The phosphatase PP1 sustains global transcription by promoting RNA polymerase II pause release

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.

RNA聚合酶II从起始到延伸的过程部分由作用于核心转录机械的蛋白激酶级联反应驱动。反之，相应的磷酸酶，尤其是PP2A和PP1——细胞中最丰富的丝氨酸/苏氨酸磷酸酶——据信主要阻碍聚合酶的进程，分别抑制启动子处的暂停释放和终止子处的聚合酶延伸。在本研究中，我们揭示了PP1在PNUTS-PP1复合体中维持整体转录激活的意外作用。PNUTS-PP1的急性破坏会导致暂停聚合酶释放的严重缺陷，以及随后大多数转录基因的下调。从机制上讲，PNUTS-PP1通过去磷酸化多个底物，包括已知的暂停释放调节因子7SK snRNP亚基MEPCE，促进暂停释放。与通常抑制暂停释放的INTAC磷酸酶相比，PNUTS-PP1表现出拮抗功能。因此，我们的研究突出了PP1和PP2A在调节全局转录暂停和基因表达中的对立作用。