小柯机器人

TRF2介导的端粒保护在多能干细胞中是非必需的
2020-11-26 15:57

近日,美国国家癌症研究所Eros Lazzerini Denchi及其研究小组发现,TRF2介导的端粒保护在多能干细胞中是非必需的。该研究于2020年11月25日在线发表于《自然》。

研究人员发现,TRF2对于小鼠胚胎干(ES)细胞的增殖和存活是非必需的。Trf2-/-(也称为Terf2)ES细胞不出现端粒融合,可以无限期扩增。响应TRF2的缺失,ES细胞表现出沉默的DNA损伤反应,其特征在于γH2AX(而非53BP1)募集到端粒。为了定义控制ES细胞这种独特的DNA损伤反应的机制,研究人员进行了CRISPR–Cas9敲除筛选。研究人员发现TRF2缺失的ES细胞对端粒相关蛋白POT1B和染色质重塑因子BRD2的强烈依赖性。POT1B或BRD2与TRF2的共耗竭可恢复端粒的经典DNA损伤反应,从而导致端粒频繁融合。研究人员发现ES细胞中的TRF2敲除会激活一个全能型两细胞阶段转录程序,其中包括高水平的ZSCAN4。研究人员发现,ZSCAN4的上调有助于TRF2缺失时的端粒保护。总之,这些结果揭示了在早期发育过程中对端粒去保护的独特反应。
 
据悉,在哺乳动物中,端粒保护是由必需蛋白TRF2介导的,该蛋白结合染色体末端并确保基因组完整性。到目前为止,TRF2敲除会导致所有细胞类型中的染色体末端融合。
 
附:英文原文

Title: TRF2-mediated telomere protection is dispensable in pluripotent stem cells

Author: Marta Markiewicz-Potoczny, Anastasia Lobanova, Anisha M. Loeb, Oktay Kirak, Teresa Olbrich, Sergio Ruiz, Eros Lazzerini Denchi

Issue&Volume: 2020-11-25

Abstract: In mammals, telomere protection is mediated by the essential protein TRF2, which binds chromosome ends and ensures genome integrity1,2. 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.

DOI: 10.1038/s41586-020-2959-4

Source: https://www.nature.com/articles/s41586-020-2959-4

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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