Affiliation:
1. Laboratory of Mucosal Ecosystem Design The Institute for Molecular and Cellular Regulation, Gunma University Maebashi Gunma Japan
2. Graduate School of Health Sciences Gunma University Maebashi Gunma Japan
3. Graduate School of Medicine Gunma University Maebashi Gunma Japan
Abstract
AbstractCellular senescence is linked to a wide range of age‐related diseases and can be triggered by a variety of stresses, including DNA damage. A variety of genotoxic stressors, such as anti‐cancer drugs, cause DNA double‐strand breaks (DSBs), which trigger the accumulation of the tumour suppressor protein p53 in the nucleus. Cellular stresses stabilize and activate the p53 signalling pathway, which regulates various cellular processes, such as apoptosis, DNA repair, and senescence. Although p53 signalling is a well‐known tumour suppressor pathway, it remains unclear how it is regulated during cellular senescence. Here, we show that p53‐binding protein 1 (53BP1) accumulation in the nuclear foci is required for DNA damage‐induced cellular senescence via p53 activation. In human immortalized fibroblast, shRNA‐mediated 53BP1 depletion decreased not only the expression of p53‐target genes but also the cellular senescence induced by adriamycin treatment. Furthermore, we confirmed that DSBs trigger the hyperaccumulation of 53BP1 in the nuclear foci, which plays a key role in the regulation of cellular senescence. To prevent the accumulation of 53BP1 in the nuclear foci, we used phase separation inhibitors, and siRNA against RNF168, which accumulates at DSB loci and forms complexes with 53BP1. This blocks the formation of 53BP1 nuclear foci and DNA damage‐induced cellular senescence by activating the p53 signaling pathway. In conclusion, we demonstrated that increased accumulation of 53BP1 in the nuclear foci following DNA damage activates p53 and governs cellular senescence via a liquid–liquid phase separation mechanism.
Funder
Japan Agency for Medical Research and Development
Japan Society for the Promotion of Science
Takeda Science Foundation
Subject
Cell Biology,General Medicine
Cited by
2 articles.
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