The PAF1 Complex Recruits Integrator to Chromatin Globally to Terminate Non-Productive Transcription

Abstract

The PAF1 complex (PAF1C) functions in multiple transcriptional processes involving RNA Polymerase II (Pol II). eRNAs and PROMPTs are pervasive transcripts transcribed by Pol II and rapidly degraded after 3’ endonucleolytic cleavage by the Integrator complex (Integrator). Here we show that PAF1C depletion results in near universal 3’ end processing defects in pervasive transcripts, leading to transcription termination dysregulation. Mechanistically, PAF1C recruits Integrator to chromatin through direct interactions, promoting timely cleavage and transcription termination of pervasive transcripts. We also show that PAF1C recruits Integrator to the promoters of coding genes, where PAF1C then dissociates from Integrator upon entry into processive elongation under the control of CDK12/13. Our results demonstrate an unexpected function for PAF1C in limiting the length and accumulation of pervasive transcripts that result from non-productive transcription, while highlighting a general requirement for PAF1C in Integrator recruitment.