PXD022962
PXD022962 is an original dataset announced via ProteomeXchange.
Dataset Summary
| Title | A PP2A-Integrator complex fine-tunes transcription by opposing CDK9 |
| Description | 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. |
| HostingRepository | PRIDE |
| AnnounceDate | 2022-08-12 |
| AnnouncementXML | Submission_2022-08-11_23:50:06.028.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Unsupported dataset by repository |
| PrimarySubmitter | Jarrod Sandow |
| SpeciesList | scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606; scientific name: Drosophila melanogaster (Fruit fly); NCBI TaxID: 7227; |
| ModificationList | phosphorylated residue |
| Instrument | Q Exactive |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2020-12-07 03:10:18 | ID requested | |
| ⏵ 1 | 2022-08-11 23:50:06 | announced |
Publication List
| 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, The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer. Cell, 184(12):3143-3162.e32(2021) [pubmed] |
Keyword List
| submitter keyword: CDK9, PP2A, transcription |
Contact List
| Ricky Johnstone | |
|---|---|
| contact affiliation | Executive Director Cancer Research, Peter MacCallum Cancer Centre. Head, The Sir Peter MacCallum Department of Oncology, The University of Melbourne. |
| contact email | ricky.johnstone@petermac.org |
| lab head | |
| Jarrod Sandow | |
| contact affiliation | WEHI |
| contact email | sandow@wehi.edu.au |
| dataset submitter | |
Full Dataset Link List
| Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/08/PXD022962 |
| PRIDE project URI |
Repository Record List
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