Elucidation of Integrator's Function

项目摘要 整合子是一种与C-末端结构域（CTD）稳定结合的多蛋白复合物 RNA聚合酶II（RNAPII）整合剂含有催化性RNA内切酶 与切割和多聚腺苷酸化具有高度同源性的亚基（INTS 11 特异性因子73（CPSF 73），负责切割和终止 信使RNA（mRNA）基因。我们发现整合子RNA加工活性是 不仅非编码基因需要，而且蛋白质编码基因也需要， 转录延伸在本提案中，目标1将详细说明 整合子调控蛋白质编码基因的3 '端加工和终止。在 目的2：探讨整合子复合物在炎症反应中的作用， 在我们发现整合子的协同作用后， 与RELA，典型NF κ B复合物的组分。这些发现扩大了 应激信号和免疫系统的整合剂。最后，在目标3中，我们将阐明 一种新的由INTS 11-INTS 9和BRAT 1蛋白组成的三聚体复合物的功能， 人类发育综合征中基因突变导致强直和多灶性 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.