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Dissecting the Pol II transcription cycle and derailing cancer with CDK inhibitors

Abstract

Largely non-overlapping sets of cyclin-dependent kinases (CDKs) regulate cell division and RNA polymerase II (Pol II)-dependent transcription. Here we review the molecular mechanisms by which specific CDKs are thought to act at discrete steps in the transcription cycle and describe the recent emergence of transcriptional CDKs as promising drug targets in cancer. We emphasize recent advances in understanding the transcriptional CDK network that were facilitated by development and deployment of small-molecule inhibitors with increased selectivity for individual CDKs. Unexpectedly, several of these compounds have also shown selectivity in killing cancer cells, despite the seemingly universal involvement of their target CDKs during transcription in all cells. Finally, we describe remaining and emerging challenges in defining functions of individual CDKs in transcription and co-transcriptional processes and in leveraging CDK inhibition for therapeutic purposes.

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Fig. 1: Multiple CDK–cyclin complexes act in sequence in the Pol II transcription cycle.
Fig. 2: Modes of Cdk8-mediated transcription regulation.
Fig. 3: CDK-dependent transitions in the Pol II transcription cycle.
Fig. 4: Strategies for selective CDK inhibition by chemical genetics.
Fig. 5: Strategies for selective CDK inhibition by covalent inhibitors.
Fig. 6: Strategies for selective CDK inhibition by degraders.

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Acknowledgements

We thank past and present members of the Fisher laboratory for helpful discussions. Work in the laboratory is supported by NIH grant R35GM127289.

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Parua, P.K., Fisher, R.P. Dissecting the Pol II transcription cycle and derailing cancer with CDK inhibitors. Nat Chem Biol 16, 716–724 (2020). https://doi.org/10.1038/s41589-020-0563-4

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