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.
We thank the Optical Imaging Centre of the Erasmus Medical Center for support with microscopes. This work is part of the Oncode Institute which is partly financed by the Dutch Cancer Society and was funded by a grant from the Dutch Cancer Society (KWF grant 10506). This work was further funded by the Dutch organization for Scientific Research (NWO-ALW) which awarded a ZonMW TOP Grant (912.12.132), VIDI (864.13.004) and VICI (VI.C.182.025) grant to J.A.M.
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