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

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Steurer, Barbara 
Janssens, Roel C 
Aprile-Garcia, Fernando  ORCID logo  https://orcid.org/0000-0002-5133-0857
Geverts, Bart 

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.


Funder: Oncode Institute

Article, /631/1647/328/1978, /631/337/4041/3196, /631/337/1427/2566, /631/337/572, /13/1, /13/109, /13/95, /14/19, /14/35, /38/35, article
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Nat Commun
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Springer Science and Business Media LLC
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research) (VI.C.182.025, 912.12.132, 864.13.004)