The metazoan-specific Integrator complex is a >1.5 MDa machinery that interacts with RNA polymerase II (RNAP2) to attenuate coding gene transcription by early termination close to transcription start sites. Using a highly related mechanism, Integrator also performs the initial 3'-end processing step for many non-coding RNAs. Its transcription regulation functions are essential for cell differentiation and response to external stimuli. Recent studies revealed that the complex incorporates phosphatase PP2A to counteract phosphorylation reactions that are required for transcription elongation. Structures of Integrator bound to RNAP2 explain the basis for its recruitment to promoter proximal RNAP2 by recognition of its paused state. Furthermore, several studies indicate that Integrator's cleavage activity is regulated at multiple levels through activators, modifications, and small molecules.
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