XPA lactylation is required for UV-induced DNA damage repair.

Xeroderma pigmentosum group A (XPA) serves as a core nucleotide excision repair (NER) factor essential for the repair process triggered by UV irradiation. Lactylation, a newly identified post-translational modification, plays a key role in tumorigenesis and cancer progression. Herein, we discovered that XPA was lactylated in the DNA-binding domain by the acyl-transferase KAT5. In addition, UV irradiation promoted XPA lactylation, thereby increasing the chromatin recruitment of XPA and NER. However, the mutation of XPA to a lactylation-deficient form impeded XPA chromatin recruitment under UV irradiation, impaired NER, and rendered cancer cells hypersensitive to UV irradiation. Our data demonstrate that the lactylation of XPA plays a crucial role in NER and reveals the link between metabolic reprogramming and DNA damage repair induced by UV irradiation.