Repair of nitric oxide-damaged DNA in beta-cells requires JNK-dependent GADD45alpha expression

Proinflammatory cytokines induce nitric oxide-dependent DNA damage and ultimately beta-cell death. Not only does nitric oxide cause beta-cell damage, it also activates a functional repair process. In this study, the mechanisms activated by nitric oxide that facilitate the repair of damaged beta-cell DNA are examined. JNK plays a central regulatory role because inhibition of this kinase attenuates the repair of nitric oxide-induced DNA damage. p53 is a logical target of JNK-dependent DNA repair; however, nitric oxide does not stimulate p53 activation or accumulation in beta-cells. Further, knockdown of basal p53 levels does not affect DNA repair. In contrast, expression of growth arrest and DNA damage (GADD) 45alpha, a DNA repair gene that can be regulated by p53-dependent and p53-independent pathways, is stimulated by nitric oxide in a JNK-dependent manner, and knockdown of GADD45alpha expression attenuates the repair of nitric oxide-induced beta-cell DNA damage. These findings show that beta-cells have the ability to repair nitric oxide-damaged DNA and that JNK and GADD45alpha mediate the p53-independent repair of this DNA damage.