Dataset Information

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): Q Exactive HF, Q Exactive

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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Dataset's files

Source:

			Action	DRS
	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]

PMID: 34004147

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