Repair of UV-Induced DNA Damage Independent of Nucleotide Excision Repair Is Masked by MUTYH

DNA lesions caused by UV damage are thought to be repaired solely by the nucleotide excision repair (NER) pathway in human cells. Patients carrying mutations within genes functioning in this pathway display a range of pathologies, including an increased susceptibility to cancer, premature aging, and neurological defects. There are currently no curative therapies available. Here we performed a high-throughput chemical screen for agents that could alleviate the cellular sensitivity of NER-deficient cells to UV-induced DNA damage. This led to the identification of the clinically approved anti-diabetic drug acetohexamide, which promoted clearance of UV-induced DNA damage without the accumulation of chromosomal aberrations, hence promoting cellular survival. Acetohexamide exerted this protective function by antagonizing expression of the DNA glycosylase, MUTYH. Together, our data reveal the existence of an NER-independent mechanism to remove UV-induced DNA damage and prevent cell death. [Display omitted] •UV-induced sensitivity of NER-deficient cells is alleviated by acetohexamide•Expression of the DNA glycosylase MUTYH is antagonized by acetohexamide•Acetohexamide promotes clearance of UV-induced DNA damage•An NER-independent mechanism can remove UV-induced DNA damage UV-induced DNA lesions in human cells are believed to be repaired exclusively by NER. Mazouzi et al. find that acetohexamide promotes clearance of UV-induced DNA damage by antagonizing expression of the DNA glycosylase MUTYH. The data reveal the existence of an NER-independent mechanism that removes UV-induced DNA damage.