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RAD51-dependent recruitment of TERRA IncRNA to telomeres through R-loops

机译：通过R-LOOPS依赖于Terra IncRNA的Terra IncRNA募集

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摘要

Telomeres-repeated, noncoding nucleotide motifs and associated proteins that are found at the ends of eukaryotic chromosomes-mediate genome stability and determine cellular lifespan~(1). Telomeric-repeat-containing RNA (TERRA) is a class of long noncoding RNAs (lncRNAs) that are transcribed from chromosome ends~(2,3); these RNAs in turn regulate telomeric chromatin structure and telomere maintenance through the telomere-extending enzyme telomerase~(4-6)and homology-directed DNA repair~(7,8). 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.
机译：在真核染色体 - 介导基因组稳定性的末端发现的端粒反复，非分量的核苷酸基序和相关蛋白质，并确定细胞寿命〜（1）。含有端粒重复的RNA（Terra）是一类从染色体末端转录的一类长的NOCODING RNA（LNCRNA）〜（2,3）;这些RNA反过来调节端粒染色质结构和通过端粒延伸酶端粒酶〜（4-6）和同源性DNA修复〜（7,8）的端粒染色质结构和端粒性维持。 Terra被募集到染色体末端的机制仍然定义不足。在这里，我们开发了一个记者系统，解剖了潜在机制，并表明Terra的UuAggg次数是必要的，并且足以瞄准Terra以染色体结束。 Terra通过形成可以在反式中形成的端粒DNA-RNA杂交（R环）结构与短端粒相关联。端粒关联和R环形成触发端粒脆性，并由重组酶RAD51及其相互作用伴侣BRCA2促进，但是由RNA监测因子RNASEH1和TRF1抵消。 Rad51与Terra和Catalyses r环形成的Rad51与Terra在体外与Terra进行了相互作用，表明该DNA重组酶直接参与通过链侵袭招募Terra的招募。我们的研究结果一起揭示了一种依赖于Rad51依赖性的途径，治理转录后的Terra介导的R环形成，提供了一种在Trans中募集到新基因座的机制。

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  • 来源
    《Nature》 |2020年第7833期|303-308|共6页
  • 作者

    Marianna Feretzaki; Michaela Pospisilova; Rita Valador Fernandes; Thomas Lunardi; Lumir Krejci; Joachim Lingner;

  • 作者单位

    Swiss Institute for Experimental Cancer Research (ISREC) School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL);

    Department of Biology and National Centre for Biomolecular Research Masaryk University;

    Swiss Institute for Experimental Cancer Research (ISREC) School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL);

    Swiss Institute for Experimental Cancer Research (ISREC) School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL);

    Department of Biology and National Centre for Biomolecular Research Masaryk University|International Clinical Research Center St Anne's University Hospital;

    Swiss Institute for Experimental Cancer Research (ISREC) School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL);

  • 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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