In mammals, telomere protection is mediated by the essential protein TRF2, which binds chromosome ends and ensures genome integrity 1 , 2 . TRF2 depletion results in end-to-end chromosome fusions in all cell types that have been tested so far. Here we find that TRF2 is dispensable for the proliferation and survival of mouse embryonic stem (ES) cells. Trf2 −/− (also known as Terf2 ) ES cells do not exhibit telomere fusions and can be expanded indefinitely. In response to the deletion of TRF2, ES cells exhibit a muted DNA damage response that is characterized by the recruitment of γH2AX—but not 53BP1—to telomeres. To define the mechanisms that control this unique DNA damage response in ES cells, we performed a CRISPR–Cas9-knockout screen. We found a strong dependency of TRF2-null ES cells on the telomere-associated protein POT1B and on the chromatin remodelling factor BRD2. Co-depletion of POT1B or BRD2 with TRF2 restores a canonical DNA damage response at telomeres, resulting in frequent telomere fusions. We found that TRF2 depletion in ES cells activates a totipotent-like two-cell-stage transcriptional program that includes high levels of ZSCAN4. We show that the upregulation of ZSCAN4 contributes to telomere protection in the absence of TRF2. Together, our results uncover a unique response to telomere deprotection during early development. Depletion of TRF2—an essential mediator of telomere protection in most mammalian cells—in mouse embryonic stem cells activates a compensatory transcriptional program that renders TRF2 dispensable for their survival and proliferation.

中文翻译：

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TRF2介导的端粒保护在多能干细胞中是可有可无的

在哺乳动物中，端粒保护由必需蛋白 TRF2 介导，该蛋白结合染色体末端并确保基因组完整性 1 , 2 。TRF2 缺失会导致迄今为止已测试的所有细胞类型中的端到端染色体融合。在这里，我们发现TRF2对于小鼠胚胎干（ES）细胞的增殖和存活是不可或缺的。Trf2 −/−（也称为 Terf2 ）ES 细胞不表现出端粒融合，并且可以无限期扩增。为了响应 TRF2 的缺失，ES 细胞表现出一种减弱的 DNA 损伤反应，其特征是 γH2AX（而非 53BP1）被募集至端粒。为了确定 ES 细胞中控制这种独特 DNA 损伤反应的机制，我们进行了 CRISPR-Cas9 敲除筛选。我们发现 TRF2 缺失的 ES 细胞对端粒相关蛋白 POT1B 和染色质重塑因子 BRD2 具有很强的依赖性。POT1B 或 BRD2 与 TRF2 的共同耗尽可恢复端粒处的典型 DNA 损伤反应，从而导致频繁的端粒融合。我们发现 ES 细胞中 TRF2 的缺失会激活类似全能的两细胞阶段转录程序，其中包括高水平的 ZSCAN4。我们发现，在 TRF2 缺失的情况下，ZSCAN4 的上调有助于端粒保护。总之，我们的结果揭示了早期发育过程中对端粒去保护的独特反应。小鼠胚胎干细胞中TRF2（大多数哺乳动物细胞端粒保护的重要介质）的耗尽会激活补偿性转录程序，使TRF2对于它们的生存和增殖来说是可有可无的。