Telomere shortening triggers a p53-dependent cell cycle arrest via accumulation of G-rich single stranded DNA fragments

Abstract

It has been repeatedly suspected that telomere shortening might be one possible trigger of the p53-dependent cell cycle arrest, although the mechanism of this arrest remained unclear. Telomeres in human cells under mild oxidative stress accumulate single-strand damage faster than interstitial repetitive sequences. In MRC-5 ®bro-blasts and U87 glioblastoma cells, which both express wild-type p53, oxidative stress-mediated production of single-strand damage in telomeres is concomitant to the accumulation of p53 and p21 and to cell cycle arrest. This response can be modeled by treatment of cells with short single stranded telomeric G-rich DNA fragments. The arrest is transient in U87 cells. Recovery from it is accompanied by up-regulation of telomerase activity and elongation of telomeres. Overexpression of mutated p53 is su cient to reverse the phenotype of inhibition as well as the delayed activation of telomerase. These data suggest that the production of G-rich single stranded fragments during the course of telomere shortening is su cient to trigger a p53 dependent cell cycle arrest.

Short Telomeres in Patients with Vascular Dementia: An Indicator of Low Antioxidative Capacity and a Possible Risk Factor?

“…Still, the correlation between both parameters is statistically significant. This result is in accordance with previous data showing a dependency of the telomere shortening rate on hyperoxia-, hydrogen peroxide-, or alkylationmediated stresses (Saretzki et al, 1999;Vaziri et al 1997;von Zglinicki et al, 1995von Zglinicki et al, , 2000. It is further in von Zglinicki et al accordance with observations indicating a correlation between telomere shortening rates in fibroblasts and the expression of the two major antioxidative enzymes, glutathione peroxidase and CuZn-superoxide dismutase (Serra et al, 2000).…”

“…Both the inability of DNA polymerases to replicate a linear DNA molecule to its very end (Olovnikov, 1973) and the action of a strand-specific exonuclease (Makarov et al, 1997;Wellinger et al, 1996) contribute to the shortening of telomeres. We have identified telomere-specific accumulation of DNA single-strand damage caused by oxygen free radicals as the major cause of telomere shortening in human fibroblasts in vitro by demonstrating that (a) telomeres in nonproliferating cells accumulate singlestrand breaks because of a specific deficiency in base excision repair (Petersen et al, 1998;von Zglinicki et al, 2000), (b) these breaks result in telomere shortening during DNA replication (Sitte et al, 1998), probably by transiently stalling the replication fork (von Zglinicki, 2000), (c) oxidative stress increases the telomere shortening rate by up to one order of magnitude (Saretzki et al, 1999;von Zglinicki et al, 1995von Zglinicki et al, , 2000, (d) diminution of oxidative stress slows down the rate of telomere shortening and decelerates replicative senescence (Sitte et al, 1998), (e) the telomere shortening rate correlates with the cell strain-specific antioxidative capacity (Serra et al, 2000). Some of these results were reproduced by others (Furumoto et al, 1998;Vaziri et al, 1997).…”

Water‐soluble C60 fullerene prevents degeneration of articular cartilage in osteoarthritis via down‐regulation of chondrocyte catabolic activity and inhibition of cartilage degeneration during disease development

“…It has been reported that oxygen-derived free radicals directly damage the guanine repeats in the telomere DNA (24)(25)(26)(27). This means that oxidative stress leads to telomere erosion, with no requirement for cell division, resulting in cellular senescence.…”

Successful Immortalization of Endometrial Glandular Cells with Normal Structural and Functional Characteristics

“…Critically short telomeres arising after a considerable number of cell divisions induce specific signals for cell-cycle arrest via DNA damage check point, resulting in replicative senescence of cells. 8,9 Telomerase is a ribonucleo-protein complex that extends and maintains the telomeres. Activation of this enzyme is therefore required for cells to overcome replicative senescence and obtain the ability to divide without limit.…”

“…Critically short telomeres arising after a considerable number of cell divisions induce specific signals for cell-cycle arrest via DNA damage check point, resulting in replicative senescence of cells. 8,9 Telomerase is a ribonucleo- …”