Advancements in chemical biology targeting the kinases and phosphatases of RNA polymerase II-mediated transcription

Wantae Kim; Blase LeBlanc; Wendy L Matthews; Zhong-Yin Zhang; Yan Zhang

doi:10.1016/j.cbpa.2021.02.002

Advancements in chemical biology targeting the kinases and phosphatases of RNA polymerase II-mediated transcription

Curr Opin Chem Biol. 2021 Aug:63:68-77. doi: 10.1016/j.cbpa.2021.02.002. Epub 2021 Mar 11.

Authors

Wantae Kim¹, Blase LeBlanc², Wendy L Matthews², Zhong-Yin Zhang³, Yan Zhang⁴

Affiliations

¹ McKetta Department of Chemical Engineering, University of Texas at Austin, Austin, TX, 78712, USA.
² Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, 78712, USA.
³ Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, and Institute for Drug Discovery, Purdue University, West Lafayette, IN, 47907, USA.
⁴ Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, 78712, USA; The Institute for Cellular and Molecular Biology. University of Texas at Austin, Austin, TX, 78712, USA. Electronic address: jeszhang@cm.utexas.edu.

Abstract

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.

Keywords: Analog-sensitive kinase; CDK; Chemical biology; Chemical genetics; PP1; PP2A; RNA polymerase II; Targeted covalent inhibitor; Transcription.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

Enzyme Inhibitors / chemistry*
Models, Molecular
Phosphoric Monoester Hydrolases / chemistry*
Phosphorylation
Phosphotransferases / chemistry*
Protein Binding
Protein Conformation
RNA Polymerase II / chemistry*
Structure-Activity Relationship
Substrate Specificity
Transcription, Genetic

Substances

Enzyme Inhibitors
Phosphotransferases
RNA Polymerase II
Phosphoric Monoester Hydrolases

Abstract

Publication types

MeSH terms

Substances

Grants and funding