Mina M. Tayari, Ramin Shiekhattar
The Integrator complex, composed of at least 19 subunits, associates with RNA polymerase II (RNAPII) and exerts critical roles in transcriptional regulation. By interacting with the C-terminal domain (CTD) of RNAPII, it cleaves nascent RNA transcripts, leading to termination of non-productive transcription in protein-coding genes and processing of diverse noncoding RNAs. Beyond RNA cleavage, Integrator regulates transcription initiation, pause-release, and elongation, while also processing enhancer RNAs. It contributes to genome stability by modulating RNAPII activity during DNA damage and replication stress. Dysfunction of Integrator subunits has been linked to neurodevelopmental disorders and cancer, underscoring its broad physiological significance. This review highlights recent advances in structure and function that illuminate Integrator's essential roles in development, neurobiology, and disease.