ATM-dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the post-translational activation of p53 protein involving poly(ADP-ribose) polymerase
| Autor: | Yu-Sung Wu, Timothy S. Davison, Michael D. West, Samuel Benchimol, Cheryl H. Arrowsmith, Guy G. Poirier, Homayoun Vaziri, Richard C. Allsopp |
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| Rok vydání: | 1997 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Senescence DNA damage Poly ADP ribose polymerase Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases Biology General Biochemistry Genetics and Molecular Biology Cyclins Humans Enzyme Inhibitors Nuclear protein Promoter Regions Genetic Molecular Biology Mitosis Transcription factor Alleles Cells Cultured Cellular Senescence General Immunology and Microbiology Tumor Suppressor Proteins General Neuroscience Nuclear Proteins Proteins DNA Fibroblasts Telomere Molecular biology DNA-Binding Proteins Oxygen Trans-Activators Poly(ADP-ribose) Polymerases Tumor Suppressor Protein p53 Protein Processing Post-Translational Cell aging Research Article DNA Damage Transcription Factors |
| Zdroj: | The EMBO Journal. 16:6018-6033 |
| ISSN: | 1460-2075 0261-4189 |
| DOI: | 10.1093/emboj/16.19.6018 |
| Popis: | Telomere loss has been proposed as a mechanism for counting cell divisions during aging in normal somatic cells. How such a mitotic clock initiates the intracellular signalling events that culminate in G1 cell cycle arrest and senescence to restrict the lifespan of normal human cells is not known. We investigated the possibility that critically short telomere length activates a DNA damage response pathway involving p53 and p21(WAF1) in aging cells. We show that the DNA binding and transcriptional activity of p53 protein increases with cell age in the absence of any marked increase in the level of p53 protein, and that p21(WAF1) promoter activity in senescent cells is dependent on both p53 and the transcriptional co-activator p300. Moreover, we detected increased specific activity of p53 protein in AT fibroblasts, which exhibit accelerated telomere loss and undergo premature senescence, compared with normal fibroblasts. We investigated the possibility that poly(ADP-ribose) polymerase is involved in the post-translational activation of p53 protein in aging cells. We show that p53 protein can associate with PARP and inhibition of PARP activity leads to abrogation of p21 and mdm2 expression in response to DNA damage. Moreover, inhibition of PARP activity leads to extension of cellular lifespan. In contrast, hyperoxia, an activator of PARP, is associated with accelerated telomere loss, activation of p53 and premature senescence. We propose that p53 is post-translationally activated not only in response to DNA damage but also in response to the critical shortening of telomeres that occurs during cellular aging. |
| Databáze: | OpenAIRE |
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