Transcription-coupled DNA-Protein Crosslink repair by CSB and CRL4CSA-mediated degradation

DNA-protein crosslinks (DPCs) arise from enzymatic intermediates, metabolism or exogenous chemicals like chemotherapeutics. DPCs are highly cytotoxic as they impede DNA-based processes such as replication, which is counteracted by proteolysis-mediated DPC removal by the protease SPRTN or the proteasome. However, whether DPCs affect transcription and how transcription-blocking DPCs are repaired remains largely unknown. Here, we show that DPCs severely impede RNA polymerase II (Pol II)-mediated transcription, resulting in the recruitment of the transcription-coupled nucleotide excision repair (TC-NER) factors CSB and CSA. Strikingly, while CSA and CSB are indispensable for transcription-coupled DPC (TC-DPC) repair, the downstream TC-NER factors UVSSA and XPA are not, indicative of a non-canonical TC-NER mechanism. TC-DPC repair functions independently of SPRTN, but is mediated by the activities of the ubiquitin ligase CRL4CSA and the proteasome. Thus, DPCs are preferentially repaired in active genes by a dedicated transcription-coupled repair mechanism, which is crucial to warrant unperturbed transcription.