Proteomics

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A PP2A-Integrator complex fine-tunes transcription by opposing CDK9

ABSTRACT: In this study, 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 antagonises 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 cell growth and pro-inflammatory 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 finely-tuned gene expression relies on the balance of kinase and phosphatase activity throughout the transcription cycle.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hela Cell

SUBMITTER: Sarah Welsh  

LAB HEAD: Alessandro Gardini

PROVIDER: PXD025060 | Pride | 2022-08-12

REPOSITORIES: Pride

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GardiniA-18-G252-GelControl-HF.raw Raw
GardiniA-18-G252-PP2CA-HF.raw Raw
GardiniA-19-G011-Gelcontrol-HF.raw Raw
GardiniA-19-G011-PP2CA-HF.raw Raw
GardiniA-19-G011-proteinGroups.xlsx Xlsx
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Publications

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

Vervoort Stephin J SJ   Welsh Sarah A SA   Devlin Jennifer R JR   Barbieri Elisa E   Knight Deborah A DA   Offley Sarah S   Bjelosevic Stefan S   Costacurta Matteo M   Todorovski Izabela I   Kearney Conor J CJ   Sandow Jarrod J JJ   Fan Zheng Z   Blyth Benjamin B   McLeod Victoria V   Vissers Joseph H A JHA   Pavic Karolina K   Martin Ben P BP   Gregory Gareth G   Demosthenous Elena E   Zethoven Magnus M   Kong Isabella Y IY   Hawkins Edwin D ED   Hogg Simon J SJ   Kelly Madison J MJ   Newbold Andrea A   Simpson Kaylene J KJ   Kauko Otto O   Harvey Kieran F KF   Ohlmeyer Michael M   Westermarck Jukka J   Gray Nathanael N   Gardini Alessandro A   Johnstone Ricky W RW  

Cell 20210517 12

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 phosphoryl  ...[more]

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