RBMX involves in telomere stability maintenance by regulating TERRA expression.
RBMX involves in telomere stability maintenance by regulating TERRA expression.
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DOI：
10.1371/journal.pgen.1010937
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发表时间：
2023-09
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
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含有端粒重复序列的RNA(Terra)是一类从染色体末端的亚端粒区转录到端粒区的长非编码RNA(LncRNAs)。Terra通过侵入端粒DNA，容易在端粒形成R-环结构。过多的端粒R-环会导致端粒不稳定，因此需要对Terra水平进行微妙的调节。然而，控制Terra水平的分子机制和因素在很大程度上仍不清楚。在本研究中，我们报道了RNA结合蛋白RBMX是一种新的Terra水平和端粒完整性调节因子。在RBMX耗竭的细胞中，Terra的表达水平显著升高，导致端粒R环形成增强，复制压力增加，端粒不稳定。我们还发现RBMX同时与Terra和核外切体靶向蛋白ZCCHC8结合，并且在RBMX耗尽时Terra的降解速度减慢，这意味着RBMX通过调节其向核外切体的运输促进Terra的降解，从而使核RNA腐烂。总之，这些发现揭示了RBMX在Terra表达调控和端粒完整性维持中的新作用，并使RBMX成为癌症治疗的潜在靶点。端粒是重复的DNA：保护线性染色体末端不被识别为双链DNA断裂的蛋白质结构。端粒承受着很高的复制压力，对染色体和基因组的稳定是必不可少的。含有端粒重复序列的RNA(Terra)从端粒转录到端粒，通过侵入端粒DNA容易形成R-环结构。在端粒酶阴性的人类癌细胞系中，通过基于同源重组的交替延长端粒(ALT)机制来维持端粒长度，Terra水平和端粒R-环均上调。过多的端粒R-环导致端粒不稳定。因此，端粒稳态只需要有限数量的Terra。在这里，我们证明，编码在X染色体上的RNA结合基序蛋白(RBMX)，也被称为hnRNP G，是一种新的Terra水平和端粒完整性的调节因子。我们的数据表明，RBMX在调节Terra表达和维持端粒完整性方面发挥了全新的作用，并为癌症治疗开辟了一条潜在的途径。此外，这项研究还提出了RBMX还针对其他核RNA到核外切体进行降解的可能性。
Telomeric repeat-containing RNA (TERRA) is a class of long noncoding RNAs (lncRNAs) that are transcribed from subtelomeric to telomeric region of chromosome ends. TERRA is prone to form R-loop structures at telomeres by invading into telomeric DNA. Excessive telomere R-loops result in telomere instability, so the TERRA level needs to be delicately modulated. However, the molecular mechanisms and factors controlling TERRA level are still largely unknown. In this study, we report that the RNA binding protein RBMX is a novel regulator of TERRA level and telomere integrity. The expression level of TERRA is significantly elevated in RBMX depleted cells, leading to enhanced telomere R-loop formation, replication stress, and telomere instability. We also found that RBMX binds to TERRA and the nuclear exosome targeting protein ZCCHC8 simultaneously, and that TERRA degradation slows down upon RBMX depletion, implying that RBMX promotes TERRA degradation by regulating its transportation to the nuclear exosome, which decays nuclear RNAs. Altogether, these findings uncover a new role of RBMX in TERRA expression regulation and telomere integrity maintenance, and raising RBMX as a potential target of cancer therapy. Telomeres are repetitive DNA: protein structures that protect linear chromosome ends from being recognized as double-strand DNA breaks. Telomeres bear very high loads of replication stress, and are essential for chromosomal stability and genome stability. Telomeric repeat-containing RNA (TERRA) is transcribed from subtelomeres to telomeres, and is prone to form R-loop structures by invading into telomeric DNA. In telomerase-negative human cancer cell lines, which maintain telomere length by homologous recombination-based alternative lengthening of telomeres (ALT) mechanism, both TERRA levels and telomeric R-loops are upregulated. Excessive telomere R-loops result in telomere instability. Therefore, only limited number of TERRA is required for telomere homeostasis. Here we show that, the RNA binding motif protein encoded on the X chromosome (RBMX), also known as hnRNP G, is a novel regulator of TERRA level and telomere integrity. Our data point to a completely new role of RBMX in TERRA expression regulation and telomere integrity maintenance, and open up a potential way for cancer therapy. In addition, this study also raises the possibility that RBMX also targeted other nuclear RNA to nuclear exosome for degradation.
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影响因子：
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