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研究揭示TERRA lncRNA被募集到端粒机制
2020-10-15 16:15

瑞士联邦理工学院(EPFL)Joachim Lingner和捷克共和国马萨里克大学Lumir Krejci课题组合作取得最新进展。他们发现通过R环将RAD51依赖的端粒重复RNA(TERRA)长非编码RNA(lncRNA)募集到端粒。2020年10月14日,《自然》杂志发表了这一成果。

由于TERRA被募集到染色体末端的机制仍然不清楚,他们开发了一个报告子系统,用以剖析其潜在机制,并表明TERRA的UUAGGG重复序列既有必要也足以使TERRA靶向染色体末端。 TERRA通过形成可以反式形成的端粒DNA-RNA杂合(R环)结构,优先与短端粒结合。端粒结合和R环形成触发端粒脆弱性,并由重组酶RAD51及其相互作用的伴侣BRCA2促进,但被RNA监视因子RNaseH1和TRF1抵消。

RAD51与TERRA发生物理相互作用,并在体外催化TERRA形成R环,表明该DNA重组酶通过链入侵直接参与TERRA募集。总之,他们的发现揭示了RAD51依赖性途径,该途径可控制转录后TERRA介导的R环形成,从而提供了将lncRNA募集到反式新基因座的机制。

据了解,端粒-在真核染色体末端发现的重复非编码核苷酸基序和相关蛋白-介导基因组稳定性并决定细胞寿命。含TERRA是一类lncRNA,它们从染色体末端转录;这些RNA依次通过端粒延伸酶端粒酶和同源性指导的DNA修复来调节端粒染色质结构和端粒维持。

附:英文原文

Title: RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops

Author: Marianna Feretzaki, Michaela Pospisilova, Rita Valador Fernandes, Thomas Lunardi, Lumir Krejci, Joachim Lingner

Issue&Volume: 2020-10-14

Abstract: Telomeres—repeated, noncoding nucleotide motifs and associated proteins that are found at the ends of eukaryotic chromosomes—mediate genome stability and determine cellular lifespan1. Telomeric-repeat-containing RNA (TERRA) is a class of long noncoding RNAs (lncRNAs) that are transcribed from chromosome ends2,3; these RNAs in turn regulate telomeric chromatin structure and telomere maintenance through the telomere-extending enzyme telomerase4,5,6 and homology-directed DNA repair7,8. The mechanisms by which TERRA is recruited to chromosome ends remain poorly defined. Here we develop a reporter system with which to dissect the underlying mechanisms, and show that the UUAGGG repeats of TERRA are both necessary and sufficient to target TERRA to chromosome ends. TERRA preferentially associates with short telomeres through the formation of telomeric DNA–RNA hybrid (R-loop) structures that can form in trans. Telomere association and R-loop formation trigger telomere fragility and are promoted by the recombinase RAD51 and its interacting partner BRCA2, but counteracted by the RNA-surveillance factors RNaseH1 and TRF1. RAD51 physically interacts with TERRA and catalyses R-loop formation with TERRA in vitro, suggesting a direct involvement of this DNA recombinase in the recruitment of TERRA by strand invasion. Together, our findings reveal a RAD51-dependent pathway that governs TERRA-mediated R-loop formation after transcription, providing a mechanism for the recruitment of lncRNAs to new loci in trans.

DOI: 10.1038/s41586-020-2815-6

Source: https://www.nature.com/articles/s41586-020-2815-6

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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