The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer
| Autor: | Magnus Zethoven, Conor J. Kearney, Matteo Costacurta, Izabela Todorovski, Alessandro Gardini, Michael Ohlmeyer, Stefan Bjelosevic, Gareth P. Gregory, Deborah A. Knight, Nathanael S. Gray, Jarrod J. Sandow, Sarah A. Welsh, Elisa Barbieri, Andrea Newbold, Madison J. Kelly, Otto Kauko, Sarah Offley, Joseph H.A. Vissers, Benjamin J. Blyth, Stephin J. Vervoort, Kaylene J. Simpson, Ben P. Martin, Ricky W. Johnstone, Jukka Westermarck, Jennifer R. Devlin, Kieran F. Harvey, Karolina Pavic, Edwin D. Hawkins, Elena Demosthenous, Isabella Y. Kong, Zheng Fan, Victoria McLeod, Simon J. Hogg |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Transcription
Genetic Integrator complex RNA polymerase II General Biochemistry Genetics and Molecular Biology Article Substrate Specificity 03 medical and health sciences 0302 clinical medicine Cyclin-dependent kinase Transcription (biology) Mice Inbred NOD Cell Line Tumor Neoplasms Gene expression Animals Humans Molecular Targeted Therapy Protein Phosphatase 2 Phosphorylation P-TEFb 030304 developmental biology 0303 health sciences biology Tumor Suppressor Proteins RNA-Binding Proteins Protein phosphatase 2 DSIF Cyclin-Dependent Kinase 9 Cell biology Gene Expression Regulation Neoplastic Drug Resistance Neoplasm biology.protein RNA Polymerase II 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Cell |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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