Biogenesis of macromolecular machines for post-transcriptional regulation of translation
用于翻译转录后调控的大分子机器的生物发生
基本信息
- 批准号:10798922
- 负责人:
- 金额:$ 12.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-17 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:ATP phosphohydrolaseAddressAffectAutoimmune DiseasesAwardBiochemicalBiochemistryBiogenesisBiological AssayBiologyCell physiologyCellsCellular StressColon CarcinomaColorectal CancerComplexCoupledCuesDataDefectDepositionDevelopmentDiseaseDown-RegulationDrug resistanceEdemaElementsEncephalopathiesEnsureEukaryotaEventFoundationsFundingFutureGene ExpressionGeneticGenetic TranscriptionGenomeGoalsGuide RNAHumanHypsarrhythmiaIndividualIsomerismKnowledgeLaboratoriesLeadLinkMalignant NeoplasmsMalignant neoplasm of brainMalignant neoplasm of lungMalignant neoplasm of prostateMapsMediatingMethylationModificationMolecularMorphologyMutationNational Institute of General Medical SciencesNerve DegenerationNucleotidesOptic AtrophyOutputPathologicPathway interactionsPatternPerceptionPlayPost-Transcriptional RegulationPrader-Willi SyndromeProcessProductionProtein BiosynthesisProteinsProteomicsPseudouridinePublic HealthRNARNA SplicingReagentRegulationRegulatory PathwayResearchResearch PersonnelRibonucleasesRibonucleoproteinsRibosomal RNARibosomesRoleSiteSmall Nucleolar RNASpliceosomesStressSyndromeTextbooksTherapeutic InterventionTranscription AlterationTranslational RegulationTranslationsUntranslated RNAUridineYeastsZebrafishcancer typecareercell growthfallshuman diseaseinsightmalignant breast neoplasmnervous system disordernew therapeutic targetnext generation sequencingnovelposttranscriptionalprogramsprotein complexstructural biologytooltranslational impacttumorigenesisyeast genetics
项目摘要
Summary:
Ribosomes are highly conserved RNA-protein complexes that direct protein synthesis in all cells. Dysregulation
of ribosome production or function is detrimental to gene expression and underlies several disease states. Over
2% of ribosomal RNA (rRNA) nucleotides are modified. These modifications play a critical role in the proper
production of ribosomes that can accurately perform protein synthesis. The two major rRNA modifications are
2’-O-methylation and pseudouridylation that are directed by highly conserved non-coding RNAs called small
nucleolar RNAs (snoRNAs). Altered levels of snoRNAs are associated with human diseases from
neurodegeneration to multiple types of cancer, underscoring their importance for proper cell growth. Therefore,
a key question is how levels of snoRNAs are regulated and how does their dysregulation lead to translation
defects in disease? Despite the textbook perception that rRNA modifications are equally deposited in all
ribosomes, recent advances in mapping modifications have revealed substoichiometric rRNA modification sites,
strongly suggesting that ribosome assembly and function may be regulated by the modification status of rRNA.
A long-term goal of my laboratory is to identify the post-transcriptional mechanisms that regulate the abundance
A prominent rRNA modification in
eukaryotes is 2’-O-methylation, the incorporation of which is guided by snoRNAs of the box C/D class. These
snoRNAs interact with a set of evolutionarily conserved proteins to form ribonucleoprotein complexes
(snoRNPs). The assembly of snoRNPs is highly regulated which, in turn, is important to maintain levels of
snoRNAs and to coordinate this process with other cellular events. However, despite their fundamental
importance, much of these regulatory events remains a black box. We have performed targeted yeast mutational
and suppressor screens of snoRNP assembly factors to determine their essential contributions and identify
genetic pathways that mediate snoRNP biogenesis. Our data indicate that regulation of box C/D snoRNP
production by assembly factors is critically important for control of the modification pattern of rRNAs and
dysregulation of this process alters the biogenesis pathway and the fidelity of ribosomes. Our goal is to combine
the novel genetic tools and reagents that we have recently developed with
to answer two key questions: 1) regulatory factors control
the steady-state levels of snoRNAs required for accurate modification of rRNA?; and 2) How do changes in
snoRNA levels alter and tune protein synthesis? These studies will provide significant insights into the control of
gene expression by snoRNAs at the translation level, and may inform our view of how snoRNA dysregulation
underlies human disease.
of snoRNAs and understand their contribution to cellular translational control.
