Coordination of RNA cleavage with end modification and processing

摘要 程序性或无意的RNA切割导致RNA5‘和3’末端“脏” 它们被RNA末端修饰酶重塑。核糖核酸末端的产物 修饰是催化RNA的RNA加工活动的底物 修复、腐烂或稳定。因为某些加工酶能识别 不同的修饰末端，RNA末端修饰酶可促进某些 处理步骤，同时抑制其他步骤。相反，RNA加工酶 催化不同的反应可能识别-并竞争-底物 用相同的末端修饰来控制RNA切割的结果。这些 不同的情景可能被用来调节RNA的结果 裂解，但我们对RNA末端修饰在过程中的作用知之甚少 RNA处理。我们发现，RNA末端被RNA5‘-修饰。 酵母tRNA连接酶Trl1的激酶活性对调节未折叠很重要 无意中蛋白质对RNA中间体的磷酸化反应 UPR激活，以促进他们的周转5“→3”腐烂，和Trl1RNA5“- 蛋白水解酶活性介导共刺激蛋白产生的mRNA片段的周转 翻译中的“no-go”信使核糖核酸衰退。人类RNA5‘-激活酶CLP1具有 在神经元新陈代谢和分化中起重要作用，但我们不知道 CLP1的底物，因此目前还不清楚RNA5‘-激酶功能障碍 活动会导致疾病。我们的发现Trl1 5‘-激酶活性介导了 MRNA切割片段的衰退也回避了这样一个问题：Trl1 连接酶也可以修复RNA，但人们只知道少数几个RNA修复的例子。 为了解决这些问题，我们将重点解决以下问题：1.什么是 人CLP1RNA5‘-激酶的底物？；2.RNA如何结束？ 修饰和加工调节未折叠的蛋白质反应？；3.如何 NO-GO信使核糖核酸衰变的产物及其生理机制 底物？；4.RNA修复是仅限于特定的底物，还是作用于 其他受损的RNA？这些研究的结果将是一个改进的 理解在RNA裂解后如何使用RNA末端修饰 调节RNA的处理，这些见解可能会帮助我们理解 RNA末端修饰功能障碍是如何导致人类疾病的。

Abstract Programmed or unintentional RNA cleavage leads to "dirty" RNA 5´ and 3´ ends that are remodeled by RNA end modification enzymes. The products of RNA end modification are substrates for RNA processing activities that catalyze RNA repair, decay or stabilization. Because some processing enzymes recognize different modified termini, RNA end modification enzymes could promote some processing steps while inhibiting others. Conversely, RNA processing enzymes that catalyze different reactions might recognize – and compete for – substrates with the same end modification to control the outcome of RNA cleavage. These different scenarios could potentially be used to regulate the outcome of RNA cleavage, but we know very little about the roles of RNA end modification during RNA processing. We discovered that RNA end modification by the RNA 5´- kinase activity of the yeast tRNA ligase Trl1 is important to regulate the unfolded protein response by phosphorylating RNA intermediates during unintentional UPR activation to facilitate their turnover by 5´→3´ decay, and that Trl1 RNA 5´- kinase activity mediates the turnover of mRNA fragments created by co- translational “no-go” mRNA decay. The human RNA 5´-kinase enzyme Clp1 has an important role in neuronal metabolism and differentiation, but we do not know the substrates of Clp1 and so it is not clear how dysfunction in RNA 5´-kinase activity leads to disease. Our discovery that Trl1 5´-kinase activity mediates the decay of mRNA cleavage fragments also begs the question of whether the Trl1 ligase can also repair RNAs, but only a few examples of RNA repair are known. To address these issues, we will focus on the following questions: 1. What are the substrates of the human Clp1 RNA 5´-kinase?; 2. How do RNA end modification and processing regulate the unfolded protein response?; 3. How are the products of no-go mRNA decay created, and what are its physiological substrates?; 4. Is RNA repair restricted to specific substrates, or does it act on other damaged RNAs? The outcomes of these studies will be an improved understanding of how RNA end modification is used after RNA cleavage to mediate RNA processing, and these insights may inform our understanding of how dysfunction in RNA end modification underlies human disease.