The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer
Copyright © 2021 Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:184 |
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| Enthalten in: |
Cell - 184(2021), 12 vom: 10. Juni, Seite 3143-3162.e32 |
| Sprache: |
Englisch |
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| Links: |
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| Anmerkungen: |
Date Completed 05.01.2022 Date Revised 26.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.cell.2021.04.022 |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Vervoort, Stephin J |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 05.01.2022 | ||
| 500 | |a Date Revised 26.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CDK9 | |
| 650 | 4 | |a CRISPR-Cas9 screen | |
| 650 | 4 | |a CTD | |
| 650 | 4 | |a Integrator | |
| 650 | 4 | |a PP2A | |
| 650 | 4 | |a PP2A activation | |
| 650 | 4 | |a RNA polymerase II | |
| 650 | 4 | |a cancer | |
| 650 | 4 | |a pause-release | |
| 650 | 4 | |a phosphatase | |
| 650 | 4 | |a transcriptional elongation | |
| 650 | 7 | |a INTS6 protein, human |2 NLM | |
| 650 | 7 | |a RNA-Binding Proteins |2 NLM | |
| 650 | 7 | |a Tumor Suppressor Proteins |2 NLM | |
| 650 | 7 | |a CDK9 protein, human |2 NLM | |
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| 650 | 7 | |a Cyclin-Dependent Kinase 9 |2 NLM | |
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| 650 | 7 | |a RNA Polymerase II |2 NLM | |
| 650 | 7 | |a EC 2.7.7.- |2 NLM | |
| 650 | 7 | |a Protein Phosphatase 2 |2 NLM | |
| 650 | 7 | |a EC 3.1.3.16 |2 NLM | |
| 700 | 1 | |a Welsh, Sarah A |e verfasserin |4 aut | |
| 700 | 1 | |a Devlin, Jennifer R |e verfasserin |4 aut | |
| 700 | 1 | |a Barbieri, Elisa |e verfasserin |4 aut | |
| 700 | 1 | |a Knight, Deborah A |e verfasserin |4 aut | |
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| 700 | 1 | |a Bjelosevic, Stefan |e verfasserin |4 aut | |
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| 700 | 1 | |a Todorovski, Izabela |e verfasserin |4 aut | |
| 700 | 1 | |a Kearney, Conor J |e verfasserin |4 aut | |
| 700 | 1 | |a Sandow, Jarrod J |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Zheng |e verfasserin |4 aut | |
| 700 | 1 | |a Blyth, Benjamin |e verfasserin |4 aut | |
| 700 | 1 | |a McLeod, Victoria |e verfasserin |4 aut | |
| 700 | 1 | |a Vissers, Joseph H A |e verfasserin |4 aut | |
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| 700 | 1 | |a Martin, Ben P |e verfasserin |4 aut | |
| 700 | 1 | |a Gregory, Gareth |e verfasserin |4 aut | |
| 700 | 1 | |a Demosthenous, Elena |e verfasserin |4 aut | |
| 700 | 1 | |a Zethoven, Magnus |e verfasserin |4 aut | |
| 700 | 1 | |a Kong, Isabella Y |e verfasserin |4 aut | |
| 700 | 1 | |a Hawkins, Edwin D |e verfasserin |4 aut | |
| 700 | 1 | |a Hogg, Simon J |e verfasserin |4 aut | |
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