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加州大学洛杉矶分校和Rutgers大学研究人员解决了一个关于DNA转录的为时已久的问题，DNA转录过程是基因执行指令的第一步。这一重大发现发表于11月17日出版的《科学》杂志，揭示了转录过程中DNA旋转的重要结构信息和旋转产生的结果。

RNAP是负责以DNA 或 RNA为模板合成RNA的一种酶，此项发现加深我们对RNAP结构和作用机制的理解，也为我们战胜每年导致全球1千3百万人死亡的细菌类疾病提供了新思路。

研究人员为RNAP和DNA双螺旋的关键结构标记上多种荧光化学物质，并利用单分子光谱技术监控转录初始过程中RNAP和DNA双螺旋间能量的转移。

荧光标记物之间距离的改变证实了转录初始过程的一种“弯转”的机制，很像垂钓者旋动转盘吊起一条鱼：RNAP位置固定，拉动RNAP分子内部的柔软的DNA链，并将酶的催化中心传递过去，以形成RNA产物。

这一发现不符合其他一些理论，那些理论认为RNAP沿着DNA链像尺蠖一样移动。

研究组由加州大学洛杉矶分校化学与生化系、生理系和加州纳米系统研究所（California NanoSystems Institute，CNSI）的Achillefs N. Kapanidis, Emmanuel Margeat, Sam On Ho, Ekaterine Kortkhonjia and Shimon Weiss组成。研究组和Rutgers大学的Howard Hughes 医学研究所、Waksman 研究所、化学系的Richard H. Ebright合作。

弯转模型暗示着弯曲的DNA从酶通道中排出，并转移至可以和转录调节蛋白相互作用的预定地点。除了解决转录起始的机制，此项研究的意义还在于指明了一个重要的调控“检查点”。弯曲的DNA很可能在未来的转录调控研究中起主要作用，并可能成为研制抗生素的靶位点。

“我们在本项研究中用到了单分子技术。以前单分子技术没有研制出来，一些问题没法解决”Ebright 说。“单分子技术涉及检测和操纵单个分子，每次针对一个分子，这是一个技术上的突破。”

“加州纳米系统研究所的纳米技术专家对分子机制、运动部件的动力学和在分子轨迹上转移的研究很感兴趣，”加州大学洛杉矶分校科研小组组长Weiss说。“除了增进对转录调控的理解，本项研究中的新方法和发现将有助于对细胞复制、转录和蛋白合成的分子机制的研究。”

UCLA researchers unravel a mystery about DNA

UCLA researchers in collaboration with researchers at Rutgers University have solved longstanding mysteries surrounding DNA transcription, the first step in carrying out instructions contained in our genes. The breakthrough described in an article in the Nov. 17 issue of the journal Science reveals important structural information about the gyrations of DNA during transcription and the effects of those gyrations on the process.

The discoveries, which inform our understanding of the structure and mechanics of RNAP -- an enzyme responsible for making RNA from a DNA or RNA template -- can help set the stage for new opportunities in combating bacterial diseases that kill 13 million people worldwide each year.

The researchers used single-molecule spectroscopy to monitor the transfer of energy between -- and hence the distance separating -- pairs of fluorescent chemical tags attached to key structural elements of RNAP and the DNA double helix during initiation of the transcription process.

The changes in the distances between these tags confirmed that transcription proceeds initially through a "scrunching" mechanism in which, much like a fisherman reeling in a catch, RNAP remains in a fixed position while it pulls the flexible DNA strand of the gene within itself and past the enzyme's reactive center to form the RNA product.

These changes are inconsistent with other theories that had suggested that RNAP moves along the DNA strand as a complete block in a process resembling the movement of an inchworm.

The research team is comprised of Achillefs N. Kapanidis, Emmanuel Margeat, Sam On Ho, Ekaterine Kortkhonjia and Shimon Weiss of the UCLA Department of Chemistry and Biochemistry, the Department of Physiology and the California NanoSystems Institute (CNSI). The team collaborated with Richard H. Ebright, Howard Hughes Medical Institute, Waksman Institute and Department of Chemistry, Rutgers University.

The scrunching model implies that the scrunched DNA is expelled from the enzyme channel at predictable sites that are available for interaction with transcription regulatory proteins. Beyond resolving the mechanism for initiation, the significance of this work is in pointing out an important regulation "checkpoint." Scrunched DNA is likely to play a major role in future studies of transcription regulation, and possibly become a focus for antibiotic drug discovery efforts.

"These are issues that we were not able to resolve until the development of the single molecule methods that we employed in these studies," Ebright said. "These methods involve detecting and manipulating single molecules, one at a time -- a breakthrough in its own right."

"The study of molecular machines, the dynamics of their moving parts and their translocation on molecular tracks is of great interest to nanotechnologists at the CNSI," said Weiss, the leader of the UCLA team. "Beyond furthering the understanding of transcription regulation, the novel methods and findings of this work will aid future studies of other molecular machines involved in cell replication, transcription and protein synthesis."

Source : University of California - Los Angeles

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