Elucidation of Integrator's Function

积分器功能说明

基本信息

批准号：
10366239
负责人：
RAMIN SHIEKHATTAR
金额：
$ 44.79万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366239
关键词：
Affinity Antibodies Architecture Atrophic B-Cell Activation BRCA1 gene Biogenesis Biological Process Bone Marrow C-terminal Catalytic Domain Catalytic RNA Cells Chromatin Cleavage And Polyadenylation Specificity Factor Code Complex Development Disease Endoribonucleases Enhancers Enzymes Epigenetic Process Funding Gene Expression Gene Expression Regulation Genes Genetic Enhancer Element Genetic Transcription Genomics Grant Growth Factor Hour Human Immediate-Early Genes Immune system Inflammation Mediators Inflammatory Inflammatory Response Knockout Mice Lead Light Malignant neoplasm of cervix uteri Mass Spectrum Analysis Messenger RNA Multiprotein Complexes Mus Mutate Mutation Neurodevelopmental Disorder Nuclear Pathogenicity Pathway interactions Play Proteins Proteomics RELA gene RNA RNA Polymerase II RNA Processing Regulation Role Seizures Set protein Signal Transduction Site Small Nuclear RNA Spliceosomes Stress Syndrome System TNF gene Testing Time Transcription Elongation Transcriptional Regulation Untranslated RNA cancer cell chromatin immunoprecipitation conditional knockout embryonic stem cell human disease insight macrophage neonate p65 pluripotency programs promoter response self-renewal stable cell line transcription factor

项目摘要

Project Summary 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 RNA processing activity is not only required for noncoding genes but also for protein coding genes facilitating transcriptional elongation. In this proposal, Aim 1; Will detail the mechanism of the Integrator regulation of 3’-end processing and termination of protein coding genes. In Aim 2; We will explore the role of the Integrator complex in regulation of inflammatory gene expression program following our discovery of cooperative association of Integrator with RELA, a component of canonical NFkB complex. These findings expand the role for Integrator in stress signaling and immune system. Finally, in Aim 3; We will elucidate the function of a new trimeric complex composed of INTS11-INTS9 and BRAT1 protein, a gene mutated in human developmental syndromes causing rigidity and multifocal seizure syndrome in neonates and neurodevelopmental disorders.

项目摘要集成剂是与C末端结构域（CTD）稳定相关的多蛋白质复合物 RNA聚合酶II（RNAPII）。集成蛋白包含催化RNA核酸内切酶具有高度同源性裂解和聚腺苷酸的亚基（INTS11）（INTS11）特异性因子73（CPSF73），该酶负责裂解和终止 Messenger RNA（mRNA）基因。我们表明积分器RNA处理活性是不仅需要非编码基因，而且还需要促进蛋白质编码基因转录伸长。在此提案中，目标1；将详细说明蛋白质编码基因的3'末端加工和终止的整合体调节。目标2；我们将探讨整合体复合物在调节炎症中的作用我们发现集成商合作协会后的基因表达程序与Rela（规范NFKB复合体的组成部分）。这些发现扩大了角色压力信号传导和免疫学系统中的积分器。最后，在目标3中；我们将阐明由INTS11-INTS9和BRAT1蛋白组成的新三聚体复合物的功能，A 在人类发育综合征中突变的基因，导致僵化和多灶新生儿和神经发育障碍中的癫痫发作综合征。