This article describes a transcription-coupled DNA–protein cross-link (DPC) repair pathway that depends on the Cockayne syndrome (CS) proteins CSA and CSB. DPCs are toxic DNA lesions that block replication and require repair by multiple pathways. The study reveals that DPC formation arrests transcription and induces ubiquitylation and degradation of RNA polymerase II. Genetic screens and DPC sequencing identified CSA and CSB as essential for DPC repair in actively transcribed genes, enabling efficient transcription recovery after DPC induction. In contrast, nucleotide excision repair factors downstream of CSB and CSA are not required for DPC repair. The study highlights a unique transcription-coupled DPC repair pathway that may contribute to the neurological features of CS. CSB and CSA are required for DPC tolerance, functioning in a pathway independent of canonical transcription-coupled nucleotide excision repair (TC-NER). The findings suggest that defects in this pathway may underlie the pathogenesis of CS. The study also demonstrates that CSB promotes recovery from DPC-induced transcription arrest by facilitating the resolution of DPCs and enabling transcription to resume. DPC-seq analysis reveals that CSB is required for DPC repair in gene bodies, particularly at transcriptionally active loci. The results indicate that CSB-dependent DPC repair is distinct from classical TC-NER and that CSB plays a critical role in transcription-coupled DPC repair. The study provides direct evidence for CSB-dependent transcriptional DPC repair in human cells.This article describes a transcription-coupled DNA–protein cross-link (DPC) repair pathway that depends on the Cockayne syndrome (CS) proteins CSA and CSB. DPCs are toxic DNA lesions that block replication and require repair by multiple pathways. The study reveals that DPC formation arrests transcription and induces ubiquitylation and degradation of RNA polymerase II. Genetic screens and DPC sequencing identified CSA and CSB as essential for DPC repair in actively transcribed genes, enabling efficient transcription recovery after DPC induction. In contrast, nucleotide excision repair factors downstream of CSB and CSA are not required for DPC repair. The study highlights a unique transcription-coupled DPC repair pathway that may contribute to the neurological features of CS. CSB and CSA are required for DPC tolerance, functioning in a pathway independent of canonical transcription-coupled nucleotide excision repair (TC-NER). The findings suggest that defects in this pathway may underlie the pathogenesis of CS. The study also demonstrates that CSB promotes recovery from DPC-induced transcription arrest by facilitating the resolution of DPCs and enabling transcription to resume. DPC-seq analysis reveals that CSB is required for DPC repair in gene bodies, particularly at transcriptionally active loci. The results indicate that CSB-dependent DPC repair is distinct from classical TC-NER and that CSB plays a critical role in transcription-coupled DPC repair. The study provides direct evidence for CSB-dependent transcriptional DPC repair in human cells.