Huber Sabrina M, Leonardi Andrea, Dedon Peter C, Begley Thomas J
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
RNA Institute, State University of New York, Albany, NY 12222, USA.
Toxics. 2019 Mar 25;7(1):17. doi: 10.3390/toxics7010017.
Living organisms respond to environmental changes and xenobiotic exposures by regulating gene expression. While heat shock, unfolded protein, and DNA damage stress responses are well-studied at the levels of the transcriptome and proteome, tRNA-mediated mechanisms are only recently emerging as important modulators of cellular stress responses. Regulation of the stress response by tRNA shows a high functional diversity, ranging from the control of tRNA maturation and translation initiation, to translational enhancement through modification-mediated codon-biased translation of mRNAs encoding stress response proteins, and translational repression by stress-induced tRNA fragments. tRNAs need to be heavily modified post-transcriptionally for full activity, and it is becoming increasingly clear that many aspects of tRNA metabolism and function are regulated through the dynamic introduction and removal of modifications. This review will discuss the many ways that nucleoside modifications confer high functional diversity to tRNAs, with a focus on tRNA modification-mediated regulation of the eukaryotic response to environmental stress and toxicant exposures. Additionally, the potential applications of tRNA modification biology in the development of early biomarkers of pathology will be highlighted.
生物体通过调节基因表达来响应环境变化和异源生物暴露。虽然热休克、未折叠蛋白和DNA损伤应激反应在转录组和蛋白质组水平上已得到充分研究，但tRNA介导的机制直到最近才成为细胞应激反应的重要调节因子。tRNA对应激反应的调节显示出高度的功能多样性，从tRNA成熟和翻译起始的控制，到通过修饰介导的编码应激反应蛋白的mRNA的密码子偏向翻译来增强翻译，以及应激诱导的tRNA片段介导的翻译抑制。tRNA需要在转录后进行大量修饰才能发挥全部活性，并且越来越清楚的是，tRNA代谢和功能的许多方面是通过修饰的动态引入和去除来调节的。本综述将讨论核苷修饰赋予tRNA高度功能多样性的多种方式，重点是tRNA修饰介导的真核生物对环境应激和毒物暴露反应的调节。此外，还将强调tRNA修饰生物学在病理学早期生物标志物开发中的潜在应用。
