A transcription-coupled DNA–protein cross-link (DPC) repair pathway depends on the Cockayne syndrome (CS) proteins CSA and CSB. DPCs, which are toxic DNA lesions, block replication and require repair. This study shows that DPC formation arrests transcription and induces ubiquitylation and degradation of RNA polymerase II. Using genetic screens and DPC sequencing, the researchers found that CSA and CSB promote DPC repair in actively transcribed genes, enabling efficient transcription restart after DPC induction. In contrast, nucleotide excision repair factors downstream of CSB and CSA are dispensable. The study describes a transcription-coupled DPC repair pathway and suggests that defects in this pathway may contribute to the unique neurological features of CS. DPCs are bulky DNA adducts that are highly toxic to cells because they can impede DNA replication. DPCs can arise by trapping enzymatic reaction intermediates such as topoisomerase cleavage complexes or DNA methyltransferase 1 (DNMT1). Non-enzymatic DPCs can be induced by platinum-based drugs and reactive endogenous metabolites such as formaldehyde. DPC repair requires DPC proteolysis by specialized proteases or the proteasome. The importance of this process is highlighted by hypomorphic SPRTN mutations causing premature aging and cancer predisposition in patients with Ruijs-Aalfs syndrome. DPC proteolysis can be initiated upon collision with the DNA replication machinery, causing SPRTN activation and replication-coupled ubiquitylation, targeting DPCs for proteasomal degradation. Additionally, global-genome (GG) DPC repair occurs through DPC SUMOylation and subsequent SUMO-dependent polyubiquitylation by RNF4 or TOPORS, which triggers proteasomal degradation or cleavage by SPRTN. DPCs stall T7 bacteriophage RNA polymerase in vitro but it is unknown whether DPCs affect transcription in mammalian cells. At ultraviolet (UV) light-induced DNA lesions, RNA polymerase II (RNAPII) stalling activates transcription-coupled nucleotide excision repair (TC-NER), leading to RNAPII degradation, local and global shut-down of transcription and lesion excision by the nucleotide excision repair (NER) machinery. TC-NER is initiated by CSB, which recognizes stalled RNAPII and recruits the CRL4–CSA E3 ubiquitin ligase complex that promotes ubiquitylation of RPB1, the largest subunit of RNAPII. This stabilizes mono-ubiquitylated UVSSA, which recruits the TFIIH complex and XPA, subsequently engaging the ERCC1–XPF and XPG endonucleases. These mediate a dual incision, excising a stretch of single-stranded DNA. The resultant gap is then closed by DNA synthesis and ensuing ligation. Several humanA transcription-coupled DNA–protein cross-link (DPC) repair pathway depends on the Cockayne syndrome (CS) proteins CSA and CSB. DPCs, which are toxic DNA lesions, block replication and require repair. This study shows that DPC formation arrests transcription and induces ubiquitylation and degradation of RNA polymerase II. Using genetic screens and DPC sequencing, the researchers found that CSA and CSB promote DPC repair in actively transcribed genes, enabling efficient transcription restart after DPC induction. In contrast, nucleotide excision repair factors downstream of CSB and CSA are dispensable. The study describes a transcription-coupled DPC repair pathway and suggests that defects in this pathway may contribute to the unique neurological features of CS. DPCs are bulky DNA adducts that are highly toxic to cells because they can impede DNA replication. DPCs can arise by trapping enzymatic reaction intermediates such as topoisomerase cleavage complexes or DNA methyltransferase 1 (DNMT1). Non-enzymatic DPCs can be induced by platinum-based drugs and reactive endogenous metabolites such as formaldehyde. DPC repair requires DPC proteolysis by specialized proteases or the proteasome. The importance of this process is highlighted by hypomorphic SPRTN mutations causing premature aging and cancer predisposition in patients with Ruijs-Aalfs syndrome. DPC proteolysis can be initiated upon collision with the DNA replication machinery, causing SPRTN activation and replication-coupled ubiquitylation, targeting DPCs for proteasomal degradation. Additionally, global-genome (GG) DPC repair occurs through DPC SUMOylation and subsequent SUMO-dependent polyubiquitylation by RNF4 or TOPORS, which triggers proteasomal degradation or cleavage by SPRTN. DPCs stall T7 bacteriophage RNA polymerase in vitro but it is unknown whether DPCs affect transcription in mammalian cells. At ultraviolet (UV) light-induced DNA lesions, RNA polymerase II (RNAPII) stalling activates transcription-coupled nucleotide excision repair (TC-NER), leading to RNAPII degradation, local and global shut-down of transcription and lesion excision by the nucleotide excision repair (NER) machinery. TC-NER is initiated by CSB, which recognizes stalled RNAPII and recruits the CRL4–CSA E3 ubiquitin ligase complex that promotes ubiquitylation of RPB1, the largest subunit of RNAPII. This stabilizes mono-ubiquitylated UVSSA, which recruits the TFIIH complex and XPA, subsequently engaging the ERCC1–XPF and XPG endonucleases. These mediate a dual incision, excising a stretch of single-stranded DNA. The resultant gap is then closed by DNA synthesis and ensuing ligation. Several human