Efficient release of promoter-proximally paused RNA Pol II into productive elongation is essential for gene expression. Recently, we reported that the Integrator complex can bind paused RNA Pol II and drive premature transcription termination, potently attenuating the activity of target genes. Premature termination requires RNA cleavage by the endonuclease subunit of Integrator, but the roles of other Integrator subunits in gene regulation have yet to be elucidated. Here we report that Integrator subunit 8 (IntS8) is critical for transcription repression and required for association with protein phosphatase 2A (PP2A). We find that Integrator-bound PP2A dephosphorylates the RNA Pol II C-terminal domain and Spt5, preventing the transition to productive elongation. Thus, blocking PP2A association with Integrator stimulates pause release and gene activity. These results reveal a second catalytic function associated with Integrator-mediated transcription termination and indicate that control of productive elongation involves active competition between transcriptional kinases and phosphatases.

启动子近端暂停的 RNA Pol II 有效释放至生产性延伸对于基因表达至关重要。最近，我们报道了 Integrator 复合物可以结合暂停的 RNA Pol II 并驱动转录过早终止，从而有效减弱靶基因的活性。过早终止需要 Integrator 的核酸内切酶亚基对 RNA 进行切割，但其他 Integrator 亚基在基因调控中的作用尚未阐明。在这里，我们报告整合子亚基 8 (IntS8) 对于转录抑制至关重要，并且是与蛋白磷酸酶 2A (PP2A) 关联所必需的。我们发现整合子结合的 PP2A 使 RNA Pol II C 末端结构域和 Spt5 去磷酸化，从而阻止向生产性延伸的转变。因此，阻断 PP2A 与 Integrator 的关联会刺激暂停释放和基因活性。这些结果揭示了与整合子介导的转录终止相关的第二种催化功能，并表明对生产性延伸的控制涉及转录激酶和磷酸酶之间的主动竞争。