Mammalian telomeres protect chromosome ends from aberrant DNA repair 1 . TRF2, a component of the telomere-specific shelterin protein complex, facilitates end protection through sequestration of the terminal telomere repeat sequence within a lariat T-loop structure 2 , 3 . Deleting TRF2 (also known as TERF2 ) in somatic cells abolishes T-loop formation, which coincides with telomere deprotection, chromosome end-to-end fusions and inviability 3 – 9 . Here we establish that, by contrast, TRF2 is largely dispensable for telomere protection in mouse pluripotent embryonic stem (ES) and epiblast stem cells. ES cell telomeres devoid of TRF2 instead activate an attenuated telomeric DNA damage response that lacks accompanying telomere fusions, and propagate for multiple generations. The induction of telomere dysfunction in ES cells, consistent with somatic deletion of Trf2 (also known as Terf2 ), occurs only following the removal of the entire shelterin complex. Consistent with TRF2 being largely dispensable for telomere protection specifically during early embryonic development, cells exiting pluripotency rapidly switch to TRF2-dependent end protection. In addition, Trf2 -null embryos arrest before implantation, with evidence of strong DNA damage response signalling and apoptosis specifically in the non-pluripotent compartment. Finally, we show that ES cells form T-loops independently of TRF2, which reveals why TRF2 is dispensable for end protection during pluripotency. Collectively, these data establish that telomere protection is solved by distinct mechanisms in pluripotent and somatic tissues. Experiments in mouse pluripotent embryonic and epiblast stem cells show that TRF2 is dispensable for telomere protection specifically specifically in the pluripotent cells that form during early embryonic development, when cells form T-loops independently of this protein.

中文翻译：

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多能性过程中不依赖于 TRF2 的染色体末端保护

哺乳动物端粒保护染色体末端免受异常 DNA 修复 1 。TRF2 是端粒特异性 shelterin 蛋白复合物的一个组成部分，通过在套索 T 环结构 2 、 3 中隔离末端端粒重复序列来促进末端保护。删除体细胞中的 TRF2（也称为 TERF2）会消除 T 环形成，这与端粒去保护、染色体端到端融合和不存活性一致 3 – 9 。在这里，我们确定，相比之下，TRF2 对于小鼠多能胚胎干细胞 (ES) 和外胚层干细胞的端粒保护在很大程度上是可有可无的。缺乏 TRF2 的 ES 细胞端粒反而会激活减弱的端粒 DNA 损伤反应，这种反应缺乏伴随的端粒融合，并繁殖多代。诱导 ES 细胞端粒功能障碍，与 Trf2（也称为 Terf2）的体细胞缺失一致，仅在整个 shelterin 复合体移除后发生。与 TRF2 对于端粒保护在很大程度上是可有可无的（特别是在早期胚胎发育期间）一致，退出多能性的细胞迅速切换到依赖于 TRF2 的末端保护。此外，Trf2-null 胚胎在植入前停滞，有证据表明在非多能室中存在强烈的 DNA 损伤反应信号和细胞凋亡。最后，我们表明 ES 细胞独立于 TRF2 形成 T 环，这揭示了为什么 TRF2 在多能性过程中对于末端保护是可有可无的。总的来说，这些数据表明端粒保护是通过多能和体细胞组织中的不同机制解决的。