Integrator complex and transcription regulation: Recent findings and pathophysiology

• Integrator has a role in snRNA processing and polymerase pause-release.
• Integrator mediates the biogenesis of enhancer RNAs.
• Some subunits participate in DNA and RNA metabolism.
• Several Integrator subunits play a role in development and differentiation.
• Mutations or altered expression of Integrator subunits are found in numerous diseases.

In the last decade, a novel molecular complex has been added to the RNA polymerase II-mediated transcription machinery as one of the major components. This multiprotein complex, named Integrator, plays a pivotal role in the regulation of most RNA Polymerase II-dependent genes. This complex consists of at least 14 different subunits. However, studies investigating its structure and composition are still lacking. Although it was originally discovered as a complex implicated in the 3′-end formation of noncoding small nuclear RNAs, recent studies indicate additional roles for Integrator in transcription regulation, for example during transcription pause-release and elongation of polymerase, in the biogenesis of transcripts derived from enhancers, as well as in DNA and RNA metabolism for some of its components. Noteworthy, several subunits have been emerging to play roles during development and differentiation; more importantly, their alterations are likely to be involved in several human pathologies, including cancer and lung diseases.