The phosphatase PP1 sustains global transcription by promoting RNA polymerase II pause release
- Mol Cell. 2024 Dec 19;84(24):4824-4842.e7. doi: 10.1016/j.molcel.2024.10.046.
- 1. Cancer 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.
- 2. Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
- 3. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
- 4. Cancer 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. Electronic address: [email protected].
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.