Disturbed proteostasis is the key event that triggers cellular senescence through the regulation of chromatin organization and genome stability

AbstractMammalian cells undergo irreversible proliferation arrest when exposed to stresses, a phenomenon termed cellular senescence. Various types of stress induce cellular senescence; nonetheless, senescent cells show similar phenotypes overall. Thus, cells undergo cellular senescence through the similar mechanisms, regardless of the type of stress encountered. Here we aimed to reveal the mechanisms underlying cellular senescence. We have previously shown that lamin b receptor (LBR), which is a protein that regulates heterochromatin organization, was downregulated in senescent cells, and downregulation of LBR induced cellular senescence. Additionally, we have shown that downregulation of protein synthesis effectively suppressed cellular senescence. Thereby, chromatin organization and protein synthesis are implicated in the regulation of cellular senescence. We examined the roles of them in cellular senescence and found that protein synthesis was upregulated during the induction of cellular senescence, and upregulated protein synthesis caused disturbed proteostasis that led to the decreased function of LBR. Furthermore, we showed that decreased LBR function induced cellular senescence through altered chromatin organization and increased genome instability. Importantly, these findings revealed a link between protein synthesis and chromatin organization and accounted for the phenotypes of senescent cells which show disturbed proteostasis, altered chromatin organization, and increased genome instability. Our findings provided the general model for the mechanisms of cellular senescence.