Investigation of copper homeostasis mRNAs regulated by the Nonsense-mediated mRNA decay pathway

项目总结 无意义介导的信使核糖核酸衰变(NMD)途径是一种特殊的途径，它有助于 带有提前终止密码子的信使核糖核酸的识别和快速降解。这防止了 生产不起作用的、可能有害的截短蛋白质。NMD会影响数字的表达 通过调节携带无义突变的基因的表达来预防人类遗传性疾病。NMD也 通过降解天然mRNAs来调节特定基因的表达。天然信使核糖核酸的调控 从酵母到人类的许多生物体中都发现了NMD。然而，程度和 大多数天然的mRNAs被作为靶点的原因通常是未知的，可能是一种方法 支持细胞对不断变化的环境条件做出适当的反应。这项研究的目的是 研究NMD在铜的动态平衡中的作用。我们假设mRNAs与铜有关 动态平衡和对NMD敏感由该通路通过相似的特征进行调节。此外, 我们推测，NMD对这些mRNAs的调节是对环境条件做出反应的。这 根据我们的初步观察，提出了假设，表明四个mRNAs参与了 铜稳态具有相同的NMD靶向功能。此外，通过以下方式调节其中一个mRNAs NMD对环境铜水平做出反应。这项研究将确定在多大程度上 由于相似的功能，功能相关的mRNAs受到NMD的调控。此外，它还将展示 该法规对环境条件的反应程度。我们计划测试我们的中央 假设并通过追求以下具体目标来实现本项目的总体目标。在……里面 目的1我们将确定靶向参与铜与NMD动态平衡的mRNAs的特征/因素。在……里面 目标2我们将确定NMD对这些mRNAs调控的环境影响以及 这种调节产生的生理后果这项研究的贡献是它将 展示来自同一官能团的天然mRNAs受NMD和 环境对这一规定的影响。成功完成这些研究将 首次展示环境条件对功能调节的影响 NMD的相关mRNAs。这一知识将允许对受调控的NMD的细胞过程进行分类， 并导致对遗传易驯化生物体S。 酿酒。了解NMD对mRNA的自然调控是很重要的，因为这些mRNA是 在包括人类在内的多种生物中发现，以及酿酒酵母调节 功能相关的mRNAs可以在其他系统和其他条件下使用。此外， 人类的NMD途径正被用于治疗由含有以下成分的基因引起的遗传病 无意义的密码子。

PROJECT SUMMARY The nonsense-mediated mRNA decay (NMD) pathway is a specialized pathway that contributes to the recognition and rapid degradation of mRNA with premature termination codons. This prevents the production of non-functional, potentially harmful truncated proteins. NMD affects the expression of a number of human genetic diseases by modulating the expression of genes carrying nonsense mutations. NMD also regulates the expression of specific genes by degrading natural mRNAs. Regulation of natural mRNAs by NMD has been identified in numerous organisms ranging from yeast to humans. However, the extent and reason for the targeting of most of these natural mRNAs is generally unknown and could be a way to support a proper cellular response to changing environmental conditions. The objective of this study is to investigate the role NMD plays in copper homeostasis. We hypothesize that mRNAs involved in copper homeostasis and are sensitive to NMD are regulated by the pathway through similar features. In addition, we postulate that the regulation of these mRNAs by NMD is responsive to environmental conditions. This hypothesis is formulated based on our preliminary observations showing that four mRNAs involved in copper homeostasis have identical NMD-targeting features. Additionally, regulation of one of the mRNAs by NMD is responsive to environment copper levels. This research will determine the extent to which functionally related mRNAs are regulated by NMD due to similar features. In addition, it will demonstrate the extent to which this regulation is responsive to environmental conditions. We plan to test our central hypothesis and accomplish the overall objective of this project by pursuing the following specific aims. In Aim 1 we will determine the features/factors that target mRNAs involved in copper homeostasis to NMD. In Aim 2 we will determine the environmental impact on the regulation of these mRNAs by NMD and the physiological consequences resulting from this regulation The contributions of this research is that it will demonstrate the extent to which natural mRNAs from the same functional group are regulated by NMD and the influence the environment has on this regulation. Successful completion of these studies would demonstrate for the first time the effect environmental conditions have on the regulation of functionally related mRNAs by NMD. This knowledge will allow the categorization of cellular processes regulated NMD, and lead to a more complete understanding of gene regulation in the genetically tractable organism S. cerevisiae. It is important to understand natural mRNA regulation by NMD given that these mRNAs are found in multiple organisms including humans and the strategies used by S. cerevisiae to regulate functionally related mRNAs could be utilized in other systems and under other conditions. Furthermore, The NMD pathway in humans is being targeted to treat genetic diseases caused by genes that contain nonsense codons.