Mechanism of end protection in stem cells

当端粒变得非常短时，它们变得功能失调，并引发染色体末端DNA损伤反应途径的激活。端粒功能失调的细胞要么经历程序性细胞死亡，进入不可逆的细胞周期停滞，要么积累基因组不稳定，最终转化为侵袭性癌细胞。通过条件删除庇护素成分，我们发现分化状态对细胞对端粒功能障碍的反应有重要影响（Lazzerini Denchi等，2006；Lobanova等，2017；Pinzaru等，2016）。我们已经证明，在对相同类型的基因操作的反应中，某些类型的细胞积累了基因组的不稳定性，并最终发展成侵袭性肿瘤。相反，其他细胞从未克服端粒功能障碍带来的增殖障碍（Lobanova et al., 2017; Pinzaru et al., 2016）。鉴于端粒驱动的基因组不稳定性在癌症发展中的重要性，这些数据突出了在关键的肿瘤启动过程中的重要知识差距。我们正在进行的研究旨在了解端粒功能障碍与分化状态之间的联系，出乎意料的是，多能胚胎干细胞（ESCs）可以在缺乏基本庇护蛋白成分的情况下存活。这一意想不到的发现开启了一系列关于多能干细胞端粒保护机制的悬而未决的问题

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