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.
Hughes
Katherine J
KJ
Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri 63104, USA.
Meares
Gordon P
GP
Chambers
Kari T
KT
Corbett
John A
JA
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair; D004789:Enzyme Activation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D009569:Nitric Oxide; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; C499073:Gadd45a protein, rat; D000097642:GADD45 Proteins