Understanding the mechanism of pre-mRNA splicing
了解前体 mRNA 剪接的机制
基本信息
- 批准号:10387298
- 负责人:
- 金额:$ 6.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:3&apos Splice Site5&apos Splice SiteATP phosphohydrolaseAddressAlternative SplicingAreaAutomobile DrivingBindingBiochemicalBiochemistryBiological AssayComplexCryoelectron MicroscopyDevelopmentDiseaseElementsEventExonsFrameshift MutationGeneticGenetic DiseasesGrowthHumanHuman GeneticsIn VitroIntronsInvestigationLeadLiquid substanceMalignant NeoplasmsMass Spectrum AnalysisModelingMolecular ConformationN-terminalOnset of illnessPatternPoint MutationProcessProteinsRNARNA HelicaseRNA SplicingRegulationResearchSiteSpliceosomesStructureSubstrate SpecificitySystemTestingTherapeuticTimeTranscriptU1 Small Nuclear RibonucleoproteinU2 Small Nuclear RibonucleoproteinUntranslated RNAYeastsdensityflexibilityhelicasein vitro activityin vivoinsightmRNA Precursornovelrecruit
项目摘要
PROJECT SUMMARY
Splicing is an essential step in pre-mRNA processing during which introns are excised, and exons are ligated.
This is catalyzed by the spliceosome which recognizes splice sites (ss) and assembles on its pre-mRNA
substrate in a stepwise manner. The spliceosome undergoes multiple rearrangements, largely driven by
DExD/H-box helicases, during the splicing cycle. Splice site recognition and structural rearrangement of the
spliceosome need to be carried out with high fidelity. Errors in splicing contribute to around 30% of human
genetic disorders and the development of many other diseases including cancer.
In spite of decades of research, the mechanism of initial splice site recognition is still largely a mystery. There
are currently two models for ss recognition, namely intron and exon definition. In the former model, the
spliceosome initially recognizes and assembles across introns which is then excised, ligating the flanking
exons. In the latter model, the spliceosome first assembles around an exon and is remodeled into a cross-
intron complex before splicing out the intron. It is unclear whether complexes assembled across an exon or an
intron are the same or different from each other, and how exactly exon definition remodeling occurs. Our lab
recently determined the yeast E-complex structure. The structure suggest that the exact same spliceosome
can assemble on an exon and carry out exon definition without the need of additional components or structural
rearrangements. To provide the first experimental evidence for this hypothesis, we will solve the structure of an
early spliceosomal complex assembled on both an intron and an exon. Results from this project will
significantly advance our understanding of initial intron/exon recognition by the spliceosome.
DExD/H-box helicases are important in driving spliceosome transitions and all four DEAH-box spliceosomal
helicases (Prp2, Prp16, Prp22 and Prp43) involved in late splicing share intriguing structural similarities. In
spite of extensive biochemical and structural analyses of these helicases, it is unclear what structural element
in DEAH-box helicases is responsible for the helicase activity. It is also unclear how they are specifically
recruited to the spliceosome and regulated to perform their dedicated action at the right time and place. I aim
to address these questions using Prp22 as a model with mostly biochemical approaches. These results may
provide important insights into the mechanism and regulation of all four DEAH-box spliceosomal helicases.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Francesca Danielle De Bortoli其他文献
Francesca Danielle De Bortoli的其他文献
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{{ truncateString('Francesca Danielle De Bortoli', 18)}}的其他基金
Understanding the mechanism of pre-mRNA splicing
了解前体 mRNA 剪接的机制
- 批准号:
10731756 - 财政年份:2022
- 资助金额:
$ 6.76万 - 项目类别:
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