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
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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DOI：
10.1093/emboj/16.19.6018
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发表时间：
1997-10-01
期刊：
影响因子：
11.4
通讯作者：
Benchimol, S
中科院分区：
文献类型：
--
作者：
Vaziri, H;West, MD;Benchimol, S
端粒丢失被认为是正常体细胞衰老过程中计算细胞分裂的一种机制，但这种有丝分裂时钟如何启动细胞内信号事件，最终导致G(1)细胞周期停滞和衰老，从而限制正常人类细胞的寿命尚不清楚。我们研究了衰老细胞中极短的端粒长度激活涉及p53和p21（WAF1）的DNA损伤反应途径的可能性。我们发现p53蛋白的DNA结合和转录活性随着细胞年龄的增长而增加，而p53蛋白的水平没有任何明显的增加，衰老细胞中的p21（WAF1）启动子活性依赖于p53和转录共激活因子p300。此外，我们检测到AT成纤维细胞中p53蛋白的特异性活性增加，与正常成纤维细胞相比，AT成纤维细胞表现出加速的端粒丢失和过早衰老。我们研究了多聚（adp -核糖）聚合酶参与衰老细胞中p53蛋白翻译后激活的可能性，我们发现p53蛋白可以与PARP相关，抑制PARP活性导致p21和mdma表达减少，以应对DNA损伤，此外，抑制PARP活性导致细胞寿命延长，相反，高氧，PARP的激活剂，与加速端粒丢失有关。我们认为，p53不仅在DNA损伤的反应中被翻译后激活，而且在细胞衰老过程中端粒的关键缩短时也被激活。
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 G(1) 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 mdma 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.