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Plasma membrane damage limits replicative lifespan in yeast and induces premature senescence in human fibroblasts.

Kojiro SudaYohsuke MoriyamaNurhanani RazaliYatzu ChiuYumiko MasukagamiKoutarou NishimuraHunter BarbeeHiroshi TakaseShinju SugiyamaYuta YamazakiYoshikatsu SatoTetsuya HigashiyamaYoshikazu JohmuraMakoto NakanishiKeiko Kono
Published in: Nature aging (2024)
Plasma membrane damage (PMD) occurs in all cell types due to environmental perturbation and cell-autonomous activities. However, cellular outcomes of PMD remain largely unknown except for recovery or death. In this study, using budding yeast and normal human fibroblasts, we found that cellular senescence-stable cell cycle arrest contributing to organismal aging-is the long-term outcome of PMD. Our genetic screening using budding yeast unexpectedly identified a close genetic association between PMD response and replicative lifespan regulations. Furthermore, PMD limits replicative lifespan in budding yeast; upregulation of membrane repair factors ESCRT-III (SNF7) and AAA-ATPase (VPS4) extends it. In normal human fibroblasts, PMD induces premature senescence via the Ca 2+ -p53 axis but not the major senescence pathway, DNA damage response pathway. Transient upregulation of ESCRT-III (CHMP4B) suppressed PMD-dependent senescence. Together with mRNA sequencing results, our study highlights an underappreciated but ubiquitous senescent cell subtype: PMD-dependent senescent cells.
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