Integrator: surprisingly diverse functions in gene expression

• The current model of UsnRNA biogenesis is discussed.
• Perspective is provided on how the RNAPII CTD is recognized by Integrator.
• CTD kinases and binding proteins influence RNAPII CTD–Integrator association.
• Integrator has a new role in pause-release of RNAPII at mRNA-encoding genes.
• Integrator has modular properties opening the possibility of new roles.

The discovery of the metazoan-specific Integrator (INT) complex represented a breakthrough in our understanding of noncoding U-rich small nuclear RNA (UsnRNA) maturation and has triggered a reevaluation of their biosynthesis mechanism. In the decade since, significant progress has been made in understanding the details of its recruitment, specificity, and assembly. While some discrepancies remain on how it interacts with the C-terminal domain (CTD) of the RNA polymerase II (RNAPII) and the details of its recruitment to UsnRNA genes, preliminary models have emerged. Recent provocative studies now implicate INT in the regulation of protein-coding gene transcription initiation and RNAPII pause-release, thereby broadening the scope of INT functions in gene expression regulation. We discuss the implications of these findings while putting them into the context of what is understood about INT function at UsnRNA genes.