Puma and p21 represent cooperating checkpoints limiting self-renewal and chromosomal instability of somatic stem cells in response to telomere dysfunction
Puma and p21 represent cooperating checkpoints limiting self-renewal and chromosomal instability of somatic stem cells in response to telomere dysfunction
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DOI：
10.1038/ncb2388
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发表时间：
2011-12
影响因子：
21.3
通讯作者：
Tobias Sperka;Zhangfa Song;Zhangfa Song;Yohei Morita;Kodandaramireddy Nalapareddy;Luis M. Guachalla;A. Lechel;Yvonne begus-Nahrmann;M. Burkhalter;M. Mach;Falk Schlaudraff;B. Liss;Z. Ju;M. Speicher;K. Rudolph
中科院分区：
文献类型：
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作者：
Tobias Sperka;Zhangfa Song;Zhangfa Song;Yohei Morita;Kodandaramireddy Nalapareddy;Luis M. Guachalla;A. Lechel;Yvonne begus-Nahrmann;M. Burkhalter;M. Mach;Falk Schlaudraff;B. Liss;Z. Ju;M. Speicher;K. Rudolph
肿瘤抑制因子p53激活puma依赖性细胞凋亡和p21依赖性细胞周期阻滞，以响应DNA损伤。缺失p21可以改善端粒功能失调的类早衰小鼠的干细胞功能和器官维护，但Puma的功能尚未在此背景下进行研究。本研究表明，删除puma可改善端粒功能失调小鼠的干细胞和祖细胞功能、器官维护和寿命。短端粒缺失损害了干细胞和祖细胞的清除，这些细胞由于端粒极短而积累了DNA损伤。然而，在这些获救的祖细胞中DNA损伤的进一步积累导致p21的激活增加。RNA干扰实验表明，p21的上调限制了端粒功能失调的puma缺陷干细胞和祖细胞染色体不平衡的增殖和进化。这些结果提供了实验证据，证明p53依赖性凋亡和细胞周期阻滞在合作检查点中起作用，限制了端粒功能障碍时干细胞和祖细胞水平的组织维持和染色体不稳定性的进化。选择性抑制puma依赖性细胞凋亡可以暂时改善端粒功能失调器官的维持。
The tumour suppressor p53 activates Puma-dependent apoptosis and p21-dependent cell-cycle arrest in response to DNA damage. Deletion ofp21improved stem-cell function and organ maintenance in progeroid mice with dysfunctional telomeres, but the function of Puma has not been investigated in this context. Here we show that deletion ofPumaimproves stem- and progenitor-cell function, organ maintenance and lifespan of telomere-dysfunctional mice.Pumadeletion impairs the clearance of stem and progenitor cells that have accumulated DNA damage as a consequence of critically short telomeres. However, further accumulation of DNA damage in these rescued progenitor cells leads to increasing activation of p21. RNA interference experiments show that upregulation of p21 limits proliferation and evolution of chromosomal imbalances of Puma-deficient stem and progenitor cells with dysfunctional telomeres. These results provide experimental evidence that p53-dependent apoptosis and cell-cycle arrest act in cooperating checkpoints limiting tissue maintenance and evolution of chromosomal instability at stem- and progenitor-cell levels in response to telomere dysfunction. Selective inhibition of Puma-dependent apoptosis can result in temporary improvements in maintenance of telomere-dysfunctional organs.