McKetta Department of Chemical Engineering, University of Texas at Austin, Austin, TX, 78712, USA.
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, 78712, USA.
Curr Opin Chem Biol. 2021 Aug;63:68-77. doi: 10.1016/j.cbpa.2021.02.002. Epub 2021 Mar 11.
Phosphorylation of RNA polymerase II (RNAP II) coordinates the temporal progression of eukaryotic transcription. The development and application of chemical genetic methods have enhanced our ability to investigate the intricate and intertwined pathways regulated by the kinases and phosphatases targeting RNAP II to ensure transcription accuracy and efficiency. Although identifying small molecules that modulate these enzymes has been challenging due to their highly conserved structures, powerful new chemical biology strategies such as targeted covalent inhibitors and small molecule degraders have significantly improved chemical probe specificity. The recent success in discovering phosphatase holoenzyme activators and inhibitors, which demonstrates the feasibility of selective targeting of individual phosphatase complexes, opens up new avenues into the study of transcription. Herein, we summarize how chemical biology is used to delineate kinases' identities involved in RNAP II regulation and new concepts in inhibitor/activator design implemented for kinases/phosphatases involved in modulating RNAP II-mediated transcription.
RNA 聚合酶 II（RNAP II）的磷酸化协调真核转录的时间进程。化学遗传学方法的发展和应用增强了我们研究针对 RNAP II 的激酶和磷酸酶调节的复杂且相互交织的途径的能力，以确保转录的准确性和效率。尽管由于其高度保守的结构，鉴定调节这些酶的小分子具有挑战性，但靶向共价抑制剂和小分子降解剂等强大的新化学生物学策略极大地提高了化学探针的特异性。最近在发现磷酸酶全酶激活剂和抑制剂方面取得的成功表明，选择性靶向单个磷酸酶复合物是可行的，这为转录研究开辟了新途径。本文总结了如何利用化学生物学来阐明参与 RNAP II 调节的激酶的身份，以及用于调节 RNAP II 介导的转录的激酶/磷酸酶的抑制剂/激活剂设计的新概念。
