biostudies-literatureYang ZHHS | NIH | National Institute of Environmental Health Sciencese2025948118https://www.ebi.ac.uk/biostudies/studies/S-EPMC8536359biostudies-literatureUnknown118(35)Global genome repair (GGR), a subpathway of nucleotide excision repair, corrects bulky helix-distorting DNA lesions across the whole genome and is essential for preventing mutagenesis and skin cancer. Here, we show that METTL14 (methyltransferase-like 14), a critical component of the N6-methyladenosine (m6A) RNA methyltransferase complex, promotes GGR through regulating m6A mRNA methylation-mediated DDB2 translation and suppresses ultraviolet B (UVB) radiation-induced skin tumorigenesis. UVB irradiation down-regulates METTL14 protein through NBR1-dependent selective autophagy. METTL14 knockdown decreases GGR and DDB2 abundance. Conversely, overexpression of wild-type METTL14 but not its enzymatically inactive mutant increases GGR and DDB2 abundance. METTL14 knockdown decreases m6A methylatProceedings of the National Academy of Sciences of the United States of AmericaMETTL14 facilitates global genome repair and suppresses skin tumorigenesis.PMC8536359ES030576ES024373ES030546Park GYang ZHe CShah PHe YYCui XWei JYang SCui YHfalseMETTL14 facilitates global genome repair and suppresses skin tumorigenesis.Global genome repair (GGR), a subpathway of nucleotide excision repair, corrects bulky helix-distorting DNA lesions across the whole genome and is essential for preventing mutagenesis and skin cancer. Here, we show that METTL14 (methyltransferase-like 14), a critical component of the N6-methyladenosine (m6A) RNA methyltransferase complex, promotes GGR through regulating m6A mRNA methylation-mediated DDB2 translation and suppresses ultraviolet B (UVB) radiation-induced skin tumorigenesis. UVB irradiation down-regulates METTL14 protein through NBR1-dependent selective autophagy. METTL14 knockdown decreases GGR and DDB2 abundance. Conversely, overexpression of wild-type METTL14 but not its enzymatically inactive mutant increases GGR and DDB2 abundance. METTL14 knockdown decreases m6A methylat2021-01-01T00:00:00Z2021 Aug2025-04-05T14:05:23.39Z2025-04-05T14:05:23.39ZS-EPMC85363593445299610.1073/pnas.2025948118