Precise control of the RNA polymerase II (RNA Pol II) cycle, including pausing and pause release, maintains transcriptional homeostasis and organismal functions. Despite previous work to understand individual transcription steps, we reveal a mechanism that integrates RNA Pol II cycle transitions. Surprisingly, KAP1/TRIM28 uses a previously uncharacterized chromatin reader cassette to bind hypo-acetylated histone 4 tails at promoters, guaranteeing continuous progression of RNA Pol II entry to and exit from the pause state. Upon chromatin docking, KAP1 first associates with RNA Pol II and then recruits a pathway-specific transcription factor (SMAD2) in response to cognate ligands, enabling gene-selective CDK9-dependent pause release. This coupling mechanism is exploited by tumor cells to aberrantly sustain transcriptional programs commonly dysregulated in cancer patients. The discovery of a factor integrating transcription steps expands the functional repertoire by which chromatin readers operate and provides mechanistic understanding of transcription regulation, offering alternative therapeutic opportunities to target transcriptional dysregulation.

精确控制 RNA 聚合酶 II (RNA Pol II) 循环，包括暂停和暂停释放，可维持转录稳态和机体功能。尽管之前的工作是了解单个转录步骤，但我们揭示了一种整合 RNA Pol II 循环转换的机制。令人惊讶的是，KAP1/TRIM28 使用先前未表征的染色质读取器盒在启动子处结合低乙酰化组蛋白 4 尾部，保证 RNA Pol II 进入和退出暂停状态的连续进展。染色质对接后，KAP1 首先与 RNA Pol II 结合，然后招募通路特异性转录因子 (SMAD2) 来响应同源配体，从而实现基因选择性 CDK9 依赖性暂停释放。肿瘤细胞利用这种偶联机制来异常维持癌症患者中通常失调的转录程序。整合转录步骤的因子的发现扩展了染色质阅读器操作的功能库，并提供了对转录调控的机制理解，为针对转录失调提供了替代治疗机会。