Cellular response pathways to formaldehyde

DNA–protein crosslinks (DPCs) form after exposure to agents such as formaldehyde, yet the pathways that repair or tolerate these lesions are not fully defined. A genome‑wide yeast deletion screen revealed that chronic low‑dose formaldehyde toxicity is primarily mitigated by homologous recombination, whereas acute high‑dose exposure depends on nucleotide excision repair (NER). Findings suggest that acute repair proceeds through NER‑dependent single‑strand break intermediates without detectable double‑strand breaks. Additional analyses show that translesion synthesis acts as a backup pathway and that Mre11 and Rad1 contribute independently to DPC tolerance. These results highlight distinct pathway requirements for chronic versus acute DPC exposure.