The phosphatase PP1 sustains global transcription by promoting RNA polymerase II pause release

Abstract

RNA polymerase II progression from initiation to elongation is driven in part by a cascade of protein kinases acting on the core transcription machinery. Conversely, the corresponding phosphatases, notably PP2A and PP1-the most abundant serine-threonine phosphatases in cells-are thought to mainly impede polymerase progression, respectively restraining pause release at promoters and elongation at terminators. Here, we reveal an unexpected role of PP1, within the phosphatase 1 nuclear targeting subunit (PNUTS)-PP1 complex, in sustaining global transcriptional activation in human cells. Acute disruption of PNUTS-PP1 leads to severe defects in the release of paused polymerase and subsequent downregulation for the majority of transcribed genes. PNUTS-PP1 promotes pause release by dephosphorylating multiple substrates, including the 7SK small nuclear ribonucleoprotein particle (snRNP) subunit MEPCE, a known pausing regulator. PNUTS-PP1 exhibits antagonistic functions compared with Integrator-PP2A (INTAC) phosphatase, which generally inhibits pause release. Our research thus highlights opposing roles of PP1 and PP2A in modulating genome-wide transcriptional pausing and gene expression.

Keywords: 7SK snRNP; INTAC; PNUTS; PNUTS-PP1; PP1; PP2A; RNA polymerase II; pausing; phosphatase; transcription.