Collaborative Research: RNA processing in trypanosome mitochondria

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This project will study a unique mechanism of gene expression in ancient single-celled parasites called trypanosomes. Unlike most organisms that use the RNA copied from DNA "as is" for directing protein synthesis, in the energy-generating mitochondria of trypanosomes (and other organisms), the RNA is edited by addition or removal of specific information. Why editing occurs is not clear, but understanding how it happens may provide important clues about the function of this type of genetic alteration. The project will have broad educational impact by providing interdisciplinary training opportunities for postdoctoral, graduate, undergraduate, and high school students. In addition, specific efforts will target students from groups traditionally underrepresented in the STEM disciplines. This project focuses on the process of RNA editing in the mitochondria of trypanosomes. Through the action of a central editing enzyme, called RECC, uridylates are inserted or deleted at thousands of specific sites in dozens of mRNAs. This extensive editing process is directed by hundreds of small non-coding guide RNAs and involves several auxiliary factors. However, the mechanistic basis of the regulation of editing remains a long-standing question in trypanosomal RNA biology. In previous work, a regulatory editing subcomplex, called REH2C, was identified and found to contain three protein subunits. Two of these, a helicase and a zinc-finger protein, appear to participate directly in editing. A combination of genetic, biochemical, bioinformatics, and proteomic approaches will be used to address how these proteins assemble with mRNAs and guide mRNAs into editosome complexes in vivo and how the complexes carry out editing functions. These studies may establish new paradigms in RNA editing regulation. In a broader sense, the studies will allow a better understanding of how this amazing process evolved. This system can be used to draw analogies with related RNA helicases and RNA processes that are directed by small guide RNAs and that evolved more recently in eukaryotic lineages.