Interactions of Transition Metal Ions with RNA: Structure and Function

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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.