It is well established that short telomeres activate an ATM-driven DNA damage response that leads to senescence in terminally differentiated cells. However, technical limitations have hampered our understanding of how telomere shortening is signaled in human stem cells. Here, we show that telomere attrition induces ssDNA accumulation (G-strand) at telomeres in human pluripotent stem cells (hPSCs), but not in their differentiated progeny. This led to a unique role for ATR in the response of hPSCs to telomere shortening that culminated in an extended S/G2 cell cycle phase and a longer period of mitosis, which was associated with aneuploidy and mitotic catastrophe. Loss of p53 increased resistance to death, at the expense of increased mitotic abnormalities in hPSCs. Taken together, our data reveal an unexpected dominant role of ATR in hPSCs, combined with unique cell cycle abnormalities and, ultimately, consequences distinct from those observed in their isogenic differentiated counterparts.

中文翻译：

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人多能干细胞中的端粒侵蚀导致ATR介导的有丝分裂灾难。

众所周知，端粒短会激活ATM驱动的DNA损伤反应，从而导致终末分化细胞衰老。但是，技术局限性阻碍了我们对端粒缩短在人类干细胞中如何发出信号的理解。在这里，我们显示端粒磨损在人多能干细胞（hPSCs）的端粒中诱导ssDNA积累（G-链），但在它们的分化后代中没有。这导致ATR在hPSC对端粒缩短的反应中发挥独特作用，最终导致延长的S / G2细胞周期阶段和更长的有丝分裂期，这与非整倍性和有丝分裂灾难有关。p53的丧失增加了对死亡的抵抗力，但以hPSCs中有丝分裂异常的增加为代价。两者合计，我们的数据揭示了ATR在hPSC中出乎意料的主导作用，