DNA-protein crosslinks (DPCs) are highly cytotoxic lesions that impede DNA-based processes such as replication and transcription. This study investigates the impact of DPCs on transcription and the mechanisms by which they are repaired. DPCs severely inhibit RNA polymerase II-mediated transcription and are preferentially repaired in active genes through a transcription-coupled (TC) repair pathway. The TC-DPC repair pathway involves the recruitment of the transcription-coupled nucleotide excision repair (TC-NER) factors CSB and CSA to DPC-stalled RNA polymerase II. While UVSSA and XPA, downstream TC-NER factors, are not essential for TC-DPC repair, the ubiquitin ligase CRL4CSA and the proteasome mediate the degradation of DPCs. This repair mechanism functions independently of the spartan (SPRTN) protease and is crucial for maintaining transcriptional activity in the presence of DPCs. The study also highlights the rapid recovery of transcription after DPC induction, suggesting that DPCs are preferentially repaired in actively transcribed genes. The findings provide insights into the non-canonical TC-NER mechanism involved in the repair of transcription-blocking DPCs and its potential role in cellular stress response.DNA-protein crosslinks (DPCs) are highly cytotoxic lesions that impede DNA-based processes such as replication and transcription. This study investigates the impact of DPCs on transcription and the mechanisms by which they are repaired. DPCs severely inhibit RNA polymerase II-mediated transcription and are preferentially repaired in active genes through a transcription-coupled (TC) repair pathway. The TC-DPC repair pathway involves the recruitment of the transcription-coupled nucleotide excision repair (TC-NER) factors CSB and CSA to DPC-stalled RNA polymerase II. While UVSSA and XPA, downstream TC-NER factors, are not essential for TC-DPC repair, the ubiquitin ligase CRL4CSA and the proteasome mediate the degradation of DPCs. This repair mechanism functions independently of the spartan (SPRTN) protease and is crucial for maintaining transcriptional activity in the presence of DPCs. The study also highlights the rapid recovery of transcription after DPC induction, suggesting that DPCs are preferentially repaired in actively transcribed genes. The findings provide insights into the non-canonical TC-NER mechanism involved in the repair of transcription-blocking DPCs and its potential role in cellular stress response.