biochemical assays, structural biology,
proteomics, and next-generation sequencing How do
概括:
核糖体是高度保守的RNA-蛋白质复合物,可导致所有细胞中的蛋白质合成。失调
核糖体的产生或功能对基因表达有害,并且是几种疾病状态的基础。超过
2%的核糖体RNA(RRNA)核动肽被修饰。这些修改在适当的
可以准确执行蛋白质合成的核糖体的产生。两个主要的rRNA修改是
由高度组成的非编码RNA指导的2'-O-甲基化和假硫岛化称为小
核仁RNA(snornas)。 snornas水平的改变与人类疾病有关
神经变性到多种类型的癌症,强调了它们对适当细胞生长的重要性。所以,
一个关键的问题是如何调节snornas的水平,以及它们的失调如何导致翻译
疾病缺陷?尽管教科书认为rRNA修改同样沉积在所有人中
核糖体,映射修饰的最新进展揭示了化学计量rRNA修饰位点,
强烈表明核糖体组装和功能可以通过rRNA的修饰状态来调节。
我实验室的长期目标是确定调节抽象的转录后机制
突出的rRNA修改
真核生物是2'-O-甲基化,其掺入的融合是由盒子C/D类的snornas指导的。这些
SNORNAS与一组进化的蛋白质相互作用,形成核糖核蛋白复合物
(snornps)。 snornps的组装受到高度调节,而这对于维持水平很重要
snornas并与其他细胞事件进行协调。但是,使他们的基本任务
重要的是,这些监管事件中的大部分仍然是黑匣子。我们已经进行了靶向酵母突变
和snornp装配因素的抑制屏幕以确定其基本贡献并确定
介导SNORNP生物发生的遗传途径。我们的数据表明Box C/D SNORNP的调节
通过组装因素生产对于控制RRNA的修饰模式至关重要
该过程的失调改变了核糖体的生物发生途径和忠诚度。我们的目标是结合
我们最近开发的新型遗传工具和试剂
回答两个关键问题:1)监管因素控制
精确修饰rRNA所需的snornas的稳态水平? 2)如何改变
SNORNA水平改变并调整蛋白质合成?这些研究将为控制
snornas在翻译层面的基因表达,并可能告知我们对snorna失调的看法
是人类疾病的基础。
snornas,并了解它们对细胞翻译控制的贡献。
生化测定,结构生物学,
蛋白质组学和下一代测序如何
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
RNA structural probing of guanine and uracil nucleotides in yeast.
- DOI:10.1371/journal.pone.0288070
- 发表时间:2023
- 期刊:
- 影响因子:3.7
- 作者:
- 通讯作者:
A Biallelic Variant of the RNA Exosome Gene EXOSC4 Causes Translational Defects Associated with a Neurodevelopmental Disorder.
RNA 外泌体基因 EXOSC4 的双等位变体会导致与神经发育障碍相关的翻译缺陷。
- DOI:10.1101/2023.10.24.23297197
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Fasken,MiloB;Leung,SaraW;Cureton,LaurynA;Al-Awadi,Maha;Al-Kindy,Adila;Khoshnevis,Sohail;Ghalei,Homa;Al-Maawali,Almundher;Corbett,AnitaH
- 通讯作者:Corbett,AnitaH
Practical advice for mentoring and supporting faculty colleagues in STEM fields: Views from mentor and mentee perspectives.
- DOI:10.1016/j.jbc.2021.101062
- 发表时间:2021-09
- 期刊:
- 影响因子:0
- 作者:Spangle JM;Ghalei H;Corbett AH
- 通讯作者:Corbett AH
Ribosomal RNA 2'-O-methylations regulate translation by impacting ribosome dynamics.
- DOI:10.1073/pnas.2117334119
- 发表时间:2022-03-22
- 期刊:
- 影响因子:11.1
- 作者:Khoshnevis S;Dreggors-Walker RE;Marchand V;Motorin Y;Ghalei H
- 通讯作者:Ghalei H
Maturation of small nucleolar RNAs: from production to function.
- DOI:10.1080/15476286.2023.2254540
- 发表时间:2023-01
- 期刊:
- 影响因子:4.1
- 作者:Webster, Sarah F.;Ghalei, Homa
- 通讯作者:Ghalei, Homa
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Homa Ghalei其他文献
Homa Ghalei的其他文献
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{{ truncateString('Homa Ghalei', 18)}}的其他基金
Biogenesis of macromolecular machines for post-transcriptional regulation of translation
用于翻译转录后调控的大分子机器的生物发生
- 批准号:
10669201 - 财政年份:2020
- 资助金额:
$ 12.1万 - 项目类别:
Biogenesis of macromolecular machines for post-transcriptional regulation of translation
用于翻译转录后调控的大分子机器的生物发生
- 批准号:
10454992 - 财政年份:2020
- 资助金额:
$ 12.1万 - 项目类别:
Biogenesis of macromolecular machines for post-transcriptional regulation of translation
用于翻译转录后调控的大分子机器的生物发生
- 批准号:
10388877 - 财政年份:2020
- 资助金额:
$ 12.1万 - 项目类别:
Biogenesis of macromolecular machines for post-transcriptional regulation of translation
用于翻译转录后调控的大分子机器的生物发生
- 批准号:
10618662 - 财政年份:2020
- 资助金额:
$ 12.1万 - 项目类别:
Biogenesis of macromolecular machines for post-transcriptional regulation of translation
用于翻译转录后调控的大分子机器的生物发生
- 批准号:
10240673 - 财政年份:2020
- 资助金额:
$ 12.1万 - 项目类别:
Biogenesis of macromolecular machines for post-transcriptional regulation of translation
用于翻译转录后调控的大分子机器的生物发生
- 批准号:
10029053 - 财政年份:2020
- 资助金额:
$ 12.1万 - 项目类别:
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