Establishment of damage dose-dependent senescence inducible system and its application for understanding molecular basis underlying geriatiric diseases

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Since induction of cellular senescence might be dependent on a number of DNA double strand breaks, we introduced various I-SceI restriction sites in normal human fibroblasts, which is not normally observed in normal human cells, and analysed whether these cells undergo senescence or not. However, during our experimental course, we found that only single DNA double strand break was sufficient for the induction of senescence when the break occurred during G2 phase. p53 activation during G2 resulted in a mitosis skip, leading to a generation of tetraploid G1 cells. This mitosis skip was collaboratively regulated by premature activation of APC-C/Cdh1 through Cdk1 and Cdk2 inhibition by induced p21 and pRb-family pocket protein dependent transcriptional repression of mitotic regulators.