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

Zhenning Wang1, Aixia Song1, Bolin Tao1

  • 1Cancer Institute & Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Medical Epigenetics, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

Molecular Cell
|November 27, 2024
PubMed

Insights

The phosphatase 1 nuclear targeting subunit (PNUTS)-PP1 complex unexpectedly sustains gene activation by promoting RNA polymerase II pause release. Disrupting this complex severely impairs transcription, revealing a novel role for PP1 in global gene expression.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Biochemistry

Background:

  • RNA polymerase II progression relies on protein kinases and phosphatases.
  • Serine-threonine phosphatases PP2A and PP1 are traditionally viewed as inhibitors of polymerase progression.
  • PP1 was thought to restrain pause release and elongation, while PP2A inhibits pause release.

Purpose of the Study:

  • To investigate the role of the phosphatase 1 nuclear targeting subunit (PNUTS)-PP1 complex in human cells.
  • To elucidate the function of PNUTS-PP1 in RNA polymerase II progression and gene expression.

Main Methods:

  • Investigated the effects of acute PNUTS-PP1 disruption on gene transcription.
  • Analyzed polymerase progression defects and gene downregulation.
  • Identified substrates of PNUTS-PP1, including the 7SK snRNP subunit MEPCE.

Main Results:

  • PNUTS-PP1 complex disruption caused severe defects in paused polymerase release.
  • Global transcriptional activation was impaired, leading to downregulation of most transcribed genes.
  • PNUTS-PP1 dephosphorylates MEPCE, a known pausing regulator, to promote pause release.
  • PNUTS-PP1 functions antagonistically to Integrator-PP2A (INTAC).

Conclusions:

  • The PNUTS-PP1 complex plays a crucial, unexpected role in sustaining global transcriptional activation.
  • PP1, via PNUTS, actively promotes RNA polymerase II pause release, contrary to previous assumptions.
  • PP1 and PP2A phosphatases exhibit opposing roles in regulating transcriptional pausing and genome-wide gene expression.
Keywords:
7SK snRNPINTACPNUTSPNUTS-PP1PP1PP2ARNA polymerase IIpausingphosphatasetranscription

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