Wang Zhenning, Song Aixia, Tao Bolin, Miao Maojian, Luo Yi-Qing, Wang Jingwen, Yin Zhinang, Xiao Ruijing, Zhou Xinwen, Shang Xue-Ying, Hu Shibin, Liang Kaiwei, Danko Charles G, Chen Fei Xavier
Cancer Institute & Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Medical Epigenetics, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
Mol Cell. 2024 Dec 19;84(24):4824-4842.e7. doi: 10.1016/j.molcel.2024.10.046. Epub 2024 Nov 26.
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 elongation at terminators. Here, we reveal an unexpected role of PP1, within the phosphatase 1 nuclear targeting subunit (PNUTS)-PP1 complex, in sustaining global transcriptional activation in human cells. Acute disruption of PNUTS-PP1 leads to severe defects in the release of paused polymerase and subsequent downregulation for the majority of transcribed genes. PNUTS-PP1 promotes pause release by dephosphorylating multiple substrates, including the 7SK small nuclear ribonucleoprotein particle (snRNP) subunit MEPCE, a known pausing regulator. PNUTS-PP1 exhibits antagonistic functions compared with Integrator-PP2A (INTAC) phosphatase, which generally inhibits pause release. Our research thus highlights 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制的一系列蛋白激酶驱动。相反，相应的磷酸酶，特别是PP2A和PP1（细胞中最丰富的丝氨酸 - 苏氨酸磷酸酶），被认为主要阻碍聚合酶的进程，分别在启动子处抑制暂停释放和在终止子处抑制延伸。在这里，我们揭示了磷酸酶1核靶向亚基（PNUTS）-PP1复合物中的PP1在维持人类细胞全局转录激活方面的意外作用。PNUTS-PP1的急性破坏导致暂停聚合酶释放的严重缺陷以及大多数转录基因随后的下调。PNUTS-PP1通过使多种底物去磷酸化来促进暂停释放，包括7SK小核核糖核蛋白颗粒（snRNP）亚基MEPCE，一种已知的暂停调节因子。与通常抑制暂停释放的整合酶-PP2A（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在调节全基因组转录暂停和基因表达方面的相反作用。
