Elucidation of Integrator's Function

项目摘要 整合子是一种与C-末端结构域(CTD)稳定结合的多蛋白质复合体 RNA聚合酶II(RNAPII)。整合子含有催化的RNA内切酶 与切割和多聚腺苷高度同源的亚基(INTS11) 特异性因子73(CPSF73)，负责切割和终止 信使RNA(信使核糖核酸)基因。我们证明了整合者RNA处理活动是 不仅需要非编码基因，也需要蛋白质编码基因促进 转录延伸。在这项提案中，目标1；将详细说明 蛋白质编码基因3‘端加工和终止的整合子调控。在……里面 目的2：我们将探讨整合子复合体在炎症调节中的作用。 我们发现积分器合作关联后的基因表达程序 对于RelA，是典型的NFkB复合体的一个组成部分。这些发现扩大了 压力信号和免疫系统的整合者。最后，在目标3中，我们将阐明 一种新的由INTS11-INTS9和BRAT1蛋白组成的三聚体复合体的功能 人类发育综合征的基因突变导致僵直和多灶性 新生儿癫痫综合征和神经发育障碍。

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.