Characterizing Novel Components Involved in 3' End Processing of Histone pre-mRNA

描述(由申请人提供)：这项建议的广泛、长期的目标是研究组蛋白前体mRNA的3‘端加工中涉及的新因素，以及这些因素如何与细胞周期调控机制进行沟通。该项目将在两个不同但互补的模型系统中进行：果蝇和哺乳动物培养细胞。最近，利用全基因组dsRNA筛选发现了处理果蝇组蛋白前mRNA所需的新成分，这一提议旨在了解这些新蛋白在果蝇和哺乳动物中所发挥的功能。此外，最近发现了这一过程中一个已知成分的新功能，它在细胞周期进程中发挥着重要作用。这项提案还将研究这一新功能的性质，以及它如何与组蛋白前mRNA加工联系在一起。 这项研究计划的主要研究员的长期目标是在终身教职的大学教师职位上运行一个独立的研究项目。这项研究计划将包括对研究生和博士后研究员的培训，以及与该职位相关的标准教学要求。这份申请对这条职业道路的发展至关重要，因为它包括我导师的进一步培训，以及与北卡罗来纳大学另一名教职员工卓有成效的合作努力的继续。了解组蛋白生物合成的调控机制对于了解与癌症相关的病理学是至关重要的。许多常见的化疗抗癌疗法的目的是抑制DNA合成。抑制组蛋白合成应该有同样有益的结果；因此，对这一途径的详细了解将增加能够治疗这种疾病的药物的重复使用。

DESCRIPTION (provided by applicant): The broad, long-term goals of this proposal are to study novel factors involved in the 3'-end processing of histone pre-mRNA and how these factors communicate with the cell cycle regulatory machinery. The project will be carried out in two different, yet complementary model systems: Drosophila and mammalian cultured cells. Novel components required for processing of Drosophila histone pre-mRNA have recently been identified using a genome-wide dsRNA screen, and this proposal is aimed at understanding the function that these new proteins play both in flies and mammals. Moreover, a novel function for a known component of this process has been recently identified as playing an essential role in the cell cycle progression. This proposal will also study the nature of this novel function and how this ties into histone pre-mRNA processing. The long-term goal of the principal investigator of this research plan is to run an independent research project in a tenure-track University faculty position. This research program would involve the training of graduate students and postdoctoral fellows as well as the standard teaching requirements associated with such a position. This application is vital to the development of this career path as it includes further training from my mentor as well as a continuation of a fruitful collaborative effort with another faculty member at the University of North Carolina. Understanding the mechanisms regulating the biosynthesis of histones is essential to understand the pathology associated with cancer. Many common chemotherapeutic anti-cancer therapies aim at inhibiting DNA synthesis. Inhibition of histone synthesis should have an equally benefical result; thus having a detailed knowledge of this pathway will increase the repetoire of drugs capable of treating this disease.