Interactions of Transition Metal Ions with RNA: Structure and Function

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The Chemistry of Life Processes Program in the Chemistry Division funds this award. Professor Victoria J. DeRose from the University of Oregon investigates the structures of complex ribonucleic acid (RNA) biopolymers. RNA takes part in a wide variety of life sustaining processes. It adopts complex and dynamic structures that are challenging to monitor and predict with current methods. In this research, new platinum compounds are developed as RNA structure probes and used to determine RNA structures in cells. The outcomes of this project are novel methods and reagents for RNA structure analysis, and new information about large RNA structures in cells. The breadth of methods applied to this project supports a unique interdisciplinary training environment for workforce development, including summer undergraduate training for women and other underrepresented groups in science, technology, engineering and mathematics (STEM). The goals of this research are to develop methods for long-range tertiary interactions in large RNAs and to understand determinants for targeting compounds to complex RNA structures. The project develops exchange-inert platinum (Pt(II)) complexes as RNA crosslinking reagents and incorporates them into approaches for RNA structure determination. Pt(II) compounds crosslink purine-rich but noncanonical regions in RNA such as internal loops and junctions and are robust through RNA isolation methods. To enable crosslink analysis, novel modified Pt(II) click reagents are synthesized with installed handles for selective post-treatment modification of Pt(II) RNA species. Structure analysis protocols based on the unique chemistry of these Pt(II) complexes and high-throughput sequencing methods are developed, along with methods to directly image crosslinked species. The specificity of small-molecule RNA interactions is probed through design of enhanced Pt ligands. These approaches are used to predict structures of RNAs in vitro and in-cell, including tertiary structures in long non-coding RNAs.