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

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. Houtsmuller, Ritwick Sawarkar and Jurgen Marteijn ()
Additional contact information
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
Jurgen Marteijn: Erasmus University Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31329-w

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