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全能性期间的染色体末端保护不依赖TRF2
2020-11-27 14:20

英国弗朗西斯克里克研究所Simon J. Boulton等研究人员合作发现了全能性期间不依赖TRF2的染色体末端保护。2020年11月25日,国际知名学术期刊《自然》在线发表了这一成果。

研究人员发现,TRF2在小鼠多能胚胎干(ES)细胞和表皮干细胞中对于端粒保护在很大程度上是非必需的。不含TRF2的ES细胞端粒反而会激活一种削弱的端粒DNA损伤反应(其缺乏端粒融合),并多代传播。与Trf2(也称为Terf2)的体细胞删除一致,ES细胞中端粒功能障碍的诱导仅在去除了整个端粒蛋白复合物之后才会发生。与TRF2在端粒的保护(尤其是在早期胚胎发育期间)在很大程度上是非必需的,退出多能性的细胞迅速转换为依赖TRF2的末端保护。
 
此外,Trf2缺失的胚胎会在着床前停滞,其证据是强烈的DNA损伤反应信号和特定于非多能区室的细胞凋亡。最后,研究人员发现ES细胞形成T环不依赖于TRF2,这揭示了为什么TRF2在多能性过程中对于末端保护而言是非必需的。总体而言,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来实现的。
 
据介绍,哺乳动物端粒可保护染色体末端免受异常的DNA修复。TRF2是端粒特异性复合物的组成部分,可通过将端粒末端重复序列限制在T环来促进末端保护。删除体细胞中的TRF2(也称为TERF2)可消除T环的形成,这与端粒去保护、染色体末端融合和无法存活相吻合。
 
附:英文原文

Title: TRF2-independent chromosome end protection during pluripotency

Author: Phil Ruis, David Van Ly, Valerie Borel, Georgia R. Kafer, Afshan McCarthy, Steven Howell, Robert Blassberg, Ambrosius P. Snijders, James Briscoe, Kathy K. Niakan, Paulina Marzec, Anthony J. Cesare, Simon J. Boulton

Issue&Volume: 2020-11-25

Abstract: Mammalian telomeres protect chromosome ends from aberrant DNA repair1. 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 structure2,3. Deleting TRF2 (also known as TERF2) in somatic cells abolishes T-loop formation, which coincides with telomere deprotection, chromosome end-to-end fusions and inviability3,4,5,6,7,8,9. 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.

DOI: 10.1038/s41586-020-2960-y

Source: https://www.nature.com/articles/s41586-020-2960-y

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
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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