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.

人们认为，由紫外线破坏引起的DNA损伤只能通过人类细胞中的核苷酸切除修复（NER）途径进行修复。在此途径中起作用的基因内携带突变的患者表现出一系列病理，包括对癌症的敏感性增加，过早衰老和神经系统缺陷。当前没有治愈性疗法。在这里，我们对试剂进行了高通量化学筛选，这些试剂可以减轻NER缺陷细胞对UV诱导的DNA损伤的细胞敏感性。这导致鉴定出临床批准的抗糖尿病药物乙酰己酰胺，该药物可促进清除紫外线诱导的DNA损伤，而不会累积染色体畸变，从而提高细胞存活率。乙酰己酰胺通过拮抗DNA糖基化酶MUTYH的表达来发挥这种保护功能。在一起，我们的数据揭示了一个独立于NER的机制的存在，以消除紫外线引起的DNA损伤并防止细胞死亡。