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 . Telomeric-repeat-containing RNA is recruited to telomeres by a mechanism that involves the DNA recombinase RAD51 and the formation of DNA–RNA hybrids, or R-loops—a process similar to that involved in homology-directed DNA repair.

中文翻译：

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RAD51 依赖性通过 R 环将 TERRA lncRNA 募集到端粒

端粒——在真核生物染色体末端发现的重复的、非编码的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 1 。含有端粒重复的 RNA (TERRA) 是一类从染色体末端 2 、 3 转录的长非编码 RNA (lncRNA)；这些 RNA 反过来通过端粒延伸酶端粒酶 4-6 和同源定向 DNA 修复 7、8 调节端粒染色质结构和端粒维护。TERRA 被招募到染色体末端的机制仍然不明确。在这里，我们开发了一个报告系统来剖析潜在机制，并表明 TERRA 的 UUAGGG 重复对于将 TERRA 靶向染色体末端是必要和充分的。TERRA 通过形成可以反式形成的端粒 DNA-RNA 杂合体（R-loop）结构优先与短端粒结合。端粒关联和 R 环形成触发端粒脆弱性，并由重组酶 RAD51 及其相互作用的伙伴 BRCA2 促进，但被 RNA 监视因子 RNaseH1 和 TRF1 抵消。RAD51 与 TERRA 物理相互作用并在体外催化与 TERRA 的 R 环形成，表明这种 DNA 重组酶直接参与通过链入侵招募 TERRA。总之，我们的研究结果揭示了一种 RAD51 依赖性途径，该途径在转录后控制 TERRA 介导的 R 环形成，为将 lncRNA 募集到反式新基因座提供了一种机制。