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PP1 PNUTS binds the “restrictor” and dephosphorylates pol II CTD Ser5 to stimulate RNA pol II transcription termination [ChIP-seq]

ABSTRACT: The restrictor complex, WDR82/ZC3H4, is the major termination factor for antisense transcription from bidirectional promoters, but its mechanism of action is poorly understood. We report that the PP1 phosphatase nuclear targeting subunit PNUTS binds to restrictor via its WDR82 subunit. AlphaFold predicts a quaternary complex, PPWZ, in which PP1-associated PNUTS and ZC3H4 both contact WDR82. A chimera comprising inactive PP1H66K fused to the C-terminal PNUTS sequences including its WDR82 binding domain binds to restrictor and acts as a dominant negative inhibitor of antisense termination and CTD Ser5 dephosphorylation. The PP1H66K-PNUTS is a substrate trap that also interacts with pol II large subunit and nuclear exosome components. Ser5 hyperphosphorylated pol II has increased processivity and pauses less frequently than total pol II. We speculate that the elevated elongation efficiency of Ser5-P pol II antagonizes early termination and that Ser5 dephosphorylation by PP1/PNUTS/WDR82/ZC3H4 is coupled to termination of antisense transcription.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269359 | GEO | 2025/04/05

REPOSITORIES: GEO

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PP1 PNUTS binds the “restrictor” and dephosphorylates pol II CTD Ser5 to stimulate RNA pol II transcription termination [eNET-seq]

Project description:The restrictor complex, WDR82/ZC3H4, is the major termination factor for antisense transcription from bidirectional promoters, but its mechanism of action is poorly understood. We report that the PP1 phosphatase nuclear targeting subunit PNUTS binds to restrictor via its WDR82 subunit. AlphaFold predicts a quaternary complex, PPWZ, in which PP1-associated PNUTS and ZC3H4 both contact WDR82. A chimera comprising inactive PP1H66K fused to the C-terminal PNUTS sequences including its WDR82 binding domain binds to restrictor and acts as a dominant negative inhibitor of antisense termination and CTD Ser5 dephosphorylation. The PP1H66K-PNUTS is a substrate trap that also interacts with pol II large subunit and nuclear exosome components. Ser5 hyperphosphorylated pol II has increased processivity and pauses less frequently than total pol II. We speculate that the elevated elongation efficiency of Ser5-P pol II antagonizes early termination and that Ser5 dephosphorylation by PP1/PNUTS/WDR82/ZC3H4 is coupled to termination of antisense transcription.

2025-04-05 | GSE269358 | GEO

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Project description:Transcription termination pathways mitigate the detrimental consequences of unscheduled promiscuous initiation occurring at hundreds of thousands of genomic cis-regulatory elements. The Restrictor complex, composed of the Pol II-interacting protein WDR82 and the RNA-binding protein ZC3H4, suppresses processive transcription at thousands of extragenic sites in mammalian genomes. Restrictor-driven termination does not involve nascent RNA cleavage and its interplay with other termination machineries is unclear. Here we show that efficient termination at Restrictor-controlled extragenic transcription units involves the recruitment of the protein phosphatase 1 (PP1) regulatory subunit PNUTS, a negative regulator of the Spt5 elongation factor, and Symplekin, a protein associated with RNA cleavage complexes but also involved in cleavage-independent and phosphatase-dependent termination of non-coding RNAs in yeast. PNUTS and Symplekin act synergistically with, but independently from Restrictor to dampen processive extragenic transcription. Moreover, the presence of limiting nuclear levels of Symplekin imposes a competition for its recruitment among multiple transcription termination machineries, resulting in mutual regulatory interactions. Hence, by synergizing with Restrictor, Symplekin and PNUTS enable efficient termination of processive, long-range extragenic transcription.

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Project description:There are thousands of unstable non-coding (nc) RNAs in humans, but their transcriptional regulation is poorly characterized compared to protein-coding transcripts. We recently identified a restrictor complex containing ZC3H4 and WDR82, which terminates non-coding transcription. Here we show that the ncRNA termination factor, ARS2, and the nuclear exosome targeting complex (NEXT) are part of this complex.ARS2/NEXT and WDR82 contact different parts of ZC3H4, which are required for its transcription regulatory function. They facilitateZC3H4-mediated termination by different mechanisms: ARS2 aids substrate targeting and WDR82 mediates RNA polymerase II interaction.ZC3H4 and WDR82 predominantly affect antisense, unstable, and intragenic ncRNAs. We provide an explanation for this by showing that U1 telescripting shields hundreds of protein-coding transcripts from their termination functions.We have defined an expanded ZC3H4 restrictor complex, its principles of action, and how protein-coding transcripts evade it.

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