DNA damage-induced transcription stress triggers the genome-wide degradation of promoter-bound Pol II.
Barbara SteurerRoel C JanssensMarit E GeijerFernando Aprile-GarciaBart GevertsArjan F TheilBarbara HummelMartin E van RoyenBastiaan EversRené BernardsAdriaan B HoutsmullerRitwick SawarkarJurgen A MarteijnPublished in: Nature communications (2022)
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.
Keyphrases
- genome wide
- dna damage
- transcription factor
- dna methylation
- dna repair
- high glucose
- diabetic rats
- oxidative stress
- induced apoptosis
- gene expression
- signaling pathway
- endothelial cells
- stress induced
- machine learning
- cell death
- deep learning
- rna seq
- drug delivery
- heat stress
- dna damage response
- cancer therapy
- electronic health record