Puma and p21 represent cooperating checkpoints limiting self-renewal and chromosomal instability of somatic stem cells in response to telomere dysfunction.
|核心內(nèi)容：
腫瘤抑制因子p53激活依賴于Puma的細(xì)胞凋亡和依賴于p21的細(xì)胞周期停滯，以響應(yīng)DNA損傷。
P21的缺失改善了端粒功能障礙的孕鼠的干細(xì)胞功能和器官維護(hù)，但Puma的功能尚未在此背景下進(jìn)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(xì)胞和祖細(xì)胞功能、器官維護(hù)和壽命。
P53抑癌基因本來是好的，其下游P21和Puma對(duì)于細(xì)胞的生理活動(dòng)，特別是增殖來說都是冷卻因素；但是在干細(xì)胞中這兩種冷卻因素確實(shí)不好的。這暗示干細(xì)胞可能有更豐富的DNA損傷修復(fù)方式，或者說干細(xì)胞并不在乎這種損傷。
美洲獅的缺失損害了干細(xì)胞和祖細(xì)胞的清除，這些干細(xì)胞和祖細(xì)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(xì)胞中的進(jìn)一步積累導(dǎo)致p21的激活增加。RNA干擾實(shí)驗(yàn)表明，p21的上調(diào)限制了端粒功能異常的彪馬缺陷干細(xì)胞和祖細(xì)胞染色體失衡的增殖和進(jìn)化。這些結(jié)果提供了實(shí)驗(yàn)證據(jù)，表明p53依賴的細(xì)胞凋亡和細(xì)胞周期停滯在協(xié)同檢查點(diǎn)中起作用，限制了干細(xì)胞和祖細(xì)胞水平上染色體不穩(wěn)定的組織維持和進(jìn)化，以響應(yīng)端粒功能障礙。選擇性抑制彪馬依賴性細(xì)胞凋亡可以暫時(shí)改善端粒功能障礙器官的維持。
原文摘要：
The tumour suppressor p53 activates Puma-dependent apoptosis and p21-dependent cell-cycle arrest in response to DNA damage.
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(xiàn)：https://www.uni-ulm.de/fileadmin/website_uni_ulm/med.inst.010/bliss-pdf/Sperkaetal_natcellbiol_puma_2011.pdf
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