Professor, Department of Biochemistry
Co-Director of New York State Center of Excellence in RNA Research and Therapeutics
Department of Biochemistry and Biophysics
University of Rochester
Title: Integrator: Enforcer of the RNA Polymerase II Paused Elongation Checkpoint
Abstract: Integrator is a promoter-proximal termination complex that removes RNA polymerase II (RNAPII) complexes not destined for productive pause release by P-TEFb. Using rapid protein depletion, we previously showed that Integrator loss releases immature and poorly processive RNAPII into gene bodies, resulting in premature intronic cleavage and polyadenylation and the accumulation of SINE-derived double-stranded RNA. Here we show that Integrator depletion also generates a large pool of biochemically poised but transcriptionally deficient RNAPII complexes. This state is accompanied by a profound redistribution of NELF to chromatin and a striking increase in NELF occupancy within gene bodies. These RNAPII complexes are defective in transcriptional activation, providing a mechanistic explanation for the long-standing but poorly understood requirement for Integrator in inducible gene expression. Strikingly, simultaneous depletion of Integrator and NELF partially restores elongation-competent RNAPII but produces a globally dysregulated transcriptional state characterized by widespread transcriptome disruption, activation of antiviral signaling, and severe loss of cellular fitness. Together, these findings uncover a previously unrecognized paused-elongation checkpoint in which Integrator-mediated termination and NELF-mediated pause stabilization cooperate to maintain RNAPII processivity and preserve transcriptional quality control.
Host: Liang Tong
