The Role of Aminoacyl-tRNA Synthesis In Translational Quality Control

生命系统的正确运作需要在处理信息传递的所有过程中保持一定程度的保真度。翻译是遗传信息从核酸序列转移到蛋白质氨基酸序列的过程。翻译的保真度主要取决于两点：核糖体选择氨酰-tRNA的准确性和氨酰化反应过程中氨酰-tRNA合成酶（阿尔斯）合成同源氨基酸/tRNA对的准确性。aaRS通过将tRNA与相应的氨基酸配对来定义遗传密码。准确的氨酰-tRNA合成通常涉及许多aaRS固有的额外编辑活性。编辑活动显着降低水平的错误在氨酰-tRNA合成在体外和体内，虽然其贡献的整体保真度的翻译尚未进行定量分析。该项目的总体目标是开发实验系统，以定量测量几种氨基酸的aaRS依赖性错误掺入的频率，并评估阿尔斯编辑对整体翻译保真度的贡献。这项研究的智力价值在于在理解基本生物学问题方面取得了重大进展，即一般的保真度控制和特别是翻译过程中采用的编辑机制。该项目产生的更广泛的影响将是为本科生和研究生提供综合实验室研究和培训计划，并建立一个新的合作网络。

The correct functioning of living systems requires maintaining a certain level of fidelity in all processes dealing with the transfer of information. Translation is the process by which genetic information is transferred from a nucleic acid sequence into the amino acid sequence of a protein. The fidelity of translation is determined at two major points: the accuracy of aminoacyl-tRNA selection by the ribosomes and synthesis of cognate amino acid/tRNA pairs by aminoacyl-tRNA synthetases (aaRS) in the course of the aminoacylation reaction. The aaRSs define the genetic code by pairing tRNAs with the corresponding amino acids. Accurate aminoacyl-tRNA synthesis often involves an additional editing activity intrinsic to many aaRSs. The editing activity significantly decreases the level of mistakes in aminoacyl-tRNA synthesis in vitro and in vivo, although quantitative analysis of its contribution to the overall fidelity of translation has not been performed. The overall aim of this project is to develop experimental systems to quantitatively measure the frequency of aaRS-dependent misincorporation for several amino acids and evaluate the contribution of aaRS editing to overall translational fidelity. The intellectual merits of this research are in achieving significant progress in understanding fundamental biological problems, namely fidelity control in general and the editing mechanisms employed during translation in particular. The broader impacts resulting from the project will be to provide integrated laboratory research and training programs for both undergraduate and graduate students and to establish a new collaborative network.