Repair of nitric oxide-damaged DNA in beta-cells requires JNK-dependent GADD45alpha expression. J Biol Chem 2009 Oct 02;284(40):27402-8
Date
08/04/2009Pubmed ID
19648647Pubmed Central ID
PMC2785669DOI
10.1074/jbc.M109.046912Scopus ID
2-s2.0-70350463891 (requires institutional sign-in at Scopus site) 34 CitationsAbstract
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.
Author List
Hughes KJ, Meares GP, Chambers KT, Corbett JAAuthor
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Cycle Proteins
Cells, Cultured
DNA Damage
DNA Repair
Enzyme Activation
Female
Gene Expression Regulation
Humans
Insulin-Secreting Cells
JNK Mitogen-Activated Protein Kinases
Nitric Oxide
Nuclear Proteins
Rats
Rats, Sprague-Dawley
Tumor Suppressor Protein p53
