Constitutive Nitric Oxide Syntheses Deficiency Impairs Cyclobutane Pyrimidine Dimer Repair Following Solar UV Exposure in Cells and Mice

TL;DR

This study shows that a lack of constitutive nitric oxide synthase impairs DNA repair after UV exposure, increasing skin damage and cancer risk.

Contribution

The study reveals a novel role for constitutive nitric oxide synthase in DNA repair following UV exposure.

Findings

cNOS deficiency leads to impaired cyclobutane pyrimidine dimer repair in cells and mice after UV exposure.

Reintroducing cNOS in deficient cells accelerates DNA damage repair.

cNOS-deficient mice show exacerbated skin lesions after chronic UV exposure.

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, have 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 to 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.