Interactions of Transition Metal Ions with RNA: Structure and Function

在美国国家科学基金会化学部生命过程化学（CLP）项目的支持下，俄勒冈大学的Victoria DeRose博士正在研究铂化合物对细胞RNA（核糖核酸）过程的影响。RNA在细胞中执行许多关键功能，包括在核糖体中执行蛋白质合成。核糖体是在细胞核内的一个亚组分——核仁中合成的。核糖体合成在细胞中起着至关重要的作用，核糖体合成的抑制剂通过核仁应激过程导致细胞死亡。DeRose博士将使用生物化学、化学合成和细胞生物学方法，研究核仁过程是如何被可引起核仁应激的小金属铂化合物所抑制的。这项研究将有助于建立金属配合物如何在核仁中相互作用的原理，以及哪些性质决定了金属配合物是否是核仁功能的抑制剂。这项研究还将有助于了解小分子如何影响核糖体生物合成的不同步骤。该项目有望开发出一套新的小分子，可供其他研究人员用于研究核仁。该项目将支持目前在STEM中代表性不足的群体的学生，并将通过结合合成化学、RNA生物学、生物信息学、分子和细胞生物学，为劳动力发展创造一个强大的跨学科培训环境。核糖体生物发生是一个高度保守的过程，生命的所有领域都需要它，它的破坏导致细胞死亡。控制核仁结构的因素，在细胞周期中是动态的，还没有得到很好的理解。现有的抑制核仁过程的方法包括广泛的“应激”诱导剂，如活性氧或热休克，它们不是核仁应激所特有的。现有的几种小分子核糖体生物发生抑制剂的机制，特别是RNA聚合酶I，在核核中转录rDNA，是一个活跃的研究领域。最近已经确定铂化合物的一小部分能够引起核糖体生物发生应激，为研究这一中心，保守的过程提供了独特的途径。本研究将探讨铂类化合物修饰对核仁过程的影响，并寻求通过生物分析和化学生物学方法确定铂类化合物的主要核仁靶点。在分子水平上理解Pt（II）诱导的核仁应力的相互作用将有助于更好地理解核仁结构和功能的决定因素。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemistry of Life Processes (CLP) Program in the NSF Division of Chemistry, Dr. Victoria DeRose from the University of Oregon is investigating the influence of platinum compounds on processes involving cellular RNA (ribonucleic acid). RNA performs many critical functions in cells, including performing protein synthesis in ribosomes. Ribosomes are synthesized in the cell nucleolus, a subcomponent within the nucleus of cells. Ribosome synthesis is a crucial function in cells, and inhibitors of ribosome synthesis cause cell death by a process known as nucleolar stress. Dr. DeRose will study how nucleolar processes are inhibited by small metal platinum compounds that can cause nucleolar stress, using biochemistry, chemical synthesis, and cell biology methods. This study will help establish principles of how metal complexes interact in the nucleolus, and which properties determine whether metal complexes are inhibitors of nucleolar function. The study will also aid in understanding how different steps of ribosome biosynthesis can be influenced by small molecules. The project is anticipated to develop a new set of small molecules that can be used by other researchers seeking to study the nucleolus. The project will support students from groups currently underrepresented in STEM, and will create a strong interdisciplinary training environment for workforce development, by combining synthetic chemistry, RNA biology, bioinformatics, and molecular and cell biology. Ribosome biogenesis is a highly conserved process required for all domains of life, and its disruption leads to cell death. Factors governing nucleolar architecture, which is dynamic through the cell cycle, are not well-understood. Existing methods to inhibit nucleolar processes include broad ‘stress’ inducers such as reactive oxygen species or heat shock, which are not specific to nucleolar stress. The mechanisms of the few existing small-molecule inhibitors of ribosome biogenesis and specifically RNA Polymerase I, which transcribes rDNA in the nucleolus, are an area of active research. It has recently been determined that a small subset of platinum compounds is able to cause ribosome biogenesis stress, providing a unique avenue to study this central, conserved process. This study will investigate the influence of platinum compound modifications on nucleolar processes, and also seek to identify the main nucleolar targets of platinum compounds by bioanalytical and chemical biology methods. Developing a molecular-level understanding of the interactions responsible for Pt(II)-induced nucleolar stress would lead to a better understanding of the determinants of nucleolar structure and function.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.