2. Academic Validation
  3. A CDK11-dependent RNA polymerase II pause-checkpoint precedes CDK9-mediated transition to transcriptional elongation

A CDK11-dependent RNA polymerase II pause-checkpoint precedes CDK9-mediated transition to transcriptional elongation

  • Mol Cell. 2025 Sep 4;85(17):3256-3274.e14. doi: 10.1016/j.molcel.2025.08.001.
Jennifer R Devlin 1,  Ben Martin 2,  Nenad Bartonicek 1,  Keziah Ting 1,  Zheng Fan 2,  Izabela Todorovski 2,  Filip Bjelosevic 2,  Sandra Verschoor 2,  Annette Ciccone 2,  Joseph A Trapani 1,  Attila Horvath 1,  Emily Tinsley 3,  Peter Fraser 2,  Andrea Newbold 1,  Jarrod J Sandow 4,  Andrea Muscat 5,  Kaylene J Simpson 6,  Matthias Geyer 7,  Stephin J Vervoort 5,  Ricky W Johnstone 8
Affiliations

Affiliations

  • 1 The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia; Peter MacCallum Cancer Centre, Laboratory Research Division, Parkville, VIC 3052, Australia.
  • 2 Peter MacCallum Cancer Centre, Laboratory Research Division, Parkville, VIC 3052, Australia.
  • 3 RCSI University of Medicine and Health Sciences, Dublin D02 DH60, Ireland.
  • 4 The Walter and Eliza Hall Institute, Parkville, VIC 3052, Australia; Ionopticks, Fitzroy, VIC 3065, Australia.
  • 5 The Walter and Eliza Hall Institute, Parkville, VIC 3052, Australia.
  • 6 The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia; Peter MacCallum Cancer Centre, Laboratory Research Division, Parkville, VIC 3052, Australia; The Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, VIC 3052, Australia.
  • 7 Institute of Structural Biology, Biomedical Centre, University of Bonn, 53127 Bonn, Germany.
  • 8 The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia; Peter MacCallum Cancer Centre, Laboratory Research Division, Parkville, VIC 3052, Australia. Electronic address: ricky.johnstone@petermac.org.
PMID: 40858114 DOI: 10.1016/j.molcel.2025.08.001
Abstract

Controlled gene expression is achieved through the intricate regulation of RNA polymerase II (Pol II) progression through transcription-cycle checkpoints. While the contribution of CDK9 for Pol II pause-release is well established, the requirement for Other cyclin-dependent kinases (CDKs) has not been fully elucidated. In this study, we propose a critical role for CDK11 in the Pol II pausing-to-elongation transition at a checkpoint that precedes and is independent from CDK9. Selective CDK11 inhibition or degradation results in acute ablation of RNA synthesis near the beginning of transcriptional units and genome-wide stalling of Pol II at transcription start site (TSS)-proximal regions. High-resolution chromatin immunoprecipitation and precision nuclear run-on assays reveal spatial differences between CDK11- and CDK9-dependent Pol II pause sites, with CDK11 regulating Pol II upstream of the CDK9 checkpoint within the pausing zone. Cancer cells exhibit profound reliance on CDK11, with CDK11 inhibition reducing tumor burden in in vivo models of blood Cancer, demonstrating the importance of CDK11-dependent Pol II regulation for aggressive hematological malignancies.

Keywords

RNA polymerase II; cancer therapy; cyclin-dependent kinases; gene-expression; transcription cycle.

Figures
Products