Work

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

Year: 2025

Type: article

Abstract: . 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.

Source: iScience

DOI: 10.1016/j.isci.2025.113508