biostudies-literatureRusso MEuropean Research CouncilConsortium ENHPATHYItalian Association for Research on CancerMarie Sklodowska-Curie ActionHorizon 2020 European Training Network1017-1040https://www.ebi.ac.uk/biostudies/studies/S-EPMC10760643biostudies-literatureUnknown37(21-24)Transcription termination pathways mitigate the detrimental consequences of unscheduled promiscuous initiation occurring at hundreds of thousands of genomic <i>cis</i>-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 RNAGenes & developmentRestrictor synergizes with Symplekin and PNUTS to terminate extragenic transcription.PMC10760643692789860002Polletti SRusso MPolizzese DPiccolo VMandana GMBedin FRodighiero SNatoli GBorriero CMarenda MMichieletto DCuomo AProsperini EfalseRestrictor synergizes with Symplekin and PNUTS to terminate extragenic transcription.Transcription termination pathways mitigate the detrimental consequences of unscheduled promiscuous initiation occurring at hundreds of thousands of genomic <i>cis</i>-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 RNA2023-01-01T00:00:00Z2023 Dec2026-06-01T23:37:07.166Z2026-05-23T03:08:04.016ZS-EPMC107606433809251810.1101/gad.351057.123