Endogenous aldehyde-induced DNA-protein crosslinks (DPCs) interfere with replication and transcription, leading to hereditary disorders such as Ruijs–Aalfs syndrome (RJALS) and AMeD syndrome (AMEDS). The study demonstrates that transcription-coupled repair (TCR) efficiently resolves these DPCs. Using a high-throughput sequencing technique called DPC-seq, the authors show that conventional TCR factors, VCP/p97, and the proteasome are essential for removing formaldehyde-induced DPCs. TFIIS-dependent cleavage of RNAPII transcripts protects against transcription obstacles. A mouse model lacking both aldehyde clearance and TCR exhibits severe haematopoietic abnormalities and systemic asthenia, confirming the importance of TCR in protecting against metabolic genotoxins. The findings provide insights into the molecular pathogenesis of AMeDS and other disorders associated with defects in TCR, such as Cockayne syndrome.Endogenous aldehyde-induced DNA-protein crosslinks (DPCs) interfere with replication and transcription, leading to hereditary disorders such as Ruijs–Aalfs syndrome (RJALS) and AMeD syndrome (AMEDS). The study demonstrates that transcription-coupled repair (TCR) efficiently resolves these DPCs. Using a high-throughput sequencing technique called DPC-seq, the authors show that conventional TCR factors, VCP/p97, and the proteasome are essential for removing formaldehyde-induced DPCs. TFIIS-dependent cleavage of RNAPII transcripts protects against transcription obstacles. A mouse model lacking both aldehyde clearance and TCR exhibits severe haematopoietic abnormalities and systemic asthenia, confirming the importance of TCR in protecting against metabolic genotoxins. The findings provide insights into the molecular pathogenesis of AMeDS and other disorders associated with defects in TCR, such as Cockayne syndrome.