KAP1 Is a Chromatin Reader that Couples Steps of RNA Polymerase II Transcription to Sustain Oncogenic Programs
KAP1 Is a Chromatin Reader that Couples Steps of RNA Polymerase II Transcription to Sustain Oncogenic Programs
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DOI：
10.1016/j.molcel.2020.04.024
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发表时间：
2020-06-18
期刊：
影响因子：
16
通讯作者：
D'Orso, Ivan
中科院分区：
文献类型：
--
作者：
Bacon, Curtis W.;Challa, Ashwini;D'Orso, Ivan
RNA聚合酶II（RNA Pol II）循环的精确控制，包括暂停和暂停释放，维持转录稳态和生物体功能。尽管以前的工作，以了解个人的转录步骤，我们揭示了一种机制，整合RNA Pol II循环转换。令人惊讶的是，KAP 1/TRIM 28使用先前未表征的染色质阅读盒在启动子处结合低乙酰化组蛋白4尾，保证RNA Pol II进入和退出暂停状态的连续进展。在染色质对接时，KAP 1首先与RNA Pol II结合，然后响应于同源配体招募途径特异性转录因子（SMAD 2），从而实现基因选择性CDK 9依赖性暂停释放。这种偶联机制被肿瘤细胞利用来异常地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械理解，为靶向转录失调提供了替代治疗机会。
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.