Elucidation of Integrator's Function

积分器功能说明

• 批准号: 9029630
• 负责人: RAMIN SHIEKHATTAR
• 金额: $ 45.28万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9029630
• 关键词: Address; Binding; Biogenesis; C-terminal; Catalytic RNA; Cleavage And Polyadenylation Specificity Factor; Code; Complex; Data; Defect; Development; Disease; Disease Progression; Distal; Endoribonucleases; Enhancers; Enzymes; Epidermal Growth Factor; Eukaryota; Funding; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genomics; Grant; Human Cell Line; Immediate-Early Genes; Link; Location; Maps; Mediating; Mediator of activation protein; Messenger RNA; Modification; Molecular; Pattern; Phosphorylation; Phosphotransferases; Poly A; Process; Production; Proteins; Publishing; RNA; RNA Polymerase II; RNA Processing; RNA polymerase II largest subunit; Recruitment Activity; Regulation; Regulator Genes; Role; Signal Transduction; Small Nuclear RNA; Stimulus; Tissues; Transcript; Transcription Coactivator; Transcriptional Activation; Transcriptional Regulation; base; endonuclease; genome-wide; insight; negative elongation factor; promoter; protein complex; public health relevance

 DESCRIPTION (provided by applicant) Integrator is a multi-protein complex stably associated with the C-terminal domain (CTD) of RNA polymerase II (RNAPII). Integrator contains a catalytic RNA endonuclease subunit (INTS11) with high degree of homology to cleavage and polyadenylation specificity factor 73 (CPSF73), the enzyme responsible for cleavage and termination of messenger RNA (mRNA) genes. We showed that Integrator occupies the small nuclear RNA genes (snRNA) and that its catalytic activity was required for the 3'-end processing of these non- polyadenylated transcripts. We have expanded our functional studies during the course of this grant funding to uncover a role for Integrator at protein-coding genes and distal enhancers. In the proposed studies we intend to illuminate the molecular mechanism underlying Integrator function at enhancers and their respective protein-coding promoters through the following specific aims: Aim1) We will investigate the molecular mechanisms by which Integrator regulates transcriptional elongation (RNAPII pause release) at protein-coding genes. Aim 2) We will elucidate the role of Integrator in enhancer RNA biogenesis and enhancer function. Aim 3) We will address the physical and functional association of Integrator and different phosphorylation states of the CTD in regulation of transcriptional activation.