CAREER: Elucidating the Targets and Functions of Mammalian tRNA methyltransferase orthologs

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The goal of this research is to understand how ribonucleic acid (RNA) molecules influence cell growth, development, and response to the environment. Current evidence shows that RNA function can be regulated by the presence of chemical groups (modifications) that are added to the RNA by specific enzymes. However, much remains to be learned about how the enzymes find their target RNAs, how the modifications change RNA functions, and how the modified RNAs regulate critical cellular processes. This research will address those questions, while providing a dynamic research environment to foster the scientific training and development of underrepresented groups in science such as minorities and women. To share new technical approaches developed during the research, students will produce video-based tutorials to serve as a teaching and training resource for the scientific community. The project will also provide educational workshops for underserved high school students to encourage curiosity and experimentation in the field of biology. Mammalian genomes are predicted to encode a diverse number of transfer RNA methyltransferase (Trm) enzymes, but the cellular functions for the majority of Trm proteins remain unknown. The following project aims to elucidate the biological roles of the numerous uncharacterized mammalian Trm enzymes by: 1) establishing the protein interaction networks of human Trm enzymes, 2) identifying the cellular targets of Trm proteins, and 3) determining the cellular processes modulated by Trm proteins. The goals will be achieved through an integrated biochemical, molecular and genetic approach involving proteomic analysis of Trm complexes together with global transcription and translation profiling of human cells with altered Trm proteins. Through these discoveries, the work promises to lay a foundation of new understanding of how the RNA modifications catalyzed by diverse Trm enzymes translate into physiological outputs that help cells respond to various environmental conditions.