2. Academic Validation
  3. The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer

The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer

  • Cell. 2021 Jun 10;184(12):3143-3162.e32. doi: 10.1016/j.cell.2021.04.022.
Stephin J Vervoort 1,  Sarah A Welsh 2,  Jennifer R Devlin 3,  Elisa Barbieri 4,  Deborah A Knight 3,  Sarah Offley 5,  Stefan Bjelosevic 3,  Matteo Costacurta 3,  Izabela Todorovski 3,  Conor J Kearney 3,  Jarrod J Sandow 6,  Zheng Fan 3,  Benjamin Blyth 7,  Victoria McLeod 7,  Joseph H A Vissers 8,  Karolina Pavic 9,  Ben P Martin 3,  Gareth Gregory 10,  Elena Demosthenous 7,  Magnus Zethoven 7,  Isabella Y Kong 6,  Edwin D Hawkins 6,  Simon J Hogg 3,  Madison J Kelly 3,  Andrea Newbold 3,  Kaylene J Simpson 7,  Otto Kauko 9,  Kieran F Harvey 11,  Michael Ohlmeyer 12,  Jukka Westermarck 9,  Nathanael Gray 13,  Alessandro Gardini 14,  Ricky W Johnstone 15
Affiliations

Affiliations

  • 1 Peter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia. Electronic address: [email protected].
  • 2 The Wistar Institute, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 3 Peter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia.
  • 4 The Wistar Institute, Philadelphia, PA 19104, USA.
  • 5 The Wistar Institute, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 6 The Walter and Eliza Hall Institute, Parkville 3010, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia.
  • 7 Peter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia.
  • 8 Peter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia; Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Parkville 3010, VIC, Australia.
  • 9 Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku FI-20014, Finland; Institute of Biomedicine, University of Turku, Turku FI-20014, Finland.
  • 10 Peter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia; School of Clinical Sciences at Monash Health, Monash University, Clayton 3168, VIC, Australia.
  • 11 Peter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia; Department of Anatomy and Developmental Biology, and Biomedicine Discovery Institute, Monash University, Clayton 3168, VIC, Australia.
  • 12 Mount Sinai School of Medicine, New York, NY 10029, USA; Atux Iskay LLC, Plainsboro, NJ 08536, USA.
  • 13 Dana Farber Cancer Institute, Boston, MA 02215, USA.
  • 14 The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: [email protected].
  • 15 Peter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia. Electronic address: [email protected].
PMID: 34004147 DOI: 10.1016/j.cell.2021.04.022
Abstract

Gene expression by RNA polymerase II (RNAPII) is tightly controlled by cyclin-dependent kinases (CDKs) at discrete checkpoints during the transcription cycle. The pausing checkpoint following transcription initiation is primarily controlled by CDK9. We discovered that CDK9-mediated, RNAPII-driven transcription is functionally opposed by a protein Phosphatase 2A (PP2A) complex that is recruited to transcription sites by the Integrator complex subunit INTS6. PP2A dynamically antagonizes phosphorylation of key CDK9 substrates including DSIF and RNAPII-CTD. Loss of INTS6 results in resistance to tumor cell death mediated by CDK9 inhibition, decreased turnover of CDK9 phospho-substrates, and amplification of acute oncogenic transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill both leukemic and solid tumor cells, providing therapeutic benefit in vivo. These data demonstrate that fine control of gene expression relies on the balance between kinase and Phosphatase activity throughout the transcription cycle, a process dysregulated in Cancer that can be exploited therapeutically.

Keywords

CDK9; CRISPR-Cas9 screen; CTD; Integrator; PP2A; PP2A activation; RNA polymerase II; cancer; pause-release; phosphatase; transcriptional elongation.

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