p53與DNA形成的復(fù)合物示意圖,，圖片來(lái)自維基共享資源。
美國(guó)耶魯大學(xué)研究人員發(fā)現(xiàn)“基因組護(hù)衛(wèi)者(guardian of the genome)”如何在精子產(chǎn)生過(guò)程中和可能也在很多其他細(xì)胞中進(jìn)行質(zhì)量控制,。2012年2月16日，這項(xiàng)研究在線(xiàn)發(fā)表在《細(xì)胞》子刊Current Biology期刊上,，從而為開(kāi)發(fā)出新的節(jié)育和不育治療方法提供可能,，甚至為開(kāi)發(fā)出對(duì)抗很多癌癥類(lèi)型的新方法提供啟示。
精子和其他細(xì)胞經(jīng)歷著由一種關(guān)鍵性調(diào)節(jié)基因p53觸發(fā)的檢驗(yàn)過(guò)程,，因?yàn)閜53會(huì)下令摧毀DNA受損的細(xì)胞,。這種能力使得p53贏(yíng)得“基因組護(hù)衛(wèi)者”的頭銜，而且在很多癌癥類(lèi)型中p53都遭到破壞,。
耶魯大學(xué)干細(xì)胞研究中心主任和這篇論文的通訊作者林海帆(Haifan Lin)教授說(shuō),，通過(guò)研究小鼠精子產(chǎn)生，“我們鑒定出p53的新上司,，它控制p53的方式科學(xué)家們以前假設(shè)過(guò)但是沒(méi)有在任何一種動(dòng)物中得到證實(shí),。”
林海帆教授領(lǐng)導(dǎo)的耶魯大學(xué)研究小組在參與很多細(xì)胞過(guò)程的1500多種microRNA分子中發(fā)現(xiàn)一種稱(chēng)作Pumilo 1的調(diào)節(jié)物，它控制精子產(chǎn)生中與p53相互作用的8種蛋白,。當(dāng)小鼠Pumilo 1缺失時(shí),，精子產(chǎn)生能力和生育力下降，因?yàn)閜53過(guò)于活躍而下令摧毀太多的精子,。林教授注意到,，這一機(jī)制可能在男性生育力上發(fā)揮著關(guān)鍵性作用,，但是它可能也參與很多生物過(guò)程，畢竟保護(hù)DNA對(duì)生命而言是最為重要的,。
林教授說(shuō),，“這是一種非常重要的允許壞細(xì)胞而不是好細(xì)胞被殺死的把關(guān)機(jī)制。這種過(guò)程可能也在其他組織如癌癥中發(fā)揮著作用,。” (生物谷：towersimper編譯)
doi:10.1016/j.cub.2012.01.039
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Pumilio 1 Suppresses Multiple Activators of p53 to Safeguard Spermatogenesis
Dong Chen, Wei Zheng, Aiping Lin, Katherine Uyhazi, Hongyu Zhao, Haifan Lin
During spermatogenesis, germ cells initially expand exponentially through mitoses. A majority of these cells are then eliminated through p53-mediated apoptosis to maintain germline homeostasis. However, the activity of p53 must be precisely modulated, especially suppressed in postmitotic spermatogenic cells, to guarantee robustness of spermatogenesis. Currently, how the suppression is achieved is not understood. Here, we show that Pumilio 1, a posttranscriptional regulator, binds to mRNAs representing 1,527 genes, with significant enrichment for mRNAs involved in pathways regulating p53, cell cycle, and MAPK signaling. In particular, eight mRNAs encoding activators of p53 are repressed by Pumilio 1. Deleting Pumilio 1 results in strong activation of p53 and apoptosis mostly in spermatocytes, which disrupts sperm production and fertility. Removing p53 reduces apoptosis and rescues testicular hypotrophy in Pumilio 1 null mice. These results indicate that key components of the p53 pathway are coordinately regulated by Pumilio 1 at the posttranscriptional level, which may exemplify an RNA operon.
