The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer.
Animals
Cell Line, Tumor
Cyclin-Dependent Kinase 9
/ antagonists & inhibitors
Drug Resistance, Neoplasm
/ genetics
Gene Expression Regulation, Neoplastic
Humans
Mice, Inbred NOD
Molecular Targeted Therapy
Neoplasms
/ drug therapy
Phosphorylation
Protein Binding
Protein Phosphatase 2
/ metabolism
RNA Polymerase II
/ chemistry
RNA-Binding Proteins
/ metabolism
Substrate Specificity
Transcription, Genetic
Tumor Suppressor Proteins
/ metabolism
CDK9
CRISPR-Cas9 screen
CTD
Integrator
PP2A
PP2A activation
RNA polymerase II
cancer
pause-release
phosphatase
transcriptional elongation
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
10 06 2021
10 06 2021
Historique:
received:
23
06
2020
revised:
27
11
2020
accepted:
14
04
2021
pubmed:
19
5
2021
medline:
6
1
2022
entrez:
18
5
2021
Statut:
ppublish
Résumé
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 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 oncogenic 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 fine control of gene expression relies on the balance between kinase and phosphatase activity throughout the transcription cycle, a process dysregulated in cancer that can be exploited therapeutically.
Identifiants
pubmed: 34004147
pii: S0092-8674(21)00502-X
doi: 10.1016/j.cell.2021.04.022
pmc: PMC8567840
mid: NIHMS1695437
pii:
doi:
Substances chimiques
INTS6 protein, human
0
RNA-Binding Proteins
0
Tumor Suppressor Proteins
0
CDK9 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 9
EC 2.7.11.22
RNA Polymerase II
EC 2.7.7.-
Protein Phosphatase 2
EC 3.1.3.16
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3143-3162.e32Subventions
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141326
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM071339
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM133398
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The Johnstone laboratory receives funding support from Roche, BMS, Astra Zeneca, and MecRx. R.W.J. is a shareholder in MecRx and receives consultancy payments.
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