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 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 fibroblasts 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 sufficient 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 sufficient to trigger a p53 dependent cell cycle arrest.
Saretzki
G
G
Institute of Pathology, Charité. Schumannstrasse 20/21. 10098 Berlin, Germany.
Sitte
N
N
Merkel
U
U
Wurm
R E
RE
von Zglinicki
T
T
D000230:Adenocarcinoma / Q000473:pathology; D019943:Amino Acid Substitution; D001932:Brain Neoplasms / Q000473:pathology; D001943:Breast Neoplasms / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology*; D002461:Cell Line, Transformed; D053938:DNA Fragmentation; D004277:DNA, Single-Stranded / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D016158:Genes, p53; D005909:Glioblastoma / Q000473:pathology; D006147:Guanine / Q000032:analysis; D006801:Humans; D008168:Lung / Q000166:cytology; D009363:Neoplasm Proteins / Q000502:physiology; D010051:Ovarian Neoplasms / Q000473:pathology; D018384:Oxidative Stress; D017354:Point Mutation; D011993:Recombinant Fusion Proteins / Q000502:physiology; D019098:Telomerase / Q000502:physiology; D016615:Telomere / Q000737:chemistry / Q000648:ultrastructure*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D004277:DNA, Single-Stranded; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D006147:Guanine; D019098:Telomerase