Elucidation of Integrator's Function

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.