Functions of mRNA Pseudouridylation
Functions of mRNA Pseudouridylation
批准号:
10442443
负责人:
Wendy Victoria Gilbert
金额:
$33.5万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2014
资助国家:
美国
项目状态:
已结题
起止时间:
2014-09-01 至 2023-08-31
关键词:
AcuteAffectAlternative SplicingBase PairingBiochemicalBiologicalBiologyCellsChromatinCodeDigestive System DisordersDiseaseDyskeratosis CongenitaEnzymesEtiologyEventGene ExpressionGene Expression RegulationGenesGoalsHealthHepG2HumanIn VitroIntellectual functioning disabilityKnock-outKnowledgeLeadLinkMalignant NeoplasmsMessenger RNAMitochondriaMitochondrial MyopathiesModificationMolecularNucleotidesProductionProteinsProteomePseudouridineRNARNA SplicingReaderRegulatory ElementReproducibilityResearchResistanceResolutionRoleSiteSmall Nuclear RNAUridineViralVirus DiseasesWorkYeastsbasedisease-causing mutationhuman diseaseinsightmRNA Precursornew therapeutic targetnoveloverexpressionstable cell linetranscriptometranscriptome sequencing
中文摘要
项目总结
多种伪尿苷合成酶(PU)与人类疾病有关,但
脓液活性丧失与线粒体肌病、消化系统疾病、
智力残疾、对病毒感染的抵抗力、先天性角化不良和多种癌症
在很大程度上仍然不为人知。在我们目前的知识中有几个关键的空白
脓液蛋白的功能。尽管PUS蛋白在催化过程中的基本生化活性
尿苷异构化为假尿苷是众所周知的,其特定的RNA靶标
大多数人类脓液蛋白是未知的或不完全知道的。我们的长期目标包括
确定所有PUS蛋白的靶标并确定其分子后果
在与疾病相关的细胞环境中用假尿苷修饰特定的RNA。这将是
对于理解脓虚引起的疾病的病因至关重要,并可能揭示
治疗的新靶点。
我们先前的研究表明,假尿苷是一种新生的普遍的修饰
前信使核糖核酸。这些结果,加上定量的体外研究表明,
伪尿嘧啶可以影响RNA-蛋白质和RNA-RNA相互作用,导致我们的中枢
前信使核糖核酸假尿路假说在基因水平控制人类基因表达
前信使核糖核酸剪接。为了支持这一假说,我们已经证明了损失一个前-
改造假尿苷合成酶PUS1的mRNA导致前mRNA的广泛变化
在人类细胞中的剪接,具有超过3,000个PUS1敏感的选择性剪接事件
已确认身份。我们的具体目标是:(1)确定与剪接相关的前mRNA靶标
主要的前信使核糖核酸酶:PUS1、PUS7和RPUSD4;以及(2)
阐明假尿苷敏感剪接的分子机制。
这项拟议的工作将为我们提供对分子功能的关键洞察
假尿苷存在于前mRNAs中,并可能揭示真核基因调控的新模式。通过
建立前mRNAs作为PUS酶的一类广泛的新底物,我们的工作
暗示有缺陷的剪接是一种看似合理但未被充分研究的连接脓液丢失的机制
对多种人类疾病的积极作用。
英文摘要
PROJECT SUMMARY
Multiple pseudouridine synthases (PUS) are implicated in human disease, but the
mechanisms that connect loss of PUS activity to mitochondrial myopathy, digestive disorders,
intellectual disability, resistance to viral infection, dyskeratosis congenita, and diverse cancers
remain largely unknown. There are several critical gaps in our current knowledge of the
functions of PUS proteins. Although the basic biochemical activity of PUS proteins in catalyzing
the isomerization of uridine to pseudouridine is well understood, the specific RNA targets of
most human PUS proteins are unknown or incompletely known. Our long-term goals include
identifying the targets of all PUS proteins and determining the molecular consequences of
modification of specific RNAs with pseudouridine in disease-relevant cellular contexts. This will
be critical for understanding the etiology of diseases caused by PUS deficiency and may reveal
new therapeutic targets for treatment.
Our previous studies revealed that pseudouridine is a prevalent modification of nascent
pre-messenger RNA. These results, together with quantitative in vitro studies showing that
pseudouridine can affect both RNA-protein and RNA-RNA interactions, lead to our central
hypothesis that pre-mRNA pseudouridylation controls human gene expression at the level of
pre-mRNA splicing. In support of this hypothesis, we have demonstrated that loss of one pre-
mRNA modifying pseudouridine synthase, PUS1, causes widespread changes to pre-mRNA
splicing in human cells, with more than 3,000 PUS1-sensitive alternative splicing events
identified. Our Specific Aims are to (1) Define the splicing-relevant pre-mRNA targets of the
predominant pre-mRNA pseudouridylating enzymes: PUS1, PUS7, and RPUSD4; and (2)
Elucidate the molecular mechanisms of pseudouridine-sensitive splicing.
The proposed work will provide key insight into the molecular functions of
pseudouridines in pre-mRNAs and may reveal novel modes of eukaryotic gene regulation. By
establishing pre-mRNAs as a broad new class of substrates for PUS enzymes, our work
implicates defective splicing as a plausible but understudied mechanism connecting loss of PUS
activity to numerous human diseases.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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Translational Control by 5'-untranslated regions
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Characterizing functional targets of a non-coding RNA oncogene, SNORA42
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Regulation and Function of snoRNA Genes
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Functions of mRNA Pseudouridylation
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批准号:10659705
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资助金额:$34.51万
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依托单位:
Functions of mRNA Pseudouridylation
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批准号:10206158
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资助金额:$33.5万
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Regulation and Function of snoRNA Genes
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批准号:8755989
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依托单位:
Functional Consequences of Ribosome Heterogeneity
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批准号:8663925
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资助金额:$29.46万
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财政年份:2012
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负责人:Wendy Victoria Gilbert
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依托单位:
Ribosome Specialization and Regulation
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资助金额:$7.26万
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Functional Consequences of Ribosome Heterogeneity
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批准号:8235558
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依托单位:
Functional Consequences of Ribosome Heterogeneity
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批准号:8479375
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资助金额:$28.48万
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Functional Consequences of Ribosome Heterogeneity
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Mechanisms and Regulation of Yeast Internal Ribosome Entry Sites
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批准号:8009950
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Upgrade of Tecan Robotic Liquid-Handling Equipment
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Mechanisms and Regulation of Yeast Internal Ribosome Entry Sites
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财政年份:2007
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依托单位:
Mechanisms and Regulation of Yeast Internal Ribosome Entry Sites
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批准号:7299796
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Mechanisms and Regulation of Yeast Internal Ribosome Entry Sites
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依托单位:
海外基金