UNDERSTANDING THE ROLES OF RNA POLYMERASE I IN TRANSCRIPTION AND BEYOND

了解 RNA 聚合酶 I 在转录及其他方面的作用

• 批准号: 10159609
• 负责人: David Alan Schneider
• 金额: $ 35.15万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10159609
• 关键词: Affect; Biochemical; Biology; Biophysics; Cancer Control; Cell Proliferation; Cell Survival; DNA Polymerase I; DNA Polymerase II; DNA Polymerase III; DNA-Directed RNA Polymerase; Development; Enzymes; Eukaryotic Cell; Foundations; Future; Gene Expression; Genetic; Genetic Transcription; Genomics; Goals; Messenger RNA; Methodology; Nuclear; Polymerase; Prokaryotic Cells; Property; RNA; RNA Polymerase I; RNA chemical synthesis; RNA, Ribosomal, 5S; Ribosomal DNA; Ribosomal RNA; Ribosomes; Role; Therapeutic; Transcriptional Regulation; Transfer RNA; anti-cancer; cell growth; chemotherapy; inhibitor/antagonist; novel; targeted treatment; therapeutic target; transcription factor

Eukaryotic cells deploy at least three multisubunit, DNA-dependent RNA polymerases to express the robust variety of RNAs required for cell survival and proliferation. In contrast to prokaryotic cells which express a single RNA polymerase, eukaryotic RNA polymerases have evolved into specialized cellular roles. RNA polymerase I (Pol I) synthesizes the majority of ribosomal RNA, Pol II synthesizes messenger RNA and most regulatory RNAs, whereas Pol III synthesizes transfer RNA and the 5S ribosomal RNA. While this "division of labor" among the nuclear Pols has been appreciated for many years, substantial gaps in our understanding of the functional divergence between the eukaryotic RNA polymerases remain. How do the enzymatic properties of these enzymes differ? How do these functional differences influence regulation of transcription by associated transcription factors? How do divergent enzymatic properties of the Pols impact their unique cellular roles? The answers to these questions are fundamentally important for understanding eukaryotic biology. It is well established that the rate of ribosome synthesis is proportional to the rates of cell growth and proliferation. As a consequence, several labs around the world seek novel inhibitors of ribosome synthesis as potential anticancer chemotherapy agents. Since transcription of the ribosomal DNA by Pol I is the first, rate-limiting step in ribosome synthesis, Pol I has emerged as a key target for the development these inhibitors. In order to selectively inhibit one RNA polymerase without affecting the others, it is crucial to understand the fundamental properties of the enzymes as well as the cellular mechanisms by which the enzymes are controlled. Thus, defining Pol I activity and its cellular roles has immediate translational value. By defining the landscape of eukaryotic transcription and the many cellular roles of Pol I, this project will reveal answers to fundamental questions in evolutionary biology while informing ongoing studies aimed at therapeutic targeting of ribosomal RNA synthesis. To reach these goals, our lab has developed a robust platform of experimental approaches including biochemical, biophysical, genetic, and genomic methodologies. We have pioneered the development of both the experimental and analytical strategies required to rigorously and thoroughly define the functional properties of RNA polymerase I. The overall goal of this project is to leverage these experimental strengths to impact our overall understanding of eukaryotic gene expression and to lay the foundation for ongoing and future studies aimed at therapeutic inhibition of Pol I.

真核细胞至少部署三种依赖于DNA的多亚单位RNA聚合酶 表达细胞生存和增殖所需的各种强健的RNA。与之形成鲜明对比的是 表达单一RNA聚合酶的原核细胞，真核RNA聚合酶有 进化成专门的细胞角色。RNA聚合酶I(Pol I)合成了大部分 核糖体RNA，Pol II合成信使RNA和大多数调节RNA，而Pol III 合成转移RNA和5S核糖体RNA。而这种“分工”在 核极多年来一直受到赞赏，但我们对核极的理解存在很大差距 真核RNA聚合酶之间的功能差异仍然存在。酶是如何 这些酶的性质不同吗？这些功能差异如何影响对 相关转录因子的转录？不同的酶性质是如何 波兰人会影响他们独特的细胞角色吗？这些问题的答案基本上是 对理解真核生物学很重要。 众所周知，核糖体合成的速度与细胞的速度成正比。 生长和扩散。因此，世界各地的几个实验室都在寻找新的抑制剂。 核糖体合成作为潜在的抗癌化疗药物。由于抄写了 由Pol I合成的核糖体DNA是核糖体合成的第一个限速步骤，Pol I已经出现 作为开发这些抑制剂的关键靶点。为了选择性地抑制一种RNA 在不影响其他聚合酶的情况下，了解其基本性质是至关重要的。 这些酶以及控制这些酶的细胞机制。因此， 定义POL I活动及其细胞角色具有直接的翻译价值。 通过定义真核转录的图景和Pol I的许多细胞作用，这 该项目将揭示进化生物学中基本问题的答案，同时告知 正在进行的研究旨在治疗靶向的核糖体RNA合成。要达到这些目标 目标，我们的实验室开发了一个强大的实验方法平台，包括 生物化学、生物物理学、遗传学和基因组学方法。我们开创了 制定实验和分析策略，以严格和 彻底定义RNA聚合酶的功能特性I.本项目的总体目标 就是利用这些实验优势来影响我们对真核生物的整体理解 基因表达，并为正在进行的和未来旨在治疗的研究奠定基础 Pol I的抑制作用。