Journal article

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 HA Vissers, Karolina Pavic, Ben P Martin, Gareth Gregory, Elena Demosthenous, Magnus Zethoven Show all

CELL | CELL PRESS | Published : 2021

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 ampl..

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Grants

Awarded by American Cancer Society


Awarded by NIH


Awarded by Rubicon fellowship (NWO)


Awarded by NHMRC EL1 fellowship


Awarded by NHMRC


Awarded by Academy of Finland


Funding Acknowledgements

We thank members of the Johnstone and Gardini laboratories, the Translational Research Laboratory, the Victorian Centre for Functional Genomics (VCFG), Molecular Genomics Core and the Flow Cytometry Core Facilities at the Peter MacCallum Cancer Center (PMCC), the Proteomics Facility at the Walter and Eliza Hall Institute, and the Genomics Core and the Proteomics Core at The Wistar Institute (P30-CA010815) for their technical expertise and for providing reagents. We thank Prof. Robert Fisher for providing phosphoSpt5 antibodies. Illustrations were made with BioRender.com. R.W.J. was supported by the Cancer Council Victoria, National Health and Medical Research Council of Australia (NHMRC) and The Kids' Cancer Project. The Gardini laboratory (A.G.) was supported the American Cancer Society (RSG18-157-01-DMC), the G. Harold & Leila Y. Mathers Foundation (A.G.), the NIH (R01 HL141326), the Emerson Collective Cancer Research Fund, and the Ovarian Cancer Research Alliance. S.J.V. was supported by a Rubicon fellowship (NWO, 019.161LW.017), NHMRC EL1 fellowship (GNT1178339), and The Kids' Cancer Project. S.A.W. was supported by a training grant from NIH (T32-GM071339). J.R.D. was supported by an Early Career Seed Grant from the Victorian Cancer Agency (VCA). S.J.H. was supported by a Postdoctoral Fellowship from the Cancer Council of Victoria (CCV). K.F.H. was supported by a NHMRC Senior Research Fellowship (APP1078220). J.W. and K.P. were supported by Academy of Finland (294850) and Finnish Cancer Foundation. K.P. was supported by Finnish Cultural Foundation. The VCFG ACRF Translational Reverse Phase Protein Array platform (K.J.S.) is funded by the Australian Cancer Research Foundation (ACRF), University of Melbourne Collaborative Research Infrastructure Program, and the PMCC Foundation. The PMCC Foundation and ACRF provide generous support for equipment and core facilities.