期刊
CELL
卷 184, 期 12, 页码 3143-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2021.04.022
关键词
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资金
- Cancer Council Victoria
- National Health and Medical Research Council of Australia (NHMRC)
- The Kids' Cancer Project
- American Cancer Society [RSG18-157-01-DMC]
- G. Harold & Leila Y. Mathers Foundation
- NIH [R01 HL141326, T32-GM071339]
- Emerson Collective Cancer Research Fund
- Ovarian Cancer Research Alliance
- Rubicon fellowship (NWO) [019.161LW.017]
- NHMRC EL1 fellowship [GNT1178339]
- Kids' Cancer Project
- Early Career Seed Grant from the Victorian Cancer Agency (VCA)
- Cancer Council of Victoria (CCV)
- NHMRC [APP1078220]
- Academy of Finland [294850]
- Finnish Cancer Foundation
- Finnish Cultural Foundation
- Australian Cancer Research Foundation (ACRF)
- University of Melbourne Collaborative Research Infrastructure Program
- PMCC Foundation
- Academy of Finland (AKA) [294850, 294850] Funding Source: Academy of Finland (AKA)
CDK9 regulates gene expression by controlling the pausing checkpoint during the transcription cycle, while PP2A counteracts CDK9-mediated phosphorylation. Loss of INTS6 leads to resistance to CDK9 inhibition-induced tumor cell death, and pharmacological activation of PP2A in combination with CDK9 inhibition provides therapeutic benefits in vivo.
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.
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