Mechanism of premature senescence induction through DNA damage responses

衰老是一种永久性生长停滞的状态，是体内抗肿瘤屏障的关键部分。尽管p53和pRb家族蛋白的抑瘤活性对衰老的诱导至关重要，但这些蛋白诱导衰老的分子机制尚不清楚。使用延时活细胞成像，我们在这里证明了暴露于各种诱导衰老的刺激下的正常人类二倍体成纤维细胞（HDFs）在进入永久性细胞周期停滞之前经历了有丝分裂跳跃。这种有丝分裂跳跃是由p53依赖的APC/CCdh1的过早激活和pRb家族蛋白依赖的有丝分裂调节因子的转录抑制介导的。重要的是，有丝分裂跳跃是衰老诱导的必要和充分条件。我们的发现为诱导和维持细胞衰老的分子基础提供了决定性的证据。

Senescence is a state of permanent growth arrest and is a pivotal part of the anti-tumorigenic barrier in vivo. Although the tumor suppressor activities of p53 and pRb family proteins are essential for the induction of senescence, molecular mechanisms by which these proteins induce senescence are still not clear. Using time-lapse live-cell imaging, we demonstrate here that normal human diploid fibroblasts (HDFs) exposed to various senescence-inducing stimuli undergo a mitosis skip before entry into permanent cell cycle arrest. This mitosis skip is mediated by both p53-dependent premature activation of APC/CCdh1 and pRb family protein-dependent transcriptional suppression of mitotic regulators. Importantly, mitotic skipping is necessary and sufficient for senescence induction. Our findings provide decisive evidence for the molecular basis underlying the induction and maintenance of cellular senescence.