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

Steurer, Barbara; Janssens, Roel C; Geijer, Marit E; Aprile-Garcia, Fernando; Geverts, Bart; Theil, Arjan F; Hummel, Barbara; van Royen, Martin E; Evers, Bastiaan; Bernards, René; Houtsmuller, Adriaan B; Sawarkar, Ritwick; Marteijn, Jurgen

doi:10.1038/s41467-022-31329-w

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

MPS-Authors

Aprile-Garcia, Fernando
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Hummel, Barbara
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Sawarkar, Ritwick
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Steurer, B., Janssens, R. C., Geijer, M. E., Aprile-Garcia, F., Geverts, B., Theil, A. F., et al. (2022). DNA damage-induced transcription stress triggers the genome-wide degradation of promoter-bound Pol II. Nature Communications, 13: 3624. doi:10.1038/s41467-022-31329-w.

Cite as: https://hdl.handle.net/21.11116/0000-000D-149F-A

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.