Probing the specificity and activity of the metazoan Integrator complex
探讨后生动物整合复合体的特异性和活性
基本信息
- 批准号:10437741
- 负责人:
- 金额:$ 64.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-15 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAmino AcidsAttenuatedBehaviorBindingBiochemicalBiologicalBruck-de Lange syndromeC-terminalCellsChromatinCodeComplexComputer AnalysisCuesDataDevelopmentDiseaseDrosophila genusElongation FactorEndoribonucleasesEnhancersExplosionFunctional disorderGene ExpressionGene Expression RegulationGenerationsGenesGenetic TranscriptionGrowthHematological DiseaseHematopoiesisHematopoietic NeoplasmsHomeostasisHuman DevelopmentIn VitroKnowledgeMalignant NeoplasmsMalignant neoplasm of liverMapsMass Spectrum AnalysisMediatingMessenger RNAModelingModificationMolecularMonitorMutationNeuronsOutputPhosphoric Monoester HydrolasesPhosphorylationPhysiologicalPlasmidsPolymerasePropertyProtein DephosphorylationProtein phosphataseProteinsRNARNA Polymerase IIRNA SplicingRNA analysisRNA chemical synthesisRegulationRegulator GenesReporterResearchRoleSerineSignal TransductionSiteSmall Nuclear RNASpecificityStimulusStructureTimeTranscriptTranscription ElongationTranscriptional RegulationUntranslated RNAWorkattenuationbasecilium biogenesiscohesindevelopmental diseaseendonucleaseexperiencefunctional genomicsgene repressionhuman diseaseimprovedin vivoinsightinterestlipid biosynthesismalignant stomach neoplasmmigrationmutantneurogenesispromoterprotein complexpublic health relevancerecruitresponsesynergismtermination factortooltranscription factortranscription terminationtranscriptome sequencing
项目摘要
PROJECT SUMMARY:
Precise control of gene expression in response to external signals and cues is essential for organismal
development, growth and homeostasis. In metazoan cells, the regulated pausing of RNA polymerase II (RNAPII)
in early transcript elongation is pivotal for defining gene output. However, the mechanisms that govern pausing
and release of RNAPII into productive elongation remain poorly defined. Our work demonstrates that the
Integrator complex (INT) targets paused RNAPII to attenuate messenger RNA (mRNA) expression. Moreover,
we find that INT is a central regulator of gene expression in Drosophila cells, through its selective recruitment to
specific gene promoters and subsequent INT-mediated termination of transcription. INT is known to be required
for 3'-end formation of small nuclear RNAs involved in splicing (snRNAs), and has been implicated in cleavage
and processing of other non-coding RNAs. Accordingly, the Integrator 11 subunit (IntS11) was found to possess
an RNA endonuclease activity. Interestingly, INT was recently shown to also associate with RNAPII at protein-
coding genes, however, our understanding of INT function on mRNAs is very limited. As described below, our
preliminary data and proposed research will address fundamental, unanswered questions about gene regulation,
and aim to elucidate the roles of INT in human disease. For example, paused RNAPII is very stable at some
mRNA gene promoters, yet highly unstable at others. This diversity of behaviors for paused RNAPII has
generated considerable interest concerning its underlying causes. In particular, the evidence for rapid turnover
of paused RNAPII suggests the presence of a promoter-proximal termination factor. However, no such factor
has been described in metazoan cells. Our work demonstrates that INT is this ‘missing’ termination factor and
suggests a role for IntS11-mediated RNA cleavage in transcript termination. In addition, we discovered that INT
recruits a protein phosphatase, PP2A, to RNAPII leading to de-phosphorylation of the RNAPII C-terminal domain
(CTD). This finding is highly significant, since RNAPII CTD phosphorylation is involved in the release of paused
RNAPII into productive mRNA elongation. The proposed work expands on this preliminary data. Aim 1 will
determine how INT is targeted to specific gene promoters, pursuing in particular evidence for an interaction
between INT and the cohesin complex. Notably, INT has already been shown to interact with cohesin in
mammalian neurons, and implicated together with cohesin in Cornelia de Lange Syndrome. Aim 2 will probe the
impact of the IntS11 RNA endonuclease activity on RNAPII elongation properties. Aim 3 will define the
substrates and consequences of INT-mediated recruitment of the PP2A phosphatase to the early elongation
complex. Critically, mutations in INT have been associated with a large number of diseases, with every one of
the 14 subunits in the INT complex being implicated a pathophysiological state(s). Consequently, improving our
understanding of INT activity will provide invaluable insights into mechanisms of diseases such as blood, hepatic
and gastric cancers, and developmental disorders, including aberrant neuronal migration.
项目总结:
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Integrator Recruits Protein Phosphatase 2A to Prevent Pause Release and Facilitate Transcription Termination.
- DOI:10.1016/j.molcel.2020.08.016
- 发表时间:2020-10-15
- 期刊:
- 影响因子:16
- 作者:Huang KL;Jee D;Stein CB;Elrod ND;Henriques T;Mascibroda LG;Baillat D;Russell WK;Adelman K;Wagner EJ
- 通讯作者:Wagner EJ
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Karen L Adelman其他文献
Karen L Adelman的其他文献
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{{ truncateString('Karen L Adelman', 18)}}的其他基金
Identifying the sequences and factors that govern the fate of elongating RNAPII
鉴定控制延长 RNAPII 命运的序列和因素
- 批准号:
10534168 - 财政年份:2021
- 资助金额:
$ 64.95万 - 项目类别:
Identifying the sequences and factors that govern the fate of elongating RNAPII
鉴定控制延长 RNAPII 命运的序列和因素
- 批准号:
10092655 - 财政年份:2021
- 资助金额:
$ 64.95万 - 项目类别:
Identifying the sequences and factors that govern the fate of elongating RNAPII
鉴定控制延长 RNAPII 命运的序列和因素
- 批准号:
10320370 - 财政年份:2021
- 资助金额:
$ 64.95万 - 项目类别:
Probing the specificity and activity of the metazoan Integrator complex
探讨后生动物整合复合体的特异性和活性
- 批准号:
10224260 - 财政年份:2019
- 资助金额:
$ 64.95万 - 项目类别:
Single molecule analyses of RNA polymerase II elongation
RNA 聚合酶 II 延伸的单分子分析
- 批准号:
6762373 - 财政年份:2002
- 资助金额:
$ 64.95万 - 项目类别:
Single molecule analyses of RNA polymerase II elongation
RNA 聚合酶 II 延伸的单分子分析
- 批准号:
6640558 - 财政年份:2002
- 资助金额:
$ 64.95万 - 项目类别:
Single molecule analyses of RNA polymerase II elongation
RNA 聚合酶 II 延伸的单分子分析
- 批准号:
6552228 - 财政年份:2002
- 资助金额:
$ 64.95万 - 项目类别:
Investigating Transcriptional Responses to the Environment
研究对环境的转录反应
- 批准号:
7968206 - 财政年份:
- 资助金额:
$ 64.95万 - 项目类别:
Investigating Transcriptional Responses to the Environment
研究对环境的转录反应
- 批准号:
8553780 - 财政年份:
- 资助金额:
$ 64.95万 - 项目类别:
Investigating Transcriptional Responses to the Environme
研究对环境的转录反应
- 批准号:
7330699 - 财政年份:
- 资助金额:
$ 64.95万 - 项目类别:
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