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

Bing Si Li,Ai Lin Jin,Ziqi Zhou,Jae Ho Seo,Byung-Min Choi

doi:10.1155/2021/7301373

Abstract

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 β-galactosidase (SA-β-gal) activity and inhibited cell growth, concomitant with increase in levels of acetyl (ac)-p53 (Lys382), ac-nuclear factor-kB (NF-κB) p65 (Lys310), p21Waf1/Cip1, and p16Ink4a and a decrease in cyclin D1. In this process, reactive oxygen species (ROS) and phosphorylation of H2A histone family member X (H2A.X), forming γ-H2A.X, were enhanced. Mechanistically, ectopic expression of DRG2 downregulated Sirtuin-1 (SIRT1), resulting in augmented acetylation of p53 and NF-κB 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.

Highlights

Aging is one of the biggest risk factors for the development of various diseases, including dementia, chronic respiratory diseases, angiocardiopathy, infection, and cancer [1]
We further examined the effect of developmentally regulated GTP-binding protein 2 (DRG2) knockdown on oxidative stress-induced premature senescence
We speculated that DRG2 may correlate with H2O2-induced cellular premature senescence

Summary

Introduction

Aging is one of the biggest risk factors for the development of various diseases, including dementia, chronic respiratory diseases, angiocardiopathy, infection, and cancer [1]. At cellular and molecular levels, senescent cells play important roles in tissue deterioration and disorganization and in organ dysfunction. Reduction of senescent cell levels is related to a significant decrease in the incidence of agingassociated ailments, such as cardiovascular diseases [2, 3]. Augmentation of senescent cells suppresses the development of cancer [4]. Cellular senescence was described first by Hayflick in the 1960s as an irreversible process of cell cycle arrest [5]. Cellular senescence exists spontaneously in vivo and in vitro and can be induced in vitro when cells are exposed to oxidative stress, such as hydrogen peroxide (H2O2) [5,6,7]. The senescence process is accompanied by abundant accumulation of reactive oxygen species (ROS), which can result in severe damage to DNA, protein, and lipids [8]

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Results

Conclusion