Christopher J Carnie, Aleida C Acampora, Aldo S Bader, Chimeg Erdenebat, Shubo Zhao, Elnatan Bitensky, Diana van den Heuvel, Avital Parnas, Vipul Gupta, Giuseppina D'Alessandro, Matylda Sczaniecka-Clift, Pedro Weickert, Fatih Aygenli, Maximilian J Götz, Jacqueline Cordes, Isabel Esain-Garcia, Larry Melidis, Annelotte P Wondergem, Simon Lam, Maria S Robles, Shankar Balasubramanian, Sheera Adar, Martijn S Luijsterburg, Stephen P Jackson, Julian Stingele
Covalent DNA-protein cross-links (DPCs) are toxic DNA lesions that block replication and require repair by multiple pathways. Whether transcription blockage contributes to the toxicity of DPCs and how cells respond when RNA polymerases stall at DPCs is unknown. Here we find that DPC formation arrests transcription and induces ubiquitylation and degradation of RNA polymerase II. Using genetic screens and a method for the genome-wide mapping of DNA-protein adducts, DPC sequencing, we discover that Cockayne syndrome (CS) proteins CSB and CSA provide resistance to DPC-inducing agents by promoting DPC repair in actively transcribed genes...
April 10, 2024: Nature Cell Biology