Human Integrator provides a quality checkpoint during elongation to facilitate RNA polymerase II processivity

Integrator is a multi-subunit complex that directly interacts with the C-terminal domain (CTD) of RNA polymerase II (RNAPII). Through its RNA endonuclease activity, Integrator is required for 3′-end processing of both non-coding and coding transcripts. Here we demonstrate that depleting Integrator subunit 11 (INTS11), the main catalytic subunit of the Integrator complex, leads to a global elongation defect as a result of decreased polymerase processivity. We observe this defect in the region approximately 12 to 35 kb downstream of the transcription start site (TSS), where RNAPII normally transitions to its maximum processivity. We also identify an important role for INTS11, possibly in association with RNAPII CTD phospho-Tyr1, in repressing antisense transcription upstream of active promoters, as well as repressing transcription of genic regions near AsiSI-induced double-strand breaks. Altogether, this study points toward a novel function of Integrator in promoting termination of incompetent RNAPII molecules while facilitating the transition to fully processive polymerase in order to enable efficient elongation.