A DNA damage checkpoint response in telomere-initiated senescence
A DNA damage checkpoint response in telomere-initiated senescence
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DOI：
10.1038/nature02118
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发表时间：
2003-11-13
期刊：
影响因子：
64.8
通讯作者：
Jackson, SP
中科院分区：
文献类型：
--
作者：
di Fagagna, FD;Reaper, PM;Jackson, SP
大多数人体细胞在体外只能经历有限数量的群体倍增（1）。当端粒（线性染色体的末端）不能完成其正常的保护功能时，就会引发这种增殖潜能的耗尽，称为衰老。在这里，我们表明，衰老的人成纤维细胞显示的分子标记特征的细胞轴承DNA双链断裂。这些标记物包括磷酸化组蛋白H2AX的核灶及其与DNA修复和DNA损伤检查点因子如53BP1、MDC 1和NBS1的共定位。我们还表明，衰老细胞含有激活形式的DNA损伤检查点激酶CHK1和CHK2。此外，通过染色质免疫沉淀和全基因组扫描的方法，我们表明，衰老细胞的染色体末端直接有助于DNA损伤反应，和未加帽的端粒直接与许多，但不是所有的，DNA损伤反应蛋白。最后，我们表明，在衰老细胞中的DNA损伤检查点激酶的失活可以恢复细胞周期进程进入S期。因此，我们认为端粒启动的衰老反映了DNA损伤检查点反应，该反应是由功能失调的端粒直接激活的。
Most human somatic cells can undergo only a limited number of population doublings in vitro(1). This exhaustion of proliferative potential, called senescence, can be triggered when telomeres the ends of linear chromosomes-cannot fulfil their normal protective functions. Here we show that senescent human fibroblasts display molecular markers characteristic of cells bearing DNA double-strand breaks. These markers include nuclear foci of phosphorylated histone H2AX and their co-localization with DNA repair and DNA damage checkpoint factors such as 53BP1, MDC1 and NBS1. We also show that senescent cells contain activated forms of the DNA damage checkpoint kinases CHK1 and CHK2. Furthermore, by chromatin immunoprecipitation and whole-genome scanning approaches, we show that the chromosome ends of senescent cells directly contribute to the DNA damage response, and that uncapped telomeres directly associate with many, but not all, DNA damage response proteins. Finally, we show that inactivation of DNA damage checkpoint kinases in senescent cells can restore cell-cycle progression into S phase. Thus, we propose that telomere-initiated senescence reflects a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres.