Mechanism of end protection in stem cells

当端粒变得非常短时，它们就会功能失调并引发激活 在染色体末端的DNA损伤反应途径。端粒功能失调的细胞 经历程序性细胞死亡，进入不可逆的细胞周期停滞，或 积累基因组不稳定性并最终转化为侵袭性癌细胞。使用 shelterin成分的条件性缺失，我们已经表明， 对端粒功能障碍的细胞反应具有重大影响（LazzeriniDenchi等人， 2006; Lobanova等人，2017; Pinzaru等人，2016年）。我们已经证明，为了应对 相同类型的遗传操作，某些细胞类型积累基因组不稳定性， 最终发展成侵袭性肿瘤相比之下，其他人从未克服过 端粒功能障碍造成的增殖屏障（Lobanova等，2017; Pinzaru等人， 2016）。考虑到端粒驱动的基因组不稳定性在基因组发育中的重要性， 癌症，这些数据突出了在一个关键的肿瘤启动知识的显着差距， 过程我们正在进行的工作旨在了解端粒功能障碍 分化状态显示，出乎意料的是，多能胚胎干细胞 （ESCs）可以在缺乏必需的保护成分的情况下存活。这一意想不到的发现 开启了一系列关于端粒保护机制的悬而未决的问题， 多能干细胞

When telomeres become critically short, they become dysfunctional and elicit activation of the DNA damage response pathway at chromosome ends. Cells with dysfunctional telomeres can either undergo programmed cell death, enter into an irreversible cell cycle arrest, or accumulate genome instability and eventually transform into an aggressive cancer cell. Using conditional deletion of shelterin components, we have shown that the differentiation status has a major impact on the cellular response to telomere dysfunction (Lazzerini Denchi et al., 2006; Lobanova et al., 2017; Pinzaru et al., 2016). We have demonstrated that, in response to the same type of genetic manipulation, certain cell types accumulate genome instability and eventually develop into aggressive tumors. In contrast, others never overcome the proliferation barrier imposed by telomere dysfunction (Lobanova et al., 2017; Pinzaru et al., 2016). Given the importance of telomere-driven genome instability in the development of cancer, these data highlight a significant gap in knowledge in a critical tumor-initiating process. Our ongoing work aimed at understanding the connection between telomere dysfunction and the differentiation status revealed that, unexpectantly, pluripotent embryonic stem cells (ESCs) could survive in the absence of essential shelterin components. This unexpected finding opens a set of outstanding questions regarding the mechanism of telomere protection in pluripotent stem cells