DNA-protein crosslinks (DPCs) are highly toxic DNA lesions that block DNA-based processes like replication and transcription. They are primarily repaired by proteolysis, either through the protease SPRTN or the proteasome. This study shows that DPCs severely inhibit RNA polymerase II (Pol II)-mediated transcription and are preferentially repaired in actively transcribed genes through a transcription-coupled DPC (TC-DPC) repair pathway. TC-DPC repair is initiated by recruiting the transcription-coupled nucleotide excision repair (TC-NER) factors CSB and CSA to DPC-stalled Pol II. While CSA and CSB are essential for TC-DPC repair, downstream TC-NER factors like UVSSA and XPA are not, indicating a non-canonical TC-NER mechanism. TC-DPC repair functions independently of SPRTN but is mediated by the ubiquitin ligase CRL4$^{CSA}$ and the proteasome. Thus, DPCs in genes are preferentially repaired in a transcription-coupled manner to facilitate unperturbed transcription. DPCs are formed by covalent linking of proteins to DNA through enzymatic or non-enzymatic reactions. They are induced by endogenously produced reactive aldehydes such as formaldehyde or acetaldehyde. DPCs block transcription by stalling Pol II at the lesion, and their repair is crucial for maintaining transcription. TC-DPC repair is initiated by the recruitment of CSB and CSA to DPC-stalled Pol II. CSB and CSA are essential for TC-DPC repair, while UVSSA and XPA are not, suggesting a non-canonical TC-NER mechanism. TC-DPC repair is mediated by the ubiquitin ligase CRL4$^{CSA}$ and the proteasome, and is independent of SPRTN. The repair of DPCs in transcribed genes is faster than the repair of total cellular DPCs, indicating that TC-DPC repair is a transcription-coupled process. This study also shows that TC-DPC repair is crucial for resolving DPCs in transcribed genes and that the repair process is distinct from canonical TC-NER. The findings highlight the importance of TC-DPC repair in maintaining transcription and cellular function.DNA-protein crosslinks (DPCs) are highly toxic DNA lesions that block DNA-based processes like replication and transcription. They are primarily repaired by proteolysis, either through the protease SPRTN or the proteasome. This study shows that DPCs severely inhibit RNA polymerase II (Pol II)-mediated transcription and are preferentially repaired in actively transcribed genes through a transcription-coupled DPC (TC-DPC) repair pathway. TC-DPC repair is initiated by recruiting the transcription-coupled nucleotide excision repair (TC-NER) factors CSB and CSA to DPC-stalled Pol II. While CSA and CSB are essential for TC-DPC repair, downstream TC-NER factors like UVSSA and XPA are not, indicating a non-canonical TC-NER mechanism. TC-DPC repair functions independently of SPRTN but is mediated by the ubiquitin ligase CRL4$^{CSA}$ and the proteasome. Thus, DPCs in genes are preferentially repaired in a transcription-coupled manner to facilitate unperturbed transcription. DPCs are formed by covalent linking of proteins to DNA through enzymatic or non-enzymatic reactions. They are induced by endogenously produced reactive aldehydes such as formaldehyde or acetaldehyde. DPCs block transcription by stalling Pol II at the lesion, and their repair is crucial for maintaining transcription. TC-DPC repair is initiated by the recruitment of CSB and CSA to DPC-stalled Pol II. CSB and CSA are essential for TC-DPC repair, while UVSSA and XPA are not, suggesting a non-canonical TC-NER mechanism. TC-DPC repair is mediated by the ubiquitin ligase CRL4$^{CSA}$ and the proteasome, and is independent of SPRTN. The repair of DPCs in transcribed genes is faster than the repair of total cellular DPCs, indicating that TC-DPC repair is a transcription-coupled process. This study also shows that TC-DPC repair is crucial for resolving DPCs in transcribed genes and that the repair process is distinct from canonical TC-NER. The findings highlight the importance of TC-DPC repair in maintaining transcription and cellular function.