Regulation and Physiological Roles of Translational Fidelity

项目摘要 基因信息从信使RNA到蛋白质的准确翻译依赖于多种质量 控制机制，其共同维持氨基酸的翻译错误的平均水平在10-4 错误掺入（错义错误）和10-2终止密码子通读。然而，越来越多的证据表明， 这种翻译忠实度不是固定的，而是受到各种环境线索和遗传因素的影响。 目前，我们才刚刚开始了解导致翻译波动的调控网络。 在环境变化和由此产生的生理反应期间的保真度。翻译错误可能导致 减少健身，如细菌的生长缺陷和哺乳动物的神经变性，但也可能受益 在一定的压力条件下。最近，我们已经表明，翻译错误率各不相同的细胞 在一个基因相同的细菌群体中，提出了一个有趣的问题，即翻译的波动是如何发生的。 错误会影响单个细胞的行为。在我的实验室，我们有兴趣开发和应用新的 技术，以了解调节和生理作用的翻译保真度在两个人口 和单细胞水平。我们正在使用我们最近开发的高通量报告系统来筛选 改变翻译保真度的条件，并且已经确定了新的环境和遗传因素 对这个过程至关重要。接下来，我们将确定底层机制并扩展我们的屏幕。 另一个研究方向是研究翻译保真度如何影响细菌-宿主相互作用， 明白我们最近的工作表明，无论是降低或增加翻译保真度损害表达 沙门氏菌的毒力基因和运动性，这表明最佳水平的翻译错误有利于 细菌与宿主的相互作用我们将进一步确定使用人口和单一的监管网络- 细胞接近。这些研究将为理解翻译忠实性在翻译中的作用提供重要的启示。 环境适应和监管机制。

PROJECT SUMMARY Accurate translation of the genetic information from messenger RNA to protein depends on multiple quality control mechanisms, which collectively maintain the average levels of translational errors at 10-4 for amino acid misincorporation (missense errors) and 10-2 for stop codon readthrough. However, increasing evidence shows that such translational fidelity is not fixed, but is rather affected by various environmental cues and genetic factors. Currently, we are only beginning to understand the regulatory networks leading to the fluctuation of translational fidelity during environmental changes and the resulting physiological responses. Translational errors can lead to reduced fitness, such as growth defects in bacteria and neurodegeneration in mammals, but may also benefit cells under certain stress conditions. Recently, we have shown that translational error rates vary from cell to cell in a genetically-identical bacterial population, raising the interesting question as to how fluctuation of translational errors affects the behavior of individual cells. In my laboratory, we are interested in developing and applying new technologies to understand the regulation and physiological roles of translational fidelity at both the population and single-cell levels. We are using our recently developed high-throughput reporter system to screen for conditions that alter translational fidelity, and have already identified novel environmental and genetic factors that are critical for this process. Next, we will determine the underlying mechanisms and expand our screens. Another research direction is to study how translational fidelity affects bacteria-host interactions, which is poorly understood. Our recent work reveals that either decreasing or increasing translational fidelity impairs expression of virulence genes and motility in Salmonella, suggesting that an optimal level of translational errors benefit bacteria during host interactions. We will further determine the regulatory networks using population and single- cell approaches. These studies will provide important insights into the roles of translational fidelity in environmental adaption and the regulatory mechanisms.