Benhamou Raphael I, Angelbello Alicia J, Wang Eric T, Disney Matthew D
Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
Department of Molecular Genetics & Microbiology, Center for NeuroGenetics, UF Genetics Institute, University of Florida, 2033 Mowry Road, Gainesville, FL 32610, USA.
Cell Chem Biol. 2020 Feb 20;27(2):223-231.e4. doi: 10.1016/j.chembiol.2020.01.003. Epub 2020 Jan 24.
Myotonic dystrophy type 2 (DM2) is a genetically defined disease caused by a toxic expanded repeat of r(CCUG) [r(CCUG)], harbored in intron 1 of CCHC-type zinc-finger nucleic acid binding protein (CNBP) pre-mRNA. This r(CCUG) 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) 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)-MBNL1 complex, reduce intron retention, subjecting the liberated intronic r(CCUG) 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.
2型强直性肌营养不良症（DM2）是一种由CCHC型锌指核酸结合蛋白（CNBP）前体mRNA内含子1中有毒的r(CCUG)重复序列扩增引起的遗传性疾病。这种r(CCUG)通过功能获得机制导致毒性，产生三个病理特征：聚集形成核灶；隔离肌肉盲样蛋白1（MBNL1），导致剪接缺陷；以及保留CNBP内含子1。我们研究了两种具有不同作用方式的小分子，一种是简单结合的小分子，另一种是在细胞中由r(CCUG)作为模板的小分子，即RNA合成自身的药物。事实上，我们在源自DM2患者的成纤维细胞中完成的研究表明，这些化合物破坏了r(CCUG)-MBNL1复合物，减少了内含子保留，使释放的内含子r(CCUG)进入天然降解途径，并挽救了其他与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本导向天然降解途径来调节RNA生物学。
