RT Journal Article
SR Electronic
T1 A PP2A-Integrator complex fine-tunes transcription by opposing CDK9
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.12.199372
DO 10.1101/2020.07.12.199372
A1 Stephin J. Vervoort
A1 Sarah A. Welsh
A1 Jennifer R. Devlin
A1 Elisa Barbieri
A1 Deborah A. Knight
A1 Matteo Costacurta
A1 Izabela Todorovski
A1 Conor J. Kearney
A1 Jarrod J. Sandow
A1 Stefan Bjelosevic
A1 Zheng Fan
A1 Joep H. A. Vissers
A1 Karolina Pavic
A1 Ben P. Martin
A1 Gareth Gregory
A1 Isabella Y. Kong
A1 Edwin D. Hawkins
A1 Simon J. Hogg
A1 Madison J. Kelly
A1 Andrea Newbold
A1 Kaylene J. Simpson
A1 Otto Kauko
A1 Kieran F. Harvey
A1 Michael Ohlmeyer
A1 Jukka Westermarck
A1 Nathanael Gray
A1 Alessandro Gardini
A1 Ricky W. Johnstone
YR 2020
UL http://biorxiv.org/content/early/2020/07/12/2020.07.12.199372.abstract
AB Gene expression is tightly controlled by Cyclin-dependent kinases (CDKs) which regulate the RNA Polymerase II (RNAPII) transcription cycle at discrete checkpoints. RNAPII pausing is a CDK9-controlled rate-limiting process that occurs shortly after initiation and is required for spatio-temporal control of transcription in multicellular organisms. We discovered that CDK9-mediated RNAPII pause-release is functionally opposed by a protein phosphatase 2A (PP2A) complex. PP2A dynamically competes for key CDK9 substrates, DSIF and RNAPII, and is recruited to transcription pausing sites by INTS6, a subunit of the Integrator complex. INTS6 depletion disrupts the Integrator-PP2A association and confers resistance to CDK9 inhibition. This results in unrestrained activity of CDK9 and dysregulation of acute transcriptional responses. Pharmacological PP2A activation amplifies RNAPII pausing mediated by CDK9 inhibitors and synergizes therapeutically in a model of MLL-rearranged leukemia. These data demonstrate that finely-tuned gene expression relies on the delicate balance of kinase and phosphatase activity throughout the transcription cycle.HIGHLIGHTSLoss of INTS6 confers resistance to CDK9 inhibitionINTS6 recruits PP2A to Integrator and chromatinPP2A/INTS6 complexes functionally oppose CDK9PP2A/INTS6 fine-tune acute transcriptional responsesSynergistic anti-cancer activity between PP2A activators and CDK9 inhibitorsCompeting Interest StatementThe Johnstone laboratory receives funding support from Roche, BMS, Astra Zeneca, and MecRx.