Impaired processing of DNA photoproducts and ultraviolet hypermutability with loss of p16^INK4a or p19^ARF

Reduced DNA repair has been linked to an increased risk of cutaneous malignant melanoma, but insights into the molecular mechanisms of that link are scarce. The INK4a/ARF (CDKN2a) locus, which codes for the p16^INK4a and p19^ARF proteins, is often mutated in sporadic and familial malignant melanoma, but it has not been directly associated with reduced DNA repair. We transfected unirradiated mouse fibroblast cells with UV-treated DNA to measure DNA repair in normal, p16^INK4a mutant, p19^ARF mutant, or double mutant mouse host cells. Loss of either p16^INK4a or p19^ARF reduced the ability of the cells to process UV-induced DNA damage, independent of cell cycle effects incurred by the loss. These results may further explain why INK4a/ARF mutations predispose to malignant melanoma, a UV-induced tumor.