Proteomics

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


ABSTRACT: Gene expression by RNA Polymerase II (RNAPII) is tightly controlled by Cyclindependent kinases (CDKs) at discrete checkpoints during the transcription cycle. The RNAPII pausing checkpoint, engaged after transcription initiation, is controlled by CDK9 to regulate transcription in metazoans. 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 RNAPIICTD, and is recruited to transcription pausing sites by the Integrator complex subunit INTS6. INTS6 depletion confers resistance to CDK9 inhibition in a variety of normal and tumor cell lines. Loss of INTS6 abolishes the Integrator-PP2A association leading to unrestrained CDK9 activity, which amplifies transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill MLLrearranged leukemias and solid tumors and provide therapeutic benefit in vivo. These data demonstrate that finely-tuned gene expression relies on the balance of kinase and phosphatase activity at the pausing checkpoint.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human) Drosophila Melanogaster (fruit Fly) Mus Musculus (mouse)

TISSUE(S): Blood Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Jarrod Sandow  

LAB HEAD: Ricky Johnstone

PROVIDER: PXD022962 | Pride | 2022-08-12

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
170717_Colin_CH1.raw Raw
170717_Colin_CH3.raw Raw
170817_Ben_1.raw Raw
170817_Ben_2.raw Raw
170817_Ben_3.raw Raw
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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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