Integrator is a genome-wide attenuator of non-productive transcription

Termination of RNA polymerase II (RNAPII) transcription in metazoans relies largely on the cleavage and polyadenylation (CPA) and integrator (INT) complexes originally found to act at the ends of protein-coding and small nuclear RNA (snRNA) genes, respectively. Here, we monitor CPA- and INT-dependent termination activities genome-wide, including at thousands of previously unannotated transcription units (TUs), producing unstable RNA. We verify the global activity of CPA occurring at pA sites indiscriminately of their positioning relative to the TU promoter. We also identify a global activity of INT, which is largely sequence-independent and restricted to a ~3-kb promoter-proximal region. Our analyses suggest two functions of genome-wide INT activity: it dampens transcriptional output from weak promoters, and it provides quality control of RNAPII complexes that are unfavorably configured for transcriptional elongation. We suggest that the function of INT in stable snRNA production is an exception from its general cellular role, the attenuation of non-productive transcription. [Display omitted] •Cleavage and polyadenylation (CPA) and integrator (INT) complexes act genome-wide•CPA acts in a sequence-dependent manner at pA sites•INT acts, largely sequence-independently, at the beginning of transcription units•INT activity provides quality control of non-productive transcription events Metazoan RNA polymerase II activity is promiscuous within and outside of conventional genes. Lykke-Andersen et al. show that cleavage and polyadenylation (CPA) and integrator (INT) transcription termination complexes operate genome-wide in sequence- and context-dependent manners, respectively. The INT complex is suggested to take part in quality control of non-productive transcription.