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| The EMBO Journal
(1997) 16, 6018–6033, doi:10.1093/emboj/16.19.6018 |
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| 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 |
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| Homayoun Vaziri1, Michael D. West2, Richard C. Allsopp2, Timothy S. Davison1, Yu-Sung Wu1, Cheryl H. Arrowsmith1, Guy G. Poirier3 and Samuel Benchimol1 |
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1 Ontario Cancer Institute and the Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9 2 Geron Corporation, 230 Constitution Drive, Menlo Park, CA 94025, USA 3 Poly(ADP-ribose) Metabolism Group, CHUL Research Centre, 9700, 2705, Boulevard Laurier, Québec, Canada G1V 4G2 Received 31 January 1997; Revised 20 June 1997. |
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| Abstract |
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| 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 p21WAF1 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 p21WAF1 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. |
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| Keywords: ATM, p53, p21WAF1, PARP, telomeres |
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