生物谷報(bào)道：來(lái)自荷蘭Delft大學(xué)Kavli納米科學(xué)研究所的科學(xué)家們最近在研究癌癥抑制劑topotecan的工作機(jī)制方面取得了重大進(jìn)展,。在這之前，人們對(duì)這一抑制劑內(nèi)在工作機(jī)理知之甚少,，但Delft的科學(xué)家們現(xiàn)在能夠觀察這種藥物對(duì)體內(nèi)單個(gè)DNA分子的作用,。
以上研究結(jié)果發(fā)表在本周出版的Nature上,。文章第一作者Daniel Koster目前還是Delft的博士生，他將于6月25日接受Delft授予的博士學(xué)位,，其部分研究結(jié)果已經(jīng)在文章中公布。
研究小組分析的這種重要的癌癥抑制劑——topotecan能和一種關(guān)鍵的蛋白質(zhì)（TopolB）發(fā)生相互作用,，從而導(dǎo)致癌細(xì)胞無(wú)法正常工作,。蛋白質(zhì)TopolB的作用主要是移除DNA分子中的環(huán)狀結(jié)構(gòu),，這會(huì)在細(xì)胞分裂過程中發(fā)生。在這一過程中,，TopolB蛋白將和DNA分子結(jié)合,，然后夾在其周圍，并最終切斷DNA雙鏈結(jié)構(gòu)中的其中一條,，在這之后DNA鏈將松開,，并通過斷裂端重新結(jié)合到一起。
來(lái)自Kavli納米科學(xué)研究所的博士生Daniel Koster,、碩士生Elisa Bot以及研究員Nynke Dekker決定用一種非常直接的手段來(lái)揭開這其中的內(nèi)在機(jī)理,。在實(shí)驗(yàn)室中，研究小組將單個(gè)DNA分子固定在一個(gè)玻璃平板和磁體小球之間,。通過兩個(gè)磁體的幫助,，科學(xué)家就可以拉動(dòng)以及扭動(dòng)DNA分子。結(jié)果當(dāng)小組將TopolB蛋白施加到扭曲的DNA分子上時(shí),，科學(xué)家們觀察到了環(huán)被慢慢的移除,。
令人意外的是一種TopolB酶對(duì)于DNA分子的作用可以被實(shí)時(shí)觀測(cè)到。通過和美國(guó)St. Jude兒童醫(yī)院合作,，這一機(jī)制同樣在活體酵母細(xì)胞中被觀察到,。（援引教育部科技發(fā)展中心）
相關(guān)報(bào)道：
Nature advance online publication 24 June 2007 | doi:10.1038/nature05938; Received 6 January 2007; Accepted 15 May 2007; Published online 24 June 2007
Antitumour drugs impede DNA uncoiling by topoisomerase I
Daniel A. Koster1, Komaraiah Palle2, Elisa S. M. Bot1, Mary-Ann Bjornsti2 & Nynke H. Dekker1
Kavli Institute of Nanoscience, Faculty of Applied Sciences, Delft University of Technology, Lorentzweg 1, 2628 CJ Delft, The Netherlands
Department of Molecular Pharmacology, St Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38105, USA
Correspondence to: Nynke H. Dekker1 Correspondence and requests for materials should be addressed to N.H.D. (Email: [email protected]).
Increasing the ability of chemotherapeutic drugs to kill cancer cells is often hampered by a limited understanding of their mechanism of action. Camptothecins, such as topotecan, induce cell death by poisoning DNA topoisomerase I, an enzyme capable of removing DNA supercoils1, 2, 3, 4. Topotecan is thought to stabilize a covalent topoisomerase–DNA complex5, 6, 7, rendering it an obstacle to DNA replication forks2, 3, 8, 9. Here we use single-molecule nanomanipulation to monitor the dynamics of human topoisomerase I in the presence of topotecan. This allowed us to detect the binding and unbinding of an individual topotecan molecule in real time and to quantify the drug-induced trapping of topoisomerase on DNA. Unexpectedly, our findings also show that topotecan significantly hinders topoisomerase-mediated DNA uncoiling, with a more pronounced effect on the removal of positive (overwound) versus negative supercoils. In vivo experiments in the budding yeast verified the resulting prediction that positive supercoils would accumulate during transcription and replication as a consequence of camptothecin poisoning of topoisomerase I. Positive supercoils, however, were not induced by drug treatment of cells expressing a catalytically active, camptothecin-resistant topoisomerase I mutant. This combination of single-molecule and in vivo data suggests a cytotoxic mechanism for camptothecins, in which the accumulation of positive supercoils ahead of the replication machinery induces potentially lethal DNA lesions.
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