Creation of tools to determine the impact of natural modifications on RNA damage

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The best-known role of RNA is to convert information stored in DNA to functional proteins. However, RNA has many other responsibilities in the cell. One group of RNAs with a less common role is small nuclear RNAs (snRNAs), which is found in the nucleus. The snRNA assists in cutting RNA into pieces, and these pieces then play roles in activating genes (for example). With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding a study by Dr. Amanda Bryant-Friedrich at the University of Toledo and Dr. Christine Chow at Wayne State University to study the protection of snRNAs from oxidative damage (damage from oxygen-containing species in the environment) that may harm cells. As a key part of this collaboration, Drs. Bryant-Friedrich and Chow train students, trainees and junior faculty from diverse backgrounds for their full participation in the scientific enterprise. While it is widely known that oxidative damage causes extensive modifications to DNA and impacts its structure and function, the same damage has not been actively explored in RNA. Due to the central nature of snRNAs in the assembly, structure, and function of the spliceosome, it is suspected that oxidative damage to snRNAs could cause lesions that impact both the structure and function of the spliceosome. Due to the high extent of post-translational modification of U2 sRNA, this small RNA is used as a prototype to determine the impact of the type and number of modifications on the outcomes of oxidative damage when compared to unmodified RNA. The effect of post-transcriptional modifications on the susceptibility of snRNA to oxidative damage is measured by a combination of synthetic, biophysical, biochemical, and analytical methods. This work may lead to new tools that can be used to understand oxidative damage in naturally-modified RNAs. The collaborative nature of the work and complementary scientific expertise of Bryant-Friedrich and Chow provide cross-mentoring opportunities for a range of trainees, particularly those from underrepresented groups who work at the chemistry-biology interface.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.