Endogenous aldehyde-induced DNA–protein crosslinks (DPCs) are efficiently resolved by transcription-coupled repair (TCR). This study demonstrates that TCR, along with VCP/p97 and the proteasome, is essential for removing formaldehyde-induced DPCs. TFIIS-dependent cleavage of RNAPII transcripts protects against transcriptional obstacles. A mouse model lacking both aldehyde clearance and TCR shows increased DPC accumulation in actively transcribed regions, highlighting the importance of TCR and aldehyde clearance in preventing aldehyde-induced DNA damage. The findings suggest that TCR and aldehyde clearance are crucial for protecting against metabolic genotoxins, explaining the molecular pathogenesis of disorders like AMeDS and Cockayne syndrome. The study also reveals that TCR is involved in the removal of histone-DPCs and that TFIIS plays a key role in resuming transcription after DPC repair. These results provide mechanistic insights into the pathogenesis of diseases associated with defects in aldehyde clearance and TCR.Endogenous aldehyde-induced DNA–protein crosslinks (DPCs) are efficiently resolved by transcription-coupled repair (TCR). This study demonstrates that TCR, along with VCP/p97 and the proteasome, is essential for removing formaldehyde-induced DPCs. TFIIS-dependent cleavage of RNAPII transcripts protects against transcriptional obstacles. A mouse model lacking both aldehyde clearance and TCR shows increased DPC accumulation in actively transcribed regions, highlighting the importance of TCR and aldehyde clearance in preventing aldehyde-induced DNA damage. The findings suggest that TCR and aldehyde clearance are crucial for protecting against metabolic genotoxins, explaining the molecular pathogenesis of disorders like AMeDS and Cockayne syndrome. The study also reveals that TCR is involved in the removal of histone-DPCs and that TFIIS plays a key role in resuming transcription after DPC repair. These results provide mechanistic insights into the pathogenesis of diseases associated with defects in aldehyde clearance and TCR.