Puma and p21 represent cooperating checkpoints limiting self-renewal and chromosomal instability of somatic stem cells in response to telomere dysfunction.
|核心內容：
腫瘤抑制因子p53激活依賴于Puma 的細胞凋亡和依賴于p21的細胞周期停滯，以響應DNA損傷。 P21的缺失改善了端粒功能障礙的孕鼠的干細胞功能和器官維護，但Puma 的功能尚未在此背景下進行研究。 在這里，我們證明了Puma基因的缺失改善了端粒功能障礙小鼠的干細胞和祖細胞功能、器官維護和壽命。 P53抑癌基因本來是好的，其下游P21和Puma對于細胞的生理活動，特別是增殖來說都是冷卻因素；但是在干細胞中這兩種冷卻因素確實不好的。這暗示干細胞可能有更豐富的DNA損傷修復方式，或者說干細胞并不在乎這種損傷。
美洲獅的缺失損害了干細胞和祖細胞的清除，這些干細胞和祖細胞由于端粒過短而積累了DNA損傷。然而，DNA損傷在這些被挽救的祖細胞中的進一步積累導致p21的激活增加。RNA干擾實驗表明，p21的上調限制了端粒功能異常的彪馬缺陷干細胞和祖細胞染色體失衡的增殖和進化。這些結果提供了實驗證據(jù)，表明p53依賴的細胞凋亡和細胞周期停滯在協(xié)同檢查點中起作用，限制了干細胞和祖細胞水平上染色體不穩(wěn)定的組織維持和進化，以響應端粒功能障礙。選擇性抑制彪馬依賴性細胞凋亡可以暫時改善端粒功能障礙器官的維持。
Deletion of p21 improved stem-cell function and organ maintenance in progeroid mice with dysfunctional telomeres, but the function of Puma has not been investigated in this context.
P21 is responsible for the cell genome stablility by stopping cell proliferation while genome is damaging，its original intention is to decrease the damage in genome. But, the DNA damage is high in stem cell? or DNA damage is allowed in stem cell(because high r-H2A.X is detected in stem cell)?
Here we show that deletion of Puma improves stem- and progenitor-cell function, organ maintenance and lifespan of telomere-dysfunctional mice. Puma deletion 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.
參考文獻：https://www./fileadmin/website_uni_ulm/med.inst.010/bliss-pdf/Sperkaetal_natcellbiol_puma_2011.pdf
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