Nucleolar stress facilitates islet β cell senescence via hijacking the DNA damage response pathways

IF 4.1 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-09-04 DOI:10.1016/j.isci.2025.113508

Yaqi Jiao , Weirong Lu , Xiaohua Wang , Wenxing Sun , Baoying Hu , Jianya Zhao , Jinghao Fang , Ying Lu , Chunhua Wan

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Abstract

Senescence is a crucial contributor to pancreatic β cell dysfunction during diabetes progression. Herein, we demonstrated that nucleolar stress, a stress event resulting from disrupted ribosomal RNA (rRNA) synthesis, drives β cell senescence. Senescent β cells exhibited altered nucleolar morphology and redistribution of the nucleolar protein nucleophosmin (NPM) in vivo. Exposure to nucleolar stress inducers CX-5461 and actinomycin D (ActD) resulted in senescence-associated β-gal staining (SA-β-gal) activity in cultured β cells. This was accompanied by upregulation of senescence markers p53, p21, and p16 and a senescence-associated secretory phenotype (SASP). Notably, nucleolar stress also induced γ-H2AX foci formation and Ataxia telangiectasia mutated (ATM) activation independently of DNA double-strand breaks (DSBs). Pharmacological inhibition of ATM with KU60019 strongly attenuated nucleolar stress-induced β cell senescence. Collectively, these findings identify nucleolar stress as a key upstream event in β cell senescence and highlight the γ-H2AX-ATM axis as a critical mediator of this process.

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核仁应激通过劫持DNA损伤反应途径促进胰岛β细胞衰老

衰老是糖尿病进展过程中胰腺β细胞功能障碍的重要因素。在这里，我们证明了核仁应激，一种由核糖体RNA （rRNA）合成中断引起的应激事件，驱动β细胞衰老。衰老的β细胞在体内表现出核仁形态的改变和核仁蛋白核磷蛋白（NPM）的重新分布。暴露于核核胁迫诱导剂CX-5461和放线菌素D （ActD）可导致培养的β细胞衰老相关β-gal染色（SA-β-gal）活性升高。这伴随着衰老标志物p53、p21和p16的上调以及衰老相关分泌表型（SASP）。值得注意的是，核核应激还诱导γ-H2AX灶形成和共济失调毛细血管扩张突变（ATM）的激活，而不依赖于DNA双链断裂（DSBs）。KU60019对ATM的药理抑制作用可显著减弱核仁应激诱导的β细胞衰老。总的来说，这些发现确定了核仁应激是β细胞衰老的关键上游事件，并强调了γ-H2AX-ATM轴是这一过程的关键介质。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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