《自然》雜志2月25日在線發(fā)表了哈佛大學(xué)莊曉薇研究組有關(guān)端粒酶組裝的最新研究結(jié)果,。端粒酶研究對腫瘤研究具有重大意義,，莊曉薇等人通過一種復(fù)雜的技術(shù)實時跟蹤觀察了單個細(xì)胞中的結(jié)構(gòu)變化，揭示了端粒酶中三種不同的蛋白質(zhì)和RNA成分是如何相互配合，并在形成過程中不斷修正以確保下一步得到正確執(zhí)行的,。
端粒酶是一種基本的核蛋白逆轉(zhuǎn)錄酶,，可將端粒DNA加至真核細(xì)胞染色體末端。端粒在各物種細(xì)胞中對于保持染色體穩(wěn)定性和細(xì)胞活性均有重要作用,，而端粒酶則能延長縮短的端粒（縮短的端粒的細(xì)胞復(fù)制能力受限）,，從而增強(qiáng)體外細(xì)胞的增殖能力。端粒酶對人體快速分裂的細(xì)胞極其重要,，比如正在發(fā)育中的胎兒,。端粒酶在正常成人人體組織中的活性被抑制，而在腫瘤中被重新激活,，端粒酶可能參與了腫瘤的惡性轉(zhuǎn)化,。端粒酶在保持端粒穩(wěn)定、基因組完整,、細(xì)胞長期的活性和潛在的持續(xù)增殖能力等方面有重要作用,。因此理解端粒酶是如何被組裝的非常重要。
莊曉薇研究組研究了一種名為嗜熱四膜蟲（Tetrahymena thermophila）的單細(xì)胞水生生物的端粒酶,，因為單細(xì)胞生物比更高等的生物結(jié)構(gòu)簡單,，更加容易控制。
端粒酶主要依靠兩種成分來實現(xiàn)其功能：一種名為端粒酶逆轉(zhuǎn)錄酶（TERT）的蛋白酶,，另一種對TERT起到指導(dǎo)作用的一小段RNA片段,。
莊解釋說：“端粒酶只要這兩樣?xùn)|西就可以起作用，但是實際上如果你僅僅把它們簡單地放到一起去,，它們是不會組裝成功能結(jié)構(gòu)的,。還需要一些其它的輔助蛋白。”莊的研究組與伯克利Kathleen Collins小組合作,，發(fā)現(xiàn)第三種分子——一種名為p65的蛋白質(zhì)促進(jìn)了端粒酶的組裝,。
莊及其合作者們利用斯坦福科學(xué)家Lubert Stryer首創(chuàng)的熒光共振能量轉(zhuǎn)移檢測系統(tǒng)（FRET）,，實時精確觀察到端粒酶一步步進(jìn)行組裝的全過程,。
莊曉薇說，下一步他們將研究更高級有機(jī)體中的端粒酶,，以期最終研究人類的端粒酶組裝機(jī)制,。
莊曉薇博士，是中國科學(xué)技術(shù)大學(xué)少年班培養(yǎng)出的杰出人才,，她19歲考取全額獎學(xué)金赴美攻讀博士學(xué)位,，現(xiàn)任哈佛大學(xué)教授，從事生物化學(xué)研究,。2003年榮獲美國麥克阿瑟基金會評選出的“天才獎”,，獨得獎金50萬美元。
部分英文原文：
Nature advance online publication 25 February 2007 | doi:10.1038/nature05600; Received 18 September 2006; Accepted 15 January 2007; Published online 25 February 2007
Stepwise protein-mediated RNA folding directs assembly of telomerase ribonucleoprotein
Michael D. Stone1, Mariana Mihalusova2, Catherine M. O'Connor5, Ramadevi Prathapam5, Kathleen Collins5 and Xiaowei Zhuang1,3,4
Department of Chemistry and Chemical Biology,
Department of Molecular and Cellular Biology,
Department of Physics, and,
Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts 02138, USA
Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA
Correspondence to: Xiaowei Zhuang1,3,4 Correspondence and requests for materials should be addressed to X.Z. (Email: [email protected]).
Telomerase is an essential cellular ribonucleoprotein (RNP) that solves the end replication problem and maintains chromosome stability by adding telomeric DNA to the termini of linear chromosomes1, 2, 3. Genetic mutations that abrogate the normal assembly of telomerase RNP cause human disease4. It is therefore of fundamental and medical importance to decipher cellular strategies for telomerase biogenesis, which will require new insights into how specific interactions occur in a precise order along the RNP assembly pathway. Here we use a single-molecule approach to dissect the individual assembly steps of telomerase. Direct observation of complex formation in real time revealed two sequential steps of protein-induced RNA folding, establishing a hierarchical RNP assembly mechanism: interaction with the telomerase holoenzyme protein p65 induces structural rearrangement of telomerase RNA, which in turn directs the binding of the telomerase reverse transcriptase to form the functional ternary complex. This hierarchical assembly process is facilitated by an evolutionarily conserved structural motif within the RNA. These results identify the RNA folding pathway during telomerase biogenesis and define the mechanism of action for an essential telomerase holoenzyme protein.
