Mis-translation as a new mechanism of stress response in biology

描述 摘要： 生物学的一个核心原则是通过遗传密码将信息从核酸准确地传递到蛋白质。人们普遍认为，在细胞内任何时候都要避免偏离遗传密码的翻译。通过使用一种新的基因组方法，我们发现相反，哺乳动物细胞可以在天然免疫激活和化学触发的氧化应激下，故意用氨基酸蛋氨酸重新编程遗传密码。对遗传密码的重新编程是通过非甲硫酰-tRNAs与蛋氨酸的氨酰化反应进行的，并可在细胞内调节产生活性氧物种(ROS)时诱导。我们认为，通过调节tRNA的错酰化导致的错译是细胞应激反应的一种常见机制。我们将探索和验证关于tRNA与蛋氨酸错酰化的生物学效应和功能的假说，并建立哺乳动物细胞中所有氨基酸及其参与翻译的tRNA错酰化的全谱。本文的研究结果和概念性理解将有助于建立误译生物学的新领域。 公共卫生相关性： 我们已经发现，哺乳动物细胞在先天性免疫激活和氧化应激时，故意用氨基酸蛋氨酸重新编程遗传密码。在这里，我们的目标是通过tRNA的错酰化建立错译的生物学机制，作为哺乳动物细胞应激反应的新机制。 科学审查干事编写了以下简历部分，以总结审查委员会关于下列问题的讨论结果。 委员会的预算建议：预算是按要求建议的。 科学审查官员指出： 由于NIH主任先锋奖的申请审查方式与其他NIH拨款机制不同，因此不分配标准分数和百分位数。请不要理会第一页的行政预算说明和以下关于再投资的通知

DESCRIPTION Abstract: A central tenet of biology is the accurate flow of information from nucleic acids to proteins through the genetic code. It is commonly believed that translation deviating from the genetic code is to be avoided at all times in cells. By using a new genomic method, we have discovered that in contrary, mammalian cells can deliberately reprogram the genetic code with the amino acid methionine upon innate immune activation and chemically triggered oxidative stress. Reprogramming the genetic code occurs through aminoacylation of non-methionyl-tRNAs with methionine, and is inducible upon regulated production of the reactive oxygen species (ROS) in the cell. We propose that mis-translation via regulated tRNA misacylation is a common mechanism for stress response for cells. We will explore and test hypotheses on biological effects and function on tRNA misacylation with methionine and establish a full spectrum of tRNA misacylation for all amino acids and their participations in translation in mammalian cells. The results and conceptual understanding obtained here shall help establish a new field of biology of mis-translation. Public Health Relevance: We have discovered that mammalian cells deliberately reprogram the genetic code with the amino acid methionine upon innate immune activation and oxidative stress. Here we aim to establish biology of mis-translation via tRNA misacylation as a new mechanism of stress response in mammalian cells. THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE ON THE FOLLOWING ISSUES. COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested. SCIENTIFIC REVIEW OFFICERS NOTES: Since the NIH Director's Pioneer Award applications are reviewed differently from other NIH grant mechanisms, criterion scores and percentiles are not assigned. Please ignore the Administrative Budget Note on page one and the Notice below regarding re