Constitutive nitric oxide synthases deficiency impairs cyclobutane pyrimidine dimer repair following solar UV exposure in cells and mice.

Abstract

Solar ultraviolet (sUV) radiation is a major environmental factor that induces DNA damage, promoting skin aging and carcinogenesis. The formation of cyclobutane pyrimidine dimers (CPDs) is one of the most prevalent forms of UV-induced DNA lesions, playing a central role in skin photocarcinogenesis. Constitutive nitric oxide synthase (cNOS), responsible for basal nitric oxide (NO^˙) production, has been implicated in various cellular processes, including the DNA damage response. However, the role of cNOS in modulating DNA repair post-UV exposure has not been explored. In this study, we investigated the impact of cNOS deficiency on CPD repair following sUV exposure using both in vivo and in vitro models. SKH-1 hairless wild-type and nNOS^+/-/eNOS^-/- (cNOS-deficient) mice were chronically exposed to sUV, revealing significantly exacerbated skin lesions in cNOS-deficient animals. Primary fibroblasts and skin explants derived from these mice, as well as HEK293 cells with stable cNOS overexpression, were analyzed for CPD formation and repair dynamics. Our findings show that cNOS knockout leads to impaired CPD repair, with CPD levels persisting longer in cNOS-deficient cells and tissues compared with wild-type controls. Reintroduction of cNOS expression in HEK293 cells accelerated CPD clearance early post-sUV exposure, suggesting a protective role for cNOS in the DNA repair process. These results highlight cNOS as a critical modulator of UV-induced DNA damage repair and underscore its potential role in mitigating skin carcinogenesis.