Quantitative proteomics reveals coordinated changes in the proteome during replicative senescence.

N&#xe1;dia Da Silva Fernandes; Fridolin Kielisch; Amitkumar Fulzele; Sivarajan Karunanithi; Justus F Gr&#xe4;f; Jia-Xuan Chen; Christian Behl; Helle D Ulrich; Petra Beli

doi:10.1038/s41467-026-77686-8

PubMed · 42749737

Quantitative proteomics reveals coordinated changes in the proteome during replicative senescence.

Nádia Da Silva Fernandes·Fridolin Kielisch·Amitkumar Fulzele·Sivarajan Karunanithi·Justus F Gräf·Jia-Xuan Chen·Christian Behl·Helle D Ulrich·Petra Beli

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Abstract

Cellular senescence is a state of irreversible cell cycle arrest triggered by telomere erosion, persistent DNA damage or chronic stress. The accumulation of senescent cells disrupts tissue function and contributes to aging and disease. Here, we employ mass spectrometry-based proteomics to systematically interrogate dynamic proteome changes at multiple levels during the progression of replicative cellular senescence. We demonstrate that proteome changes during senescence occur in a coordinated manner, characterized by widespread protein depletion on chromatin. Moreover, components of the cytoplasmic translation machinery are depleted, while mitochondrial proteins display increased insolubility. Autophagic and proteasome activity is compromised in senescent cells along with remodeling of ubiquitin linkages and depletion of ubiquitin E3 ligases. Comparison of the senescent proteome with different pathophysiological cellular states reveals a distinctive senescent signature shaped by changes in the proteostasis network. Collectively, we provide a resource for the exploration of temporally resolved changes in the senescent proteome.

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Cellular Senescence Proteome Proteomics Humans Proteasome Endopeptidase Complex Mass Spectrometry Autophagy Chromatin Proteostasis Ubiquitin-Protein Ligases Animals Ubiquitin Journal Article Research Support, Non-U.S. Gov't

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Nádia Da Silva Fernandes, Fridolin Kielisch, Amitkumar Fulzele, Sivarajan Karunanithi, Justus F Gräf, Jia-Xuan Chen, Christian Behl, Helle D Ulrich, Petra Beli. 2026-09-16. Quantitative proteomics reveals coordinated changes in the proteome during replicative senescence.. https://doi.org/10.1038/s41467-026-77686-8

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