Work

Role of SIRT3 in the regulation of Gadd45α expression and DNA repair in β-cells

Year: 2025

Type: article

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.

Source: Journal of Biological Chemistry

DOI: 10.1016/j.jbc.2025.108451