This research award in the Inorganic, Bioinorganic and Organometallic Chemistry program supports work by Professor Janet Morrow at the University at Buffalo, State University of New York, to examine the structure-selective cleavage of RNA by mononuclear and dinuclear metal ion catalysts with the goal of developing catalysts for RNA structure mapping and developing small molecules for specific interaction with common secondary structures of nucleic acids. First, mononuclear and dinuclear complexes of scandium(III) and lanthanides(III) will be prepared and studied as structure-selective RNA cleavage catalysts. Second, recognition agents that bind to uridine or thymidine containing bulges, mismatches or loops in RNA or DNA, respectively, will be developed. These recognition agents are based on zinc(II) macrocyclic complexes with attached pendent aromatic groups. Third, zinc(II) complex binders will be tethered to scandium(III) or europium(III) catalysts and the structure-selective cleavage of RNAs containing uridines in bulges and loops will be studied. Lanthanide ion complexes and their interactions with nucleic acids will be characterized by using luminescence spectroscopy. In addition to training graduate and undergraduate students in multidisciplinary research, research training will be extended to undergraduate courses by the creation of a new laboratory module for our CASPiE program (Center for Authentic Practice in Education). This module will involve studies to monitor binding of small molecules to DNA. The Morrow group will develop and maintain a specialized laser system for the direct excitation of lanthanide luminescence and keep the facility open to all researchers. This includes students and faculty members from the State University of New York at Fredonia for our collaborative work on the study of metal ion complex binding to nucleic acids. This work will provide new tools for the study of RNA protein interactions and RNA structure in vitro and in cell culture and will be a first step towards targeting specific RNA structures to control biological function.
The design and synthesis of molecules that selectively bind to nucleic acids (DNA and RNA) is important for many applications. These molecules may act to block biological function based on recognition of specific nucleic acid structures. Alternatively, these molecules may enable detection of unusual structures in nucleic acids. For example, the discovery of molecules that selectively bind to bulges in DNA and light up upon binding may facilitate the detection of bulges that form during errors in replication. Molecules that bind to nucleic acid loops such as those in four-stranded nucleic acids called G-quadruplexes may modulate gene expression. The fundamental principles of nucleic acid recognition are useful towards the design of molecules for drug development or as tools for understanding cellular processes. Our molecules are unique in that they contain metal ions. One class contains the biologically relevant metal ion, zinc, and the other class contains lanthanide ions. The metal ion gives unique binding modes in the case of zinc complexes, or provides a spectroscopic handle for determining binding sites in the case of lanthanide complexes. Our research examines ways to couple the metal ion center to organic fragments to create new ways to bind to specific nucleic acid structures of biological significance. Our NSF-supported research has had a large training component. Students from diverse backgrounds and levels of education in science have participated. Nine graduate students, one postdoc and seventeen undergraduates have been trained on this project over the past four years. Most students are from the University at Buffalo, State University of New York, but several undergraduate researchers were from colleges in New York, Pennsylvania, Ohio or were from as far away as Puerto Rico. Our faculty collaborators include a professor at SUNY, College at Fredonia and several of his students. High school teachers from Buffalo public schools did collaborative research projects in our laboratories to identify DNA in microbes in Lake Erie. Our research has been presented at many conferences including several American Chemical Society meetings and Gordon Research Conferences on Metals in Biology and Metals in Medicine. This work has been published in several peer-reviewed articles.
