Repair of Nitric Oxide-damaged DNA in -Cells Requires JNK-dependent GADD45 Expression*

Proinflammatory cytokines induce nitric oxide-dependent DNA damage and ultimately -cell death. Not only does nitric oxide cause -cell damage, it also activates a functional repair process. In this study, the mechanisms activated by nitric oxide that facilitate the repair of damaged -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 -cells. Further, knockdown of basal p53 levels does not affect DNA repair. In contrast, expression of growth arrest and DNA damage (GADD) 45 , 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 GADD45 expression attenuates the repair of nitric oxide-induced -cell DNA damage. These findings show that -cells have the ability to repair nitric oxide-damagedDNA and that JNK and GADD45 mediate the p53-independent repair of this DNA damage.