SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2
Citations Over TimeTop 1% of 2016 papers
Abstract
SIRT6 belongs to the mammalian homologs of Sir2 histone NAD(+)-dependent deacylase family. In rodents, SIRT6 deficiency leads to aging-associated degeneration of mesodermal tissues. It remains unknown whether human SIRT6 has a direct role in maintaining the homeostasis of mesodermal tissues. To this end, we generated SIRT6 knockout human mesenchymal stem cells (hMSCs) by targeted gene editing. SIRT6-deficient hMSCs exhibited accelerated functional decay, a feature distinct from typical premature cellular senescence. Rather than compromised chromosomal stability, SIRT6-null hMSCs were predominately characterized by dysregulated redox metabolism and increased sensitivity to the oxidative stress. In addition, we found SIRT6 in a protein complex with both nuclear factor erythroid 2-related factor 2 (NRF2) and RNA polymerase II, which was required for the transactivation of NRF2-regulated antioxidant genes, including heme oxygenase 1 (HO-1). Overexpression of HO-1 in SIRT6-null hMSCs rescued premature cellular attrition. Our study uncovers a novel function of SIRT6 in maintaining hMSC homeostasis by serving as a NRF2 coactivator, which represents a new layer of regulation of oxidative stress-associated stem cell decay.
Related Papers
- → SIRT6: Novel Mechanisms and Links to Aging and Disease(2016)270 cited
- → The Role of Increased Expression of Sirtuin 6 in the Prevention of Premature Aging Pathomechanisms(2023)19 cited
- → SIRT6 Activities in DNA Damage Repair and Premature Aging: Functions of SIRT6(2019)
- → Results-II. Haploinsufficiency of p53 Rescues Lifespan and Premature Aging-Associated Abnormalities in Sirt6-Deficient Mice(2019)
- → SIRT6 Activities in DNA Damage Repair and Premature Aging(2019)