2014 DNA Topoisomerases in Biology and Medicine Gordon Research Conference

描述(申请人提供)：DNA的螺旋性质导致其复制的拓扑问题。沃森和克里克很清楚这个潜在的问题，并在1953年声明：“由于我们模型中的两条链是相互交织的，如果他们要分开，解开这两条链是必不可少的……尽管目前很难看到这些过程是如何发生的，而一切都不会纠缠在一起，但我们不认为这个反对意见将是无法克服的。”我们现在知道，DNA拓扑异构酶解决了这个问题，1971年James Wang首次报道了细菌拓扑异构酶I的发现。在过去的40年里，这些酶在所有生物(原核生物、真核生物、病毒和古生物)中都被发现，并发挥着对生存至关重要的作用，支持复制、转录和其他需要解决DNA拓扑问题的过程。这些酶是“神奇的分子机器”，催化一段DNA穿过另一段DNA以催化DNA拓扑变化这一看似神奇的任务。其中一些酶是分子马达，将ATP水解的自由能转化为DNA中的扭应力(超螺旋)。尽管它们的作用机制已经确定，但仍有许多未知之处，需要应用新兴技术，如单分子方法，以更深入地了解这些酶及其在细胞过程中的作用。拓扑异构酶已成为抗细菌和抗癌化疗的关键药物靶点。这是由于它们的本质和作用机制，包括瞬间的DNA切割，如果被破坏，可能会导致高度的细胞毒事件。在无数细胞过程中研究这些酶在导致新化疗药物开发的研究中是至关重要的。首届2014年DNA拓扑异构酶在生物学和癌症药物戈登研究会议上努力吸引来自广泛学科的科学家，重点介绍了拓扑异构酶结构生物学的最新进展，以及单分子技术的应用，以促进在详细分子水平上理解拓扑异构酶的令人兴奋的新研究。在天平的另一端，成像技术和蛋白质组学/基因组学的进步使人们能够对拓扑异构酶的细胞作用及其在人类癌症中的重要性有新的见解。会议将由Tony Maxwell教授(John Innes Centre)主持，Mary-Ann Bjornsti博士(阿拉巴马大学伯明翰分校)担任副主席，他们都是拓扑异构酶领域的领导者，分别代表细菌酶和抗生素，以及真核酶和抗肿瘤药物。这项申请寻求资金，以支持来自不同背景的才华横溢的年轻研究人员(学生、博士后和研究员)的参与，以发挥他们的想象力并与该领域的领导者进行互动。戈登研究会议的非正式性质，以及对高水平科学的高度重视，以及发人深省的评论，确保了一次高度互动的会议，以激发对生物和医学中拓扑异构酶的新观点。

DESCRIPTION (provided by applicant): The helical nature of DNA causes a topological problem for its replication. Watson and Crick were well aware of this potential problem, and in 1953 they stated: "Since the two chains in our model are intertwined, it is essential for them to untwist if they are to separate... Although it is difficult at the moment to see how these processes occur without everything getting tangled, we do not feel that this objection will be insuperable". We now know that this problem is solved by the DNA topoisomerases, first reported in 1971 by James Wang with the discovery of bacterial topoisomerase I. Over the past ~40 years these enzymes have been found in all organisms (prokaryotes, eukaryotes, viruses and archaea) and to perform roles that are vital for survival, supporting replication, transcriptio and other processes where DNA topological problems need to be resolved. The enzymes are 'marvelous molecular machines' catalyzing the seemingly magical task of passing one piece of DNA through another to catalyze changes in DNA topology. Some of the enzymes are molecular motors, transducing the free energy of ATP hydrolysis into torsional stress in DNA (supercoiling). Although the outline of their mechanisms has been established, a great deal is unknown and emerging technologies, such as single-molecule methods, need to be applied to gain a deeper understanding of these enzymes and their roles in cellular processes. Topoisomerases have become key drug targets both for anti-bacterial and anti-cancer chemotherapy. This is due to their essential nature and their mechanism of action, which involves transient DNA cleavage that, if disrupted, can lead to highly cytotoxic events. Study of these enzymes in the context of myriad cellular processes is critical in research leading to the development of new chemotherapeutic agents. The inaugural 2014 DNA Topoisomerases in Biology and Medicine of Cancer Gordon Research Conference strives to attract scientists from a broad range of disciplines, highlighting recent advances in structural biology of topoisomerases and the application of single-molecule technologies to promote exciting new research on understanding topoisomerases at the detailed molecular level. At other end of the scale, advances in imaging technologies and proteomics/genomics enable new insights into the cellular roles of topoisomerases and their significance in human cancers. The meeting will be chaired by Prof. Tony Maxwell (John Innes Centre), with Dr. Mary-Ann Bjornsti (University of Alabama at Birmingham) as Vice Chair, both leaders in the topoisomerase field, representing bacterial enzymes and antibiotics, and eukaryotic enzymes and anti-tumor agents, respectively. This application seeks funds to support the participation of exceptionally talented young investigators (students, post-docs and fellows) from diverse backgrounds, to engage their imagination and interactions with leaders in the field. The informal nature of Gordon Research Conferences and the strong emphasis placed on high-caliber science presented with thought-provoking commentary ensures a highly interactive meeting to stimulate new perspectives on topoisomerases in biology and medicine.