DRG2 Accelerates Senescence via Negative Regulation of SIRT1 in Human Diploid Fibroblasts

Accumulating evidence suggests that developmentally regulated GTP-binding protein 2 (DRG2), an evolutionarily conserved GTP-binding protein, plays an important role in regulating cell growth, inflammation, and mitochondria dynamics. However, the effect of DRG2 in aging remains unclear. In this study, we found that endogenous DRG2 protein expression is upregulated in oxidative stress-induced premature senescence models and tissues of aged mice. Ectopic expression of DRG2 significantly promoted senescence-associated beta-galactosidase (SA-beta-gal) activity and inhibited cell growth, concomitant with increase in levels of acetyl (ac)-p53 (Lys382), ac-nuclear factor-kB (NF-kappa B) p65 (Lys310), p21(Waf1/Cip1), and p16(Ink4a) and a decrease in cyclin D1. In this process, reactive oxygen species (ROS) and phosphorylation of H2A histone family member X (H2A.X), forming gamma-H2A.X, were enhanced. Mechanistically, ectopic expression of DRG2 downregulated Sirtuin-1 (SIRT1), resulting in augmented acetylation of p53 and NF-kappa B p65. Additionally, DRG2 knockdown significantly abolished oxidative stress-induced premature senescence. Our results provide a possible molecular mechanism for investigation of cellular senescence and aging regulated by DRG2.

Automated summary

The study showed that DRG2 is upregulated in oxidative stress-induced premature senescence and aged tissues, promoting cellular aging through multiple pathways such as inhibiting SIRT1, increasing acetylation of p53 and NF-kappa B p65, and elevating ROS and γ-H2A.X levels.