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Targeting transcription cycles in cancer

Abstract

Accurate control of gene expression is essential for normal development and dysregulation of transcription underpins cancer onset and progression. Similar to cell cycle regulation, RNA polymerase II-driven transcription can be considered as a unidirectional multistep cycle, with thousands of unique transcription cycles occurring in concert within each cell. Each transcription cycle comprises recruitment, initiation, pausing, elongation, termination and recycling stages that are tightly controlled by the coordinated action of transcriptional cyclin-dependent kinases and their cognate cyclins as well as the opposing activity of transcriptional phosphatases. Oncogenic dysregulation of transcription can entail defective control of gene expression, either at select loci or more globally, impacting a large proportion of the genome. The resultant dependency on the core-transcriptional machinery is believed to render ‘transcriptionally addicted’ cancers sensitive to perturbation of transcription. Based on these findings, small molecules targeting transcriptional cyclin-dependent kinases and associated proteins hold promise for the treatment of cancer. Here, we utilize the transcription cycles concept to explain how dysregulation of these finely tuned gene expression processes may drive tumorigenesis and how therapeutically beneficial responses may arise from global or selective transcriptional perturbation. This conceptual framework helps to explain tumour-selective transcriptional dependencies and facilitates the rational design of combination therapies.

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Fig. 1: An updated view of Pol II transcription cycles.
Fig. 2: Multi-tiered regulation of transcription cycles.
Fig. 3: Distinct properties define the vulnerability of transcription cycles to dysregulation in cancer.
Fig. 4: Selective dysregulation of transcription cycles.
Fig. 5: Distinct features of oncogenic transcription are targetable by tCDK inhibitors.

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All authors made substantial contributions to researching data for the article, the discussion of content, writing and editing of the manuscript before final submission.

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Correspondence to Nathanael S. Gray or Ricky W. Johnstone.

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The Johnstone laboratory receives research support from Roche, BMS, AstraZeneca and MecRx. R.W.J. is a scientific consultant and shareholder in MecRx. N.S.G. is a founder, science advisor and equity holder in C4, Syros, Soltego, B2S, Jengu, Allorion, EoCys and Larkspur Pharmaceuticals. The Gray laboratory receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi, Arbella, Deerfield and Sanofi. N.S.G. and N.K. are inventors on a patent application covering THZ1, which is licensed to a company co-founded by N.S.G.. N.K. is an employee of Kymera Therapeutics. S.J.V., J.R.D. and M.T. declare no competing interests.

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Nature Reviews Cancer thanks Ivan D’Orso, Shudong Wang, who co-reviewed with Muhammed Rahaman, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Vervoort, S.J., Devlin, J.R., Kwiatkowski, N. et al. Targeting transcription cycles in cancer. Nat Rev Cancer (2021). https://doi.org/10.1038/s41568-021-00411-8

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