UVA-induced DNA damage and mutations in human melanocytes: relevance for melanoma mutations

Abstract UVB radiation (280–320 nm) from sunlight induces skin cancer through DNA damage-induced mutations. Melanomas carry mutational signatures associated with UVB-induced cyclobutane pyrimidine dimers (CPDs). However, there are several other melanoma signatures of unknown origin. To test if these signatures are linked to UVA, we exposed human melanocytes to UVA (340–400 nm) and to UVB for comparison. We mapped DNA damage in the form of CPDs or 8-oxoguanines (8-oxoG) genome-wide at base resolution. We then determined mutational patterns in single melanocyte cell clones by whole genome sequencing. Different from UVB, UVA induces CPDs more selectively at TT sequences resembling melanoma signature SBS7d. We did not observe rising CPD levels after cessation of radiation (dark CPDs). The UVA-induced CPDs were not mutagenic in the mutation analysis. 8-oxoG was present in melanocytes but did not substantially increase after UVA. G/C to T/A mutations were prominent in melanocyte single-cell clones with no major shift after UVA radiation. These mutations matched SBS18, a signature present in melanomas. Although UVA damages DNA, it has a surprisingly limited mutagenic effect on human melanocytes. However, the oxidative base lesions in melanocytes and their associated mutations may be linked to a subset of melanoma mutations.