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DNA damage-induced transcription stress triggers the genome-wide degradation of promoter-bound Pol II

Author

Listed:
  • Barbara Steurer

    (Erasmus University Medical Center)

  • Roel C. Janssens

    (Erasmus University Medical Center)

  • Marit E. Geijer

    (Erasmus University Medical Center)

  • Fernando Aprile-Garcia

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Bart Geverts

    (Erasmus MC)

  • Arjan F. Theil

    (Erasmus University Medical Center)

  • Barbara Hummel

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Martin E. Royen

    (Erasmus MC)

  • Bastiaan Evers

    (The Netherlands Cancer Institute)

  • René Bernards

    (The Netherlands Cancer Institute)

  • Adriaan B. Houtsmuller

    (Erasmus MC)

  • Ritwick Sawarkar

    (Max Planck Institute of Immunobiology and Epigenetics
    University of Cambridge)

  • Jurgen Marteijn

    (Erasmus University Medical Center)

Abstract

The precise regulation of RNA Polymerase II (Pol II) transcription after genotoxic stress is crucial for proper execution of the DNA damage-induced stress response. While stalling of Pol II on transcription-blocking lesions (TBLs) blocks transcript elongation and initiates DNA repair in cis, TBLs additionally elicit a response in trans that regulates transcription genome-wide. Here we uncover that, after an initial elongation block in cis, TBLs trigger the genome-wide VCP-mediated proteasomal degradation of promoter-bound, P-Ser5-modified Pol II in trans. This degradation is mechanistically distinct from processing of TBL-stalled Pol II, is signaled via GSK3, and contributes to the TBL-induced transcription block, even in transcription-coupled repair-deficient cells. Thus, our data reveal the targeted degradation of promoter-bound Pol II as a critical pathway that allows cells to cope with DNA damage-induced transcription stress and enables the genome-wide adaptation of transcription to genotoxic stress.

Suggested Citation

  • Barbara Steurer & Roel C. Janssens & Marit E. Geijer & Fernando Aprile-Garcia & Bart Geverts & Arjan F. Theil & Barbara Hummel & Martin E. Royen & Bastiaan Evers & René Bernards & Adriaan B. Houtsmull, 2022. "DNA damage-induced transcription stress triggers the genome-wide degradation of promoter-bound Pol II," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31329-w
    DOI: 10.1038/s41467-022-31329-w
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    References listed on IDEAS

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    Cited by:

    1. Yongchang Zhu & Xiping Zhang & Meng Gao & Yanchao Huang & Yuanqing Tan & Avital Parnas & Sizhong Wu & Delin Zhan & Sheera Adar & Jinchuan Hu, 2024. "Coordination of transcription-coupled repair and repair-independent release of lesion-stalled RNA polymerase II," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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