IntS6 and the Integrator phosphatase module tune the efficiency of select premature transcription termination events

Mol Cell. 2023 Dec 21;83(24):4445-4460.e7. doi: 10.1016/j.molcel.2023.10.035. Epub 2023 Nov 22.


The metazoan-specific Integrator complex catalyzes 3' end processing of small nuclear RNAs (snRNAs) and premature termination that attenuates the transcription of many protein-coding genes. Integrator has RNA endonuclease and protein phosphatase activities, but it remains unclear if both are required for complex function. Here, we show IntS6 (Integrator subunit 6) over-expression blocks Integrator function at a subset of Drosophila protein-coding genes, although having no effect on snRNAs or attenuation of other loci. Over-expressed IntS6 titrates protein phosphatase 2A (PP2A) subunits, thereby only affecting gene loci where phosphatase activity is necessary for Integrator function. IntS6 functions analogous to a PP2A regulatory B subunit as over-expression of canonical B subunits, which do not bind Integrator, is also sufficient to inhibit Integrator activity. These results show that the phosphatase module is critical at only a subset of Integrator-regulated genes and point to PP2A recruitment as a tunable step that modulates transcription termination efficiency.

Keywords: 3′ end processing; INTAC; Integrator complex; Integrator subunit 6; PP2A; RNA polymerase II; promoter-proximal termination; protein phosphatase 2A; snRNA; transcription.

MeSH terms

  • Animals
  • Drosophila Proteins* / metabolism
  • Drosophila melanogaster
  • RNA
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism
  • RNA, Small Nuclear / genetics
  • Transcription Factors / metabolism
  • Transcription Termination, Genetic*


  • RNA
  • RNA Polymerase II
  • RNA, Small Nuclear
  • Transcription Factors
  • Drosophila Proteins