Chemical Genetics of Transcriptional Regulation by CDKs in Human Cells
人类细胞中 CDK 转录调控的化学遗传学
基本信息
- 批准号:8630081
- 负责人:
- 金额:$ 32.21万
- 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
- 起止时间:2014-02-15 至 2017-12-31
- 项目状态:已结题
- 来源:
- 关键词:Antineoplastic AgentsAntiviral AgentsArchaeal RNABindingCatalytic DomainCell Cycle ProgressionCell ProliferationCell divisionCellsChemicalsChromatinColon CarcinomaCyclin-Dependent KinasesDNA Polymerase IIDNA-Directed RNA PolymeraseDefectDevelopmentDrug TargetingElongation FactorEnsureEnzymesEukaryotaEvaluationFission YeastGene ExpressionGene Expression RegulationGenesGenetic ScreeningGenetic TranscriptionGenomeHumanHuman DevelopmentHuman EngineeringHuman IdentificationsIn VitroIndividualKineticsLabelMalignant NeoplasmsMessenger RNAModelingNormal tissue morphologyOrganismOrthologous GenePathway interactionsPatternPeptide Initiation FactorsPharmaceutical PreparationsPhasePhosphorylationPhosphotransferasesPlayPolymerasePositive Transcriptional Elongation Factor BProcessPropertyProteinsRNARNA Polymerase IIRNA ProcessingRNA chemical synthesisReadingRecruitment ActivityRegulationRoleSignal TransductionStagingTestingTimeTorpedoTranscriptTranscription ElongationTranscription InitiationTranscriptional RegulationVariantViralYeastsadenine analoganalogbasecancer cellchemical geneticschemotherapychromatin modificationchromatin proteincrosslinkcyclin T1cyclin-dependent kinase-activating kinasefeedinggenome-widehuman diseasein vivomutantnovelnovel strategiespreventpromoterpublic health relevancereconstitutionresearch studysmall moleculetranscription factor TFIIEtranscription factor TFIIHtranscription termination
项目摘要
Project Summary
The transcription cycle of RNA polymerase II (Pol II) depends on sequential functions of
distinct cyclin-dependent kinases (CDKs), but the mechanisms that order those functions
are still emerging. We have taken a chemical-genetic approach-replacement of wild-
type with analog-sensitive (AS) mutant CDKs-to reveal both "early" and "late" functions
of the CDK network in transcription. First, by selective inhibition of Cdk7-a component
of transcription initiation factor TFIIH-in human cells, we uncovered two unexpected,
and seemingly antagonistic functions. Cdk7 activity is required to recruit factors that
establish a promoter-proximal pause by Pol II, and to activate Cdk9, catalytic subunit of
positive transcription elongation factor b (P-TEFb), which releases the pause. Therefore
the CDK network appears to depend on incoherent feedforward to raise a transient
kinetic barrier to Pol II elongation, and thus create a temporal window to recruit mRNA-
processing and chromatin-modifying machinery. Consistent with a requirement for CDK-
directed pausing to ensure faithful RNA processing, inhibition of Cdk7 or Cdk9 leads to
defects in termination and 3'-end maturation of Pol II transcripts. Second, in a chemical-
genetic screen for Cdk9 substrates, we identified multiple proteins involved in RNA 5'-
end decapping and the "torpedo" pathway of transcription termination, which has
recently been suggested to influence pausing and divergent antisense transcription. We
will dissect the initiation-elongation transition of Pol II, and elucidate regulation of
transcription termination and polarity, to uncover novel modes of gene regulation by
CDKs. The specific aims are:
1. To identify functions and targets of CDKs at the initiation-elongation transition
2. To investigate possible regulation of the transcription termination pathway by P-
TEFb, uncovered in a chemical genetic screen for Cdk9 targets
3. To dissect functions of Cdk7 and Cdk9 by chemical genetics in human cells
Our studies reveal a CDK cascade at the core of the Pol II transcription cycle;
completion of our aims will illuminate how Cdk7 and Cdk9 collaborate to ensure
unidirectional transitions between phases of that cycle. By turning CDKs into chemical
switches that can be manipulated with customized small molecules, we will distinguish
their specific roles and substrates, and reveal new anti-cancer or anti-viral drug targets.
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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{{ truncateString('ROBERT P FISHER', 18)}}的其他基金
Cyclin-dependent kinase control of cell-division and transcription cycles
细胞分裂和转录周期的细胞周期蛋白依赖性激酶控制
- 批准号:
10559139 - 财政年份:2018
- 资助金额:
$ 32.21万 - 项目类别:
Cyclin-dependent kinase control of cell-division and transcription cycles
细胞分裂和转录周期的细胞周期蛋白依赖性激酶控制
- 批准号:
10370800 - 财政年份:2018
- 资助金额:
$ 32.21万 - 项目类别:
Cyclin-dependent kinase control of cell-division and transcription cycles
细胞分裂和转录周期的细胞周期蛋白依赖性激酶控制
- 批准号:
10378005 - 财政年份:2018
- 资助金额:
$ 32.21万 - 项目类别:
Cyclin-dependent kinase control of cell-division and transcription cycles
细胞分裂和转录周期的细胞周期蛋白依赖性激酶控制
- 批准号:
9903405 - 财政年份:2018
- 资助金额:
$ 32.21万 - 项目类别:
Chemical Genetics of Transcriptional Regulation by CDKs in Human Cells
人类细胞中 CDK 转录调控的化学遗传学
- 批准号:
8806563 - 财政年份:2014
- 资助金额:
$ 32.21万 - 项目类别:
Chemical Genetics of Transcriptional Regulation by CDKs in Human Cells
人类细胞中 CDK 转录调控的化学遗传学
- 批准号:
9198169 - 财政年份:2014
- 资助金额:
$ 32.21万 - 项目类别:
Chemical Genetic Analysis of the Human Cell Cycle
人类细胞周期的化学遗传分析
- 批准号:
8727082 - 财政年份:2013
- 资助金额:
$ 32.21万 - 项目类别:
Chemical Genetic Analysis of the Human Cell Cycle
人类细胞周期的化学遗传分析
- 批准号:
9128664 - 财政年份:2013
- 资助金额:
$ 32.21万 - 项目类别:
Chemical Genetic Analysis of the Human Cell Cycle
人类细胞周期的化学遗传分析
- 批准号:
8919920 - 财政年份:2013
- 资助金额:
$ 32.21万 - 项目类别:
Chemical Genetic Analysis of the Human Cell Cycle
人类细胞周期的化学遗传分析
- 批准号:
8479753 - 财政年份:2013
- 资助金额:
$ 32.21万 - 项目类别:
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