National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing 210093, China.
National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing 210093, China.
FEBS Lett. 2014 Nov 28;588(23):4369-74. doi: 10.1016/j.febslet.2014.09.043. Epub 2014 Oct 12.
Telomeres are specialized structures protecting chromosomes against genome instability. Telomeres shorten with cell division, and replicative senescence is induced when telomeres are badly eroded. Whereas TRF2 (telomeric-repeat binding factor 2), ATM (ataxia telangiectasia mutated) and p53 have been identified involved in senescence induction, how it is triggered remains unclear. Here, we propose an integrated model associating telomere loss with senescence trigger. We characterize the dynamics of telomere shorting and the p53-centered regulatory network. We show that senescence is initiated in a switch-like manner when both the shortest telomere becomes uncapped and the TRF2-ATM-p53-Siah1 positive feedback loop is switched on. This work provides a coherent picture of senescence induction in terms of telomere shortening and p53 activation.
端粒是保护染色体免受基因组不稳定的特殊结构。端粒随着细胞分裂而缩短，当端粒严重磨损时，会诱导复制性衰老。虽然已经确定 TRF2（端粒重复结合因子 2）、ATM（共济失调毛细血管扩张突变）和 p53 参与了衰老的诱导，但它是如何被触发的仍然不清楚。在这里，我们提出了一个将端粒丢失与衰老触发联系起来的综合模型。我们描述了端粒缩短的动力学和以 p53 为中心的调控网络。我们表明，当最短的端粒去帽化并且 TRF2-ATM-p53-Siah1 正反馈环被打开时，衰老会以开关的方式被启动。这项工作提供了一个关于端粒缩短和 p53 激活的衰老诱导的连贯图景。
