Integrator is a metazoan-specific protein complex capable of inducing termination at all RNAPII-transcribedloci. Integrator recognizes paused, promoter-proximal RNAPII and drives premature termination using dualenzymatic activities: an endonuclease that cleaves nascent RNA and a protein phosphatase that removes stim-ulatory phosphorylation associated with RNAPII pause release and productive elongation. Recent break-throughs in structural biology have revealed the overall architecture of Integrator and provided insights intohow multiple Integrator modules are coordinated to elicit termination effectively. Furthermore, functional geno-mics and biochemical studies have unraveled how Integrator-mediated termination impacts protein-coding andnoncoding loci. Here, we review the current knowledge about the assembly and activity of Integrator anddescribe the role of Integrator in gene regulation, highlighting the importance of this complex for human health.
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