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The phosphatase PP1 sustains global transcription by promoting RNA polymerase II pause release [RNA-seq]

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 polymerase elongation at terminators. Here we reveal an unexpected role of PP1, within the PNUTS-PP1 complex, in sustaining global transcriptional activation. Acute disruption of PNUTS-PP1 leads to severe defects in the release of paused polymerase and subsequent downregulation for the majority of transcribed genes. Mechanistically, PNUTS-PP1 promotes pause release by dephosphorylating multiple substrates, including the 7SK snRNP subunit MEPCE, a known regulator of pause release. PNUTS-PP1 exhibits antagonistic functions compared to INTAC phosphatase, which generally inhibits pause release. Our research thus highlights the opposing roles of PP1 and PP2A in modulating genome-wide transcriptional pausing and gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279150 | GEO | 2024/12/02

REPOSITORIES: GEO

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The phosphatase PP1 sustains global transcription by promoting RNA polymerase II pause release [TT-seq]

Project description: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 polymerase elongation at terminators. Here we reveal an unexpected role of PP1, within the PNUTS-PP1 complex, in sustaining global transcriptional activation. Acute disruption of PNUTS-PP1 leads to severe defects in the release of paused polymerase and subsequent downregulation for the majority of transcribed genes. Mechanistically, PNUTS-PP1 promotes pause release by dephosphorylating multiple substrates, including the 7SK snRNP subunit MEPCE, a known regulator of pause release. PNUTS-PP1 exhibits antagonistic functions compared to INTAC phosphatase, which generally inhibits pause release. Our research thus highlights the opposing roles of PP1 and PP2A in modulating genome-wide transcriptional pausing and gene expression.

2024-12-02 | GSE279151 | GEO

The PNUTS phosphatase complex controls transcription pause release [ChIP-Seq]

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The PNUTS phosphatase complex controls transcription pause release

Project description:Gene expression is regulated by controlling distinct steps of the transcriptional cycle, including initiation, pausing, elongation, and termination. Kinases phosphorylate RNA Polymerase II and associated factors to control transitions between these steps and act as central gene regulatory nodes. Similarly, phosphatases that dephosphorylate these components are emerging as important regulators of transcription, though their roles remain less well understood. Here we discover that the PNUTS-PP1 phosphatase complex plays an essential role in controlling transcription pause release in addition to its previously described function in transcription termination. Transcription pause release by the PNUTS complex is essential for almost all RNA Pol II-dependent gene transcription, relies on its PP1 phosphatase subunit, and controls the phosphorylation of factors required for pause release and elongation. Together, this reveals an essential new role for a phosphatase complex in transcription pause release and shows that the PNUTS complex is essential for RNA Poll II-dependent transcription.

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TOX4 Facilitates Promoter-Proximal Pausing and C-Terminal Domain Dephosphorylation of RNA Polymerase II in Human Cells

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Integrator Recruits Protein Phosphatase 2A to Prevent Pause Release and Enable Transcription Termination

Project description:Efficient release of promoter-proximally paused Pol II into productive elongation is essential for gene expression. Recently, we reported that the Integrator complex can bind paused Pol II and drive premature transcription termination, potently attenuating the activity of target genes. Premature termination requires RNA cleavage by the endonuclease subunit of Integrator, but the roles of other Integrator subunits in gene regulation have yet to be elucidated. Here, we report that Integrator subunit 8 (IntS8) is critical for transcription repression through its association with Protein Phosphatase 2A (PP2A). We find that Integrator-bound PP2A dephosphorylates the Pol II C-terminal domain and Spt5, and prevents the transition to productive elongation. Blocking PP2A association with Integrator thus stimulates pause release and gene activation. These results reveal a second catalytic function associated with Integrator-mediated transcription termination, and suggest a new model for the control of productive elongation involving active competition between transcriptional kinases and phosphatases.

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