Emerging regulatory roles for tRNA fragments

标题：转运RNA（Transfer RNAs，tRNA）是一种氨基酸载体，能将信使RNA（messenger RNAs，mRNA）的核苷酸序列中所含的信息解码成特定的多肽序列。除了在蛋白质合成中发挥关键作用外，tRNA还参与各种生物过程，包括应激反应，基因调控和质粒复制。tRNA被转录为前tRNA转录物，并被核糖核酸酶和多种修饰酶加工以释放成熟的tRNA以及tRNA衍生片段（tRF）。tRNA衍生片段（tRFs）长期以来被认为是“垃圾”RNA，最近被证明是真核和原核细胞的重要功能元件。在高通量测序和全基因组分析的帮助下，最近的报道描述了这些分子令人惊讶的功能。虽然大多数已鉴定的tRNA片段的作用仍然难以捉摸，但最新发现表明，它们可以使用与特征良好的小调控RNA类似的机制（基因沉默，蛋白质螯合，sRNA缓冲）。考虑到这一领域的最新发现，很明显，tRNA代表了各种功能RNA的令人印象深刻的来源。我的实验室成功地描述了原核生物中第一个功能性tRF。受最近结果的启发，我的学生在模式生物大肠杆菌中进行了一次新tRF的全球筛选。我们发现了许多潜在的候选人，这些候选人将成为本提案的重点。其中一个tRFs似乎调控着全局翻译起始，这可能会极大地影响我们对基因表达的看法。另一个感兴趣的tRF可能调节参与抗生素耐药性的特定mRNA的表达。我们还观察到至少一种RNA结合蛋白可以影响tRNA的加工，这也首次表明tRF生物合成可以由细胞调节。我们将探索这些令人兴奋的分子的生物起源和功能，它们在其中发挥着重要作用。了解tRFs如何与其他RNA相互作用将有助于理解基因表达的全新机制。我们认为tRFs可能有助于协调翻译机制和控制细胞代谢的基因的表达，这是一种以前从未描述过的机制。

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.