期刊
CELL CYCLE
卷 7, 期 22, 页码 3601-3606出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.7.22.7152
关键词
cellular senescence; mouse embryo fibroblasts (MEFs); DNA damage response (DDR); ataxia-telangiectasia mutated (ATM); oxidative stress
类别
资金
- IFOM-IEO
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- Association for International Cancer Research (AICR)
- Human Frontier Science Program (HFSP)
- European Union
- EMBO Young Investigator Program (YIP)
Primary mouse embryonic fibroblasts (MEFs) are a popular tool for molecular and cell biology studies. However, when MEFs are grown in vitro under standard tissue culture conditions, they proliferate only for a limited number of population doublings (PD) and eventually undergo cellular senescence. Presently, the molecular mechanisms halting cell cycle progression and establishing cellular senescence under these conditions are unclear. Here, we show that a robust DNA damage response (DDR) is activated when MEFs undergo replicative cellular senescence. Senescent cells accumulate senescence-associated DDR foci (SDFs) containing the activated form of ATM, its phosphorylated substrates and gamma H2AX. In senescent MEFs, DDR markers do not preferentially accumulate at telomeres, the end of linear chromosomes. It has been observed that proliferation of MEFs is extended if they are cultured at low oxygen tension (3% O-2). We observed that under these conditions, DDR is not observed and senescence is not established. Importantly, inactivation of ATM in senescent MEFs allows escape from senescence and progression through the S-phase. Therefore, MEFs undergoing cellular senescence arrest their proliferation due to the activation of a DNA damage checkpoint mediated by ATM kinase. Finally, we observed that spontaneously immortalized proliferating MEFs display markers of an activated DDR, indicating the presence of chromosomal DNA damage in these established cell lines.
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