A Toxic RNA Catalyzes the Cellular Synthesis of Its Own Inhibitor, Shunting It to Endogenous Decay Pathways.,Cell Chemical Biology

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A Toxic RNA Catalyzes the Cellular Synthesis of Its Own Inhibitor, Shunting It to Endogenous Decay Pathways.
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2020-01-24 , DOI: 10.1016/j.chembiol.2020.01.003
Raphael I Benhamou ₁ , Alicia J Angelbello ₁ , Eric T Wang ₂ , Matthew D Disney ₁

Affiliation

Myotonic dystrophy type 2 (DM2) is a genetically defined disease caused by a toxic expanded repeat of r(CCUG) [r(CCUG)exp], harbored in intron 1 of CCHC-type zinc-finger nucleic acid binding protein (CNBP) pre-mRNA. This r(CCUG)exp causes toxicity via a gain-of-function mechanism, resulting in three pathological hallmarks: aggregation into nuclear foci; sequestration of muscleblind-like-1 (MBNL1) protein, leading to splicing defects; and retention of CNBP intron 1. We studied two types of small molecules with different modes of action, ones that simply bind and ones that are templated by r(CCUG)exp in cells, i.e., the RNA synthesizes its own drug. Indeed, our studies completed in DM2 patient-derived fibroblasts showed that the compounds disrupt the r(CCUG)exp-MBNL1 complex, reduce intron retention, subjecting the liberated intronic r(CCUG)exp to native decay pathways, and rescue other DM2-associated cellular defects. Importantly, this study shows that small molecules can modulate RNA biology by shunting toxic transcripts toward native decay pathways.

中文翻译：

有毒RNA催化其自身抑制剂的细胞合成，使其分流至内源性衰变途径。

2型强直性肌营养不良症（DM2）是由r（CCUG）[r（CCUG）exp]的有毒扩展重复序列引起的遗传定义的疾病，存在于CCHC型锌指核酸结合蛋白（CNBP）内含子1中-mRNA。该r（CCUG）exp通过功能获得机制引起毒性，从而导致三个病理学特征：聚集成核灶；螯合肌盲样1（MBNL1）蛋白，导致剪接缺陷；CNBP内含子的保留和保留1.我们研究了两种具有不同作用方式的小分子，一种简单地结合，另一种通过r（CCUG）exp在细胞中进行模板化，即RNA合成了自己的药物。实际上，我们在DM2患者来源的成纤维细胞中完成的研究表明，这些化合物破坏了r（CCUG）exp-MBNL1复合物，减少了内含子的保留，使释放的内含子r（CCUG）exp经历天然的衰变途径，并挽救其他与DM2相关的细胞缺陷。重要的是，这项研究表明，小分子可以通过将有毒转录物分流至天然衰变途径来调节RNA生物学。

更新日期：2020-01-24

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