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TRF2-mediated telomere protection is dispensable in pluripotent stem cells

机译：TRF2介导的端粒保护可分配在多能干细胞中

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摘要

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.
机译：在哺乳动物中，端粒保护由必需蛋白质TRF2介导，其结合染色体末端并确保基因组完整性〜（1,2）。 TRF2耗竭导致到目前为止已经过测试的所有细胞类型的端到端染色体融合。在这里，我们发现TRF2可分配小鼠胚胎茎（ES）细胞的增殖和存活。 TRF2〜（ - / - ）（也称为TERF2）ES细胞没有表现出端粒融合，并且可以无限期地扩展。响应于TRF2的缺失，ES细胞表现出柔软的DNA损伤响应，其特征在于募集γH2AX-但不是53bp1-端粒。为了定义控制ES细胞中这种独特的DNA损伤响应的机制，我们执行了CRISPR-CAS9淘汰赛屏幕。我们发现TRF2-NULL ES细胞对端粒相关的蛋白质POT1B和染色质重塑因子BRD2的强烈依赖性。用TRF2的Pot1b或Brd2的共消耗恢复端粒的规范DNA损伤响应，导致频繁的端粒融合。我们发现ES细胞中的TRF2耗竭激活包括高水平的ZScan4的单型类似的双细胞级转录程序。我们表明，ZScan4的上调有助于在没有TRF2的情况下进行端粒保护。我们的结果在一起发现了在早期发展期间对端粒脱保护的独特反应。

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  • 来源
    《Nature》 |2021年第7840期|110-115|共6页
  • 作者

    Marta Markiewicz-Potoczny; Anastasia Lobanova; Anisha M Loeb; Oktay Kirak; Teresa Olbrich; Sergio Ruiz; Eros Lazzerini Denchi;

  • 作者单位

    Laboratory of Genome Integrity National Cancer Institute;

    The Scripps Research Institute;

    Laboratory of Genome Integrity National Cancer Institute;

    Division of Pediatric Hematology and Oncology Department of Pediatrics and Adolescent Medicine Faculty of Medicine Medical Center University of Freiburg;

    Laboratory of Genome Integrity National Cancer Institute;

    Laboratory of Genome Integrity National Cancer Institute;

    Laboratory of Genome Integrity National Cancer Institute;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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