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

Stephin J. Vervoort, Sarah A. Welsh, Jennifer R. Devlin, Elisa Barbieri, Deborah A. Knight, Sarah Offley, Stefan Bjelosevic, Matteo Costacurta, Izabela Todorovski, Conor J. Kearney, Jarrod J. Sandow, Zheng Fan, Benjamin Blyth, Victoria McLeod, Joseph H.A. Vissers, Karolina Pavic, Ben P. Martin, Gareth Gregory, Elena Demosthenous, Magnus ZethovenIsabella Y. Kong, Edwin D. Hawkins, Simon J. Hogg, Madison J. Kelly, Andrea Newbold, Kaylene J. Simpson, Otto Kauko, Kieran F. Harvey, Michael Ohlmeyer, Jukka Westermarck, Nathanael Gray, Alessandro Gardini, Ricky W. Johnstone

Research output: Contribution to journalArticleResearchpeer-review

48 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)3143-3162.E32
Number of pages52
Issue number12
Publication statusPublished - 10 Jun 2021


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

Cite this