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

It has been repeatedly suspected that telomere shortening might be one poss ible trigger of the p53-dependent cell cycle arrest, although the mechanism of this arrest remained unclear. Telomeres in human cells under mild oxida tive stress accumulate single-strand damage faster than interstitial repeti tive sequences, In MRC-5 fibroblasts and U87 glioblastoma cells, which both express wild-type p53, oxidative stress-mediated production of single-stra nd damage in telomeres is concomitant to the accumulation of p53 and p21 an d 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 tr ansient in U87 cells. Recovery from it is accompanied by up-regulation of t elomerase activity and elongation of telomeres, Overexpression of mutated p 53 is sufficient to reverse the phenotype of inhibition as well as the dela yed activation of telomerase, These data suggest that the production of G-r ich single stranded fragments during the course of telomere shortening is s ufficient to trigger a p53 dependent cell cycle arrest.