Mammalian telomeric RNA (TERRA) can be translated to produce valine-arginine and glycine-leucine dipeptide repeat proteins.
Mammalian telomeric RNA (TERRA) can be translated to produce valine-arginine and glycine-leucine dipeptide repeat proteins.
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DOI：
10.1073/pnas.2221529120
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发表时间：
2023-02-28
影响因子：
11.1
通讯作者：
Griffith, Jack D.
中科院分区：
文献类型：
--
作者：
Al-Turki, Taghreed M.;Griffith, Jack D.
在过去的十年中，研究表明真核生物的端粒会被转录，产生一种富含G的RNA，被称为TERRA。人们一直认为这种RNA纯粹是结构性的，不编码蛋白质。然而，在几种人类疾病中阐明的重复相关非ATG翻译机制（RAN），如果被哺乳动物的TERRA所利用，可能会产生两种二肽重复蛋白，即缬氨酸 - 精氨酸重复序列和甘氨酸 - 亮氨酸重复序列。我们为这一假设提供了证据，并表明当细胞经历端粒危机时，这些重复的二肽蛋白会大量产生。它们的大量存在可能会改变核酸代谢和一般蛋白质合成，并引发细胞炎症反应。
哺乳动物的端粒由(TTAGGG)n重复序列组成。富含C的链转录产生一种富含G的RNA，即TERRA，它含有G - 四链体结构。在几种人类核苷酸扩增疾病中的最新发现表明，含有可形成强二级结构的3个或6个核苷酸长重复序列的RNA转录本能够在多个读码框中被翻译，从而产生同肽或二肽重复蛋白，并且多项研究表明它们对细胞有毒性。我们注意到TERRA的翻译会产生两种二肽重复蛋白：高电荷的缬氨酸 - 精氨酸重复序列(VR)n和疏水性的甘氨酸 - 亮氨酸重复序列(GL)n。在这里，我们合成了这两种二肽蛋白，并制备了针对VR的多克隆抗体。VR二肽重复蛋白结合核酸，并强烈定位于DNA的复制叉处。VR和GL都能形成具有淀粉样特性的长8纳米纤维。使用标记的VR抗体和激光扫描共聚焦显微镜，在TERRA含量升高的细胞系细胞核中观察到的VR量是原代成纤维细胞系的三到四倍。通过敲低TRF2诱导端粒功能障碍会导致VR量增加，并且使用锁核酸（LNA）GapmeR改变TERRA水平会导致大量的核VR聚集体。这些观察结果表明，端粒，特别是在经历端粒功能障碍的细胞中，可能会表达两种具有潜在强大生物学特性的二肽重复蛋白。
Over the past decade, studies have shown that eukaryotic telomeres are transcribed producing a G-rich RNA termed TERRA. It has been assumed that this RNA is purely structural and does not encode proteins. However, the repeat associated non-ATG translation mechanism (RAN) elucidated in several human diseases could, if utilized by mammalian TERRA, generate two dipeptide repeat proteins, repeating valine–arginine and repeating glycine–leucine. We present evidence for this hypothesis and suggest that these repeating dipeptide proteins are generated in greater amounts when cells undergo a telomere crisis. Their abundance could alter nucleic acid metabolism and general protein synthesis and trigger cellular inflammation responses. Mammalian telomeres consist of (TTAGGG)n repeats. Transcription of the C-rich strand generates a G-rich RNA, termed TERRA, containing G-quadruplex structures. Recent discoveries in several human nucleotide expansion diseases revealed that RNA transcripts containing long runs of 3 or 6 nt repeats which can form strong secondary structures can be translated in multiple frames to generate homopeptide or dipeptide repeat proteins, and multiple studies have shown them to be toxic in cells. We noted that the translation of TERRA would generate two dipeptide repeat proteins: highly charged repeating valine–arginine (VR)n and hydrophobic repeating glycine–leucine (GL)n. Here, we synthesized these two dipeptide proteins and raised polyclonal antibodies to VR. The VR dipeptide repeat protein binds nucleic acids and localizes strongly to replication forks in DNA. Both VR and GL form long 8-nm filaments with amyloid properties. Using labeled antibodies to VR and laser scanning confocal microscopy, threefold to fourfold more VR was observed in the nuclei of cell lines containing elevated TERRA as contrasted to a primary fibroblast line. Induction of telomere dysfunction via knockdown of TRF2 led to higher amounts of VR, and alteration of TERRA levels using a locked nucleic acid (LNA) GapmeR led to large nuclear VR aggregates. These observations suggest that telomeres, in particular in cells undergoing telomere dysfunction, may express two dipeptide repeat proteins with potentially strong biological properties.
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影响因子：
16.2
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Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
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