PXD025060

PXD025060 is an original dataset announced via ProteomeXchange.

Title	A PP2A-Integrator complex fine-tunes transcription by opposing CDK9
Description	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.
HostingRepository	PRIDE
AnnounceDate	2022-08-12
AnnouncementXML	Submission_2022-08-11_23:53:29.766.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sarah Welsh
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	deaminated residue; monohydroxylated residue; acetylated residue
Instrument	Q Exactive HF; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-29 02:45:37	ID requested
⏵ 1	2022-08-11 23:53:30	announced

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]

submitter keyword: Human, PP2A, Integrator, transcription

Alessandro Gardini
contact affiliation	Assistant Professor, Gene Expression & Regulation Program, Wistar Institute Cancer Center, Philadelphia PA, USA
contact email	agardini@wistar.org
lab head
Sarah Welsh
contact affiliation	Wistar Institute
contact email	swelsh@wistar.org
dataset submitter

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/PXD025060

PRIDE project URI

• PRIDE
  1. PXD025060
     1. Label: PRIDE project
     2. Name: A PP2A-Integrator complex fine-tunes transcription by opposing CDK9