Tissue-specific regulation of RNA-based enzymes by their protein subunits

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Although most enzymes are proteins, there are a few, known as ribozymes, that are multi-subunit complexes containing both protein and RNA. Ribozymes typically catalyze essential processes without which cells could not use or inherit genetic information correctly. This project will investigate two different ribozymes known as RNase P and RNase MRP. Their normal function is to modify other RNA molecules that are themselves are essential for protein synthesis. Both of these ribozymes are comprised of multiple protein subunits and an RNA molecule. The proposed work will use a combination of biochemistry, genetics, and cell biology to ascertain the functional significance of each of the protein subunits, focusing on mammalian cells. The broader impacts of this work include better understanding of ribozymes found in all cells. The project also aims to broaden participation in science by providing mentored research experiences to graduate students and first-year undergraduates, some of whom are from groups under-represented in science, technology, engineering and mathematics. RNases P and MRP are essential endonucleases critical for maturation of tRNAs and rRNAs, respectively. All components of RNases P and MRP, including the catalytic RNA and several associated proteins, are considered essential for life, and mutations in the genes encoding them can cause disease. Nevertheless, the roles of the protein subunits of these RNA-based enzymes are poorly understood. Several fundamental questions remain open: How do individual subunits impact enzymatic function? Why are so many protein subunits found in eukaryotes but just one in bacteria? What are the roles of subunit variants in animals? This study will expand our understanding of the molecular and cellular roles of RNase P/MRP protein subunits by focusing on their variants. A particular emphasis will be on two alternative subunit variants that display tissue-specific expression and non-redundant cellular functions. Understanding how alternative subunit composition might allow for functional diversification of metazoan RNases P and MRP will be of widespread significance across biological sciences.This research is funded by the Genetic Mechanisms program in the Division of Molecular and Cellular Biosciences in the Directorate of Biological Sciences.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.