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 noncoding 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.

中文翻译：

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限制子与 Symplekin 和 PNUTS 协同作用终止基因外转录

转录终止途径减轻了数十万个基因组顺式调控元件中发生的计划外混杂起始的有害后果。该限制性复合物由 Pol II 相互作用蛋白 WDR82 和 RNA 结合蛋白 ZC3H4 组成，可抑制哺乳动物基因组中数千个基因外位点的持续转录。限制子驱动的终止不涉及新生 RNA 切割，其与其他终止机制的相互作用尚不清楚。在这里，我们表明，限制性蛋白控制的基因外转录单位的有效终止涉及蛋白磷酸酶 1 (PP1) 调节亚基 PNUTS（SPT5 延伸因子的负调节因子）和 Symplekin（一种与 RNA 裂解复合物相关但也参与其中的蛋白质）的募集。酵母中非编码 RNA 的非切割依赖性和磷酸酶依赖性终止。PNUTS 和 Symplekin 与限制子协同但独立地发挥作用，以抑制持续的基因外转录。此外，Symplekin 核水平有限的存在会在多个转录终止机制之间对其招募产生竞争，从而导致相互调节相互作用。因此，通过与限制子协同作用，Symplekin 和 PNUTS 能够有效终止持续的、长程的外源转录。