Coordination of RNA cleavage with end modification and processing
Coordination of RNA cleavage with end modification and processing
批准号:
9141543
负责人:
Jay R Hesselberth
金额:
$37.82万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-08-01 至 2021-05-31
关键词:
AddressBiochemicalCellsDNA SequenceDiseaseEndoribonucleasesEnzymesFunctional disorderGeneticHumanLeadLigaseMediatingMessenger RNAMethodsModificationNeuronal DifferentiationOutcomeOutcome StudyPhosphotransferasesPhysiologicalProcessProteinsRNARNA ProcessingReactionRoleStressYeastsabstractingbasecell growthhuman diseaseimprovedinsightmRNA Decayneuronal metabolismprogramsrepairedresponseyeast tRNA ligase
中文摘要
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。
英文摘要
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.
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会议论文
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