Targeting the m(6)A RNA demethylase FTO enhances UVB-induced DNA damage repair and suppresses skin tumor growth.

Nonmelanoma skin cancers are rising in incidence and are largely driven by solar ultraviolet B radiation (UVB) exposure. A growing body of evidence suggests that m(6)A RNA methylation plays a critical role in regulating the DNA damage response to UVB. Here, we identify a novel function for the m(6)A demethylase FTO in modulating the UVB damage response and skin carcinogenesis. We show that FTO loss enhances the repair of cyclobutane pyrimidine dimers (CPD), the major DNA lesions induced by UV radiation, in a METTL14-dependent manner, at least in part by promoting protein translation of the global genome repair (GGR) factor DDB2 through increased m(6)A methylation of DDB2 mRNA. These effects were recapitulated using two small-molecule FTO inhibitors, CS1 and FB23-2. Furthermore, loss of FTO reduced tumor growth in mice and FTO expression was upregulated in cutaneous squamous cell carcinoma (cSCC) compared with normal skin. Together, these findings uncover a critical role for FTO in regulating post-transcriptional gene expression in the UVB damage response and suggest that FTO may be a therapeutic target in skin cancer.