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

Vervoort, SJ; Welsh, SA; Devlin, JR; Barbieri, E; Knight, DA; Offley, S; Bjelosevic, S; Costacurta, M; Todorovski, I; Kearney, CJ; Sandow, JJ; Fan, Z; Blyth, B; McLeod, V; Vissers, JHA; Pavic, K; Martin, BP; Gregory, G; Demosthenous, E; Zethoven, M; Kong, IY; Hawkins, ED; Hogg, SJ; Kelly, MJ; Newbold, A; Simpson, KJ; Kauko, O; Harvey, KF; Ohlmeyer, M; Westermarck, J; Gray, N; Gardini, A; Johnstone, RW

Author(s): Vervoort, SJ; Welsh, SA; Devlin, JR; Barbieri, E; Knight, DA; Offley, S; Bjelosevic, S; Costacurta, M; Todorovski, I; Kearney, CJ; Sandow, JJ; Fan, Z; Blyth, B; McLeod, V; Vissers, JHA; Pavic, K; Martin, BP; Gregory, G; Demosthenous, E; Zethoven, M; Kong, IY; Hawkins, ED; Hogg, SJ; Kelly, MJ; Newbold, A; Simpson, KJ; Kauko, O; Harvey, KF; Ohlmeyer, M; Westermarck, J; Gray, N; Gardini, A; Johnstone, RW;
Details: Publication Year 2021-05-12,Volume 184,Issue #12,Page 3134-3162.e32
Journal Title: Cell
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.
Publisher: Cell Press
Keywords: Cdk9; CRISPR-Cas9 screen; Ctd; Integrator; Pp2a; PP2A activation; RNA polymerase II; cancer; pause-release; phosphatase; transcriptional elongation
Research Division(s): Advanced Technology And Biology; Inflammation
PubMed ID: 34004147
Publisher's Version: https://doi.org/10.1016/j.cell.2021.04.022
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2021-06-02 01:28:06

Last Modified: 2021-07-07 10:56:36