研究揭示TERRA lncRNA被募集到端粒機制
作者：
小柯機器人發布時間：2020/10/15 16:15:52
瑞士聯邦理工學院（EPFL）Joachim Lingner和捷克共和國馬薩裡克大學Lumir Krejci課題組合作取得最新進展。他們發現通過R環將RAD51依賴的端粒重複RNA（TERRA）長非編碼RNA（lncRNA）募集到端粒。2020年10月14日，《自然》雜誌發表了這一成果。
由於TERRA被募集到染色體末端的機制仍然不清楚，他們開發了一個報告子系統，用以剖析其潛在機制，並表明TERRA的UUAGGG重複序列既有必要也足以使TERRA靶向染色體末端。 TERRA通過形成可以反式形成的端粒DNA-RNA雜合（R環）結構，優先與短端粒結合。端粒結合和R環形成觸發端粒脆弱性，並由重組酶RAD51及其相互作用的伴侶BRCA2促進，但被RNA監視因子RNaseH1和TRF1抵消。
RAD51與TERRA發生物理相互作用，並在體外催化TERRA形成R環，表明該DNA重組酶通過鏈入侵直接參與TERRA募集。總之，他們的發現揭示了RAD51依賴性途徑，該途徑可控制轉錄後TERRA介導的R環形成，從而提供了將lncRNA募集到反式新基因座的機制。
據了解，端粒-在真核染色體末端發現的重複非編碼核苷酸基序和相關蛋白-介導基因組穩定性並決定細胞壽命。含TERRA是一類lncRNA，它們從染色體末端轉錄；這些RNA依次通過端粒延伸酶端粒酶和同源性指導的DNA修復來調節端粒染色質結構和端粒維持。
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