ATM-DEPENDENT TELOMERE LOSS IN AGING HUMAN-DIPLOID FIBROBLASTS AND DNA-DAMAGE LEAD TO THE POSTTRANSLATIONAL ACTIVATION OF P53 PROTEIN INVOLVING POLY(ADP-RIBOSE) POLYMERASE

Telomere loss has been proposed as a mechanism for counting cell divis ions during aging in normal somatic cells, How such a mitotic clock in itiates the intracellular signalling events that culminate in G(1) cel l cycle arrest and senescence to restrict the lifespan of normal human cells is not known, We investigated the possibility that critically s hort telomere length activates a DNA damage response pathway involving p53 and p21(WAF1) in aging cells, We show that the DNA binding and tr anscriptional activity of p53 protein increases with cell age in the a bsence of any marked increase in the level of p53 protein, and that p2 1(WAF1) promoter activity in senescent cells is dependent on both p53 and the transcriptional co-activator p300, Moreover, we detected incre ased 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 o f p53 protein in aging cells, We show that p53 protein can associate w ith PARP and inhibition of PARP activity leads to abrogation of p21 an d mdma expression in response to DNA damage, Moreover, inhibition of P ARP activity leads to extension of cellular lifespan, In contrast, hyp eroxia, 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 b ut also in response to the critical shortening of telomeres that occur s during cellular aging.