Emerging regulatory roles for tRNA fragments

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TITLE: Emerging regulatory roles for tRNA fragments Transfer RNAs (tRNAs) are mostly considered to be amino acid carriers that decode information contained in the nucleotide sequence of messenger RNAs (mRNA) into specific polypeptide sequences. Beside playing a crucial role in protein synthesis, tRNAs are also involved in various biological processes including stress response, gene regulation and plasmid replication. tRNAs are transcribed as pre-tRNA transcripts and are processed by ribonucleases and diverse modification enzymes to release mature tRNAs as well as tRNA-derived fragments (tRFs). Long considered as “junk” RNAs, tRNA-derived fragments (tRFs) recently turned out to be important functional elements of eukaryotic and prokaryotic cells. With the help of high-throughput sequencing and genome-wide analysis, recent reports have described surprising functions for these molecules. Although roles of most identified tRNA fragments are still elusive, latest discoveries demonstrate that they could use similar mechanisms than well-characterized small regulatory RNAs (gene silencing, protein sequestration, sRNA buffering). Taking into consideration the latest findings in this field, it appears clear that tRNAs represent an impressive source of various functional RNAs. My laboratory successfully described the first functional tRF in prokaryotes. Inspired by recent results, my students have performed a global screen for new tRFs in the model organism Escherichia coli. We found many potential candidates that will be the focus of this proposal. One of these tRFs seems to regulate global translation initiation, which could dramatically impact our view of gene expression. Another tRF of interest might regulate the expression of particular mRNAs involved in antibiotics resistance. We also observed that at least one RNA-binding protein can affect the processing of tRNAs, which also suggests for the first time that tRF biogenesis can be modulated by the cell. We will explore the biogenesis and function of these exciting molecules where they were shown to play important roles. Understanding how tRFs interact with other RNAs will help understanding a totally new mechanism of gene expression. We believe that tRFs might help the coordination of translation machinery and the expression of gene controlling the cellular metabolism, a mechanism that has never been described previously.