DNA Containing Cyclobutane Pyrimidine Dimers Is Released from UVB-Irradiated Keratinocytes in a Caspase-Dependent Manner

Abstract

Solar radiation induces the formation of cyclobutane pyrimidine dimers (CPDs) and other UV photoproducts in the genomic DNA of epidermal keratinocytes. Although CPDs have been detected in urine from UV- and sun-exposed individuals, the pathway by which they arrive there and the mechanisms by which UV-induced DNA damage in the skin has systemic effects throughout the body are not clear. Consistent with previous reports that DNA associates with small extracellular vesicles that are released from a variety of cell types, we observed that a small fraction of CPDs formed in genomic DNA after UVB exposure can later be detected in the culture medium. These extracellular CPDs are found within large fragments of histone-associated DNA and are released in a time- and UVB dose‒dependent manner. Moreover, studies with both cultured cells and human skin explants revealed that CPD release into the extracellular environment is blocked by caspase inhibition, which indicates a role for apoptotic signaling in CPD release from UVB-irradiated keratinocytes. Finally, we show that this released CPD-containing DNA can be taken up by other keratinocytes. These results therefore provide possible mechanisms for the export of damaged DNA from UVB-irradiated cells and for systemic effects of UVB exposure throughout the body.