Guan Lirui, Luo Yiling, Ja William W, Disney Matthew D
Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, United States.
Department of Neuroscience, Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, United States.
Bioorg Med Chem Lett. 2018 Sep 1;28(16):2794-2796. doi: 10.1016/j.bmcl.2017.10.034. Epub 2017 Oct 18.
RNA regulation and maintenance are critical for proper cell function. Small molecules that specifically alter RNA sequence would be exceptionally useful as probes of RNA structure and function or as potential therapeutics. Here, we demonstrate a photochemical approach for altering the trinucleotide expanded repeat causative of myotonic muscular dystrophy type 1 (DM1), r(CUG). The small molecule, 2H-4-Ru, binds to r(CUG) and converts guanosine residues to 8-oxo-7,8-dihydroguanosine upon photochemical irradiation. We demonstrate targeted modification upon irradiation in cell culture and in Drosophila larvae provided a diet containing 2H-4-Ru. Our results highlight a general chemical biology approach for altering RNA sequence in vivo by using small molecules and photochemistry. Furthermore, these studies show that addition of 8-oxo-G lesions into RNA 3' untranslated regions does not affect its steady state levels.
RNA调控与维持对于细胞的正常功能至关重要。能够特异性改变RNA序列的小分子作为RNA结构与功能的探针或潜在治疗药物将格外有用。在此，我们展示了一种光化学方法，用于改变导致1型强直性肌营养不良（DM1）的三核苷酸重复序列r(CUG)。小分子2H-4-Ru与r(CUG)结合，并在光化学照射下将鸟苷残基转化为8-氧代-7,8-二氢鸟苷。我们证明，在细胞培养物中以及在含有2H-4-Ru的饮食喂养的果蝇幼虫中进行照射时可实现靶向修饰。我们的结果突出了一种通过使用小分子和光化学在体内改变RNA序列的通用化学生物学方法。此外，这些研究表明，在RNA的3'非翻译区添加8-氧代-G损伤不会影响其稳态水平。
