors of genotoxic stresses to stop cell cycle progression prematurely and long before cells would have entered replicative senescence. This stable growth arrest, triggered by dysfunctional telomeres that are not necessarily critically short, likely evolved as a tumor-suppressing mechanism as it prevents proliferation of cells that are at risk for acquiring potentially hazardous and transforming mutations both in vitro and in vivo. Here, we review studies supporting the concept that telomeres are important cellular structures whose function not only is to count cell divisions, but also to act as molecular switches that can rapidly stop cell cycle progression permanently in response to a variety of stresses, including oncogenic signals.

Keywords: DNA damage; aging; cellular senescence; hTERT; p53; telomerase; telomere; tumor suppression.

Figure 1

Telomerase protects cells from telomere dysfunction in response to DNA replication stress. (A) Progressive and moderate telomere erosion is observed following each cell division cycle. This is due to a combination of factors including the end replication problem, nucleolytic processing of chromosome ends, aberrant telomeric homologous recombination events, and oxidative damage, among others. Once telomeres are critically short, they initiate replicative senescence (RS) (B) Certain oncogenes cause hyperproliferation, DNA replication stress, and replication fork stalling, including in telomeric repeats. Some stalled replication forks are converted into double-strand DNA breaks, causing the activation of a DNA damage response (DDR). While most chromosome internal breaks are repaired, telomeric breaks impede repair activities, resulting in persistent telomeric DDR activation and telomere dysfunction-induced senescence (TDIS). (C) In the presence of high telomerase activity, DNA replication stress does not result in TDIS. This may be due to an ability of telomerase to suppress a telomeric DDR, facilitate replication of telomeric repeats, or promote repair of telomeric DNA breaks.