Kelley Jessica R, Dimitrova Emilia, Maciuszek Maciej, Nguyen Hieu T, Szczurek Aleksander T, Hughes Amy L, Blackledge Neil P, Kettenbach Arminja N, Klose Robert J
Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
Mol Cell. 2024 Dec 19;84(24):4843-4861.e8. doi: 10.1016/j.molcel.2024.10.045. Epub 2024 Nov 26.
Gene expression is regulated by controlling distinct steps of the transcriptional cycle, including initiation, pausing, elongation, and termination. Kinases phosphorylate RNA polymerase II (RNA Pol II) and associated factors to control transitions between these steps and to act as central gene regulatory nodes. Similarly, phosphatases that dephosphorylate these components are emerging as important regulators of transcription, although their roles remain less well understood. Here, we discover that the mouse PNUTS-PP1 phosphatase complex plays an essential role in controlling transcription pause release in addition to its previously described function in transcription termination. Transcription pause release by the PNUTS complex is essential for almost all RNA Pol II-dependent gene transcription, relies on its PP1 phosphatase subunit, and controls the phosphorylation of factors required for pause release and elongation. Together, these observations reveal an essential new role for a phosphatase complex in transcription pause release and show that the PNUTS complex is essential for RNA Pol II-dependent transcription.
基因表达通过控制转录周期的不同步骤来调节，包括起始、暂停、延伸和终止。激酶使RNA聚合酶II（RNA Pol II）及相关因子磷酸化，以控制这些步骤之间的转换，并作为核心基因调控节点发挥作用。同样，使这些组分去磷酸化的磷酸酶正逐渐成为转录的重要调节因子，尽管它们的作用仍不太清楚。在这里，我们发现小鼠PNUTS-PP1磷酸酶复合物除了其先前描述的在转录终止中的功能外，在控制转录暂停释放中也起着至关重要的作用。PNUTS复合物介导的转录暂停释放对几乎所有依赖RNA Pol II的基因转录至关重要，依赖于其PP1磷酸酶亚基，并控制暂停释放和延伸所需因子的磷酸化。这些观察结果共同揭示了磷酸酶复合物在转录暂停释放中的一个重要新作用，并表明PNUTS复合物对依赖RNA Pol II的转录至关重要。
