Role of SIRT3 in the regulation of Gadd45α expression and DNA repair in β-cells. J Biol Chem 2025 May;301(5):108451
Date
03/28/2025Pubmed ID
40147772Pubmed Central ID
PMC12051128DOI
10.1016/j.jbc.2025.108451Scopus ID
2-s2.0-105003152914 (requires institutional sign-in at Scopus site)Abstract
In previous studies, we have shown that growth arrest and DNA damage (Gadd) 45α is required for the repair of nitric oxide-mediated DNA damage in β-cells. Gadd45α expression is stimulated by nitric oxide and requires forkhead box protein (Fox) O1 and NAD+-dependent deacetylase activity. Based on inhibitor studies, we attributed this activity to Sirtuin (SIRT)1; however, the inhibitors used in this previous study also attenuate the deacetylase activity of SIRT2, 3, and 6. We now provide experimental evidence that SIRT1 is dispensable for β-cell expression of Gadd45α and that the mitochondrial localized isoform SIRT3, is required for DNA repair in β-cells. We show that siRNA knockdown of Sirt3 attenuates nitric oxide-stimulated Gadd45α mRNA accumulation in both wildtype and Sirt1-/- INS 832/13 cells as well as isolated rat islets and that SIRT3 inhibition increases FoxO1 acetylation and attenuates DNA repair in response to nitric oxide. While SIRT3 is predominantly localized to mitochondria, a small fraction is localized in the nucleus of insulin-containing cells and functions to participate in the regulation of FoxO1-dependent, nitric oxide-stimulated DNA repair.
Author List
Naatz A, Bohl KS, Jones Lipinski RA, Nord JA, Gehant AL, Hansen PA, Smith BC, Corbett JAAuthors
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinBrian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AcetylationAnimals
Cell Cycle Proteins
DNA Damage
DNA Repair
Forkhead Box Protein O1
Forkhead Transcription Factors
Gene Expression Regulation
Insulin-Secreting Cells
Male
Mice
Mitochondria
Nitric Oxide
Nuclear Proteins
Rats
Sirtuin 1
Sirtuin 3
Sirtuins
