Biomolecular Sciences Research Complex, School of Biology, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, UK.
Division of Cell Signalling and Immunology, School of Life Science, University of Dundee, Dundee DD1 5EH, UK.
Dis Model Mech. 2022 Jul 1;15(7). doi: 10.1242/dmm.049294. Epub 2022 Aug 2.
RNA regulation in mammalian cells requires complex physical compartmentalisation, using structures thought to be formed by liquid-liquid phase separation. Disruption of these structures is implicated in numerous degenerative diseases. Myotonic dystrophy type 1 (DM1) is a multi-systemic trinucleotide repeat disorder resulting from an expansion of nucleotides CTG (CTGexp) in the DNA encoding DM1 protein kinase (DMPK). The cellular hallmark of DM1 is the formation of nuclear foci that contain expanded DMPK RNA (CUGexp) (with thymine instead of uracil). We report here the deregulation of stress granules (SGs) and processing bodies (P-bodies), two cytoplasmic structures key for mRNA regulation, in cell culture models of DM1. Alterations to the rates of formation and dispersal of SGs suggest an altered ability of cells to respond to stress associated with DM1, while changes to the structure and dynamics of SGs and P-bodies suggest that a widespread alteration to the biophysical properties of cellular structures is a consequence of the presence of CUGexp RNA.
哺乳动物细胞中的 RNA 调控需要复杂的物理区隔，使用的结构被认为是由液-液相分离形成的。这些结构的破坏与许多退行性疾病有关。1 型肌强直性营养不良（DM1）是一种多系统三核苷酸重复紊乱，由编码 DM1 蛋白激酶（DMPK）的 DNA 中核苷酸 CTG（CTGexp）的扩展引起。DM1 的细胞特征是形成包含扩展的 DMPK RNA（CUGexp）（胸腺嘧啶而不是尿嘧啶）的核焦点。我们在这里报告 DM1 细胞培养模型中应激颗粒（SGs）和加工体（P-bodies）这两个关键的细胞质结构的失调，这两种结构对 mRNA 调控至关重要。SGs 形成和分散速率的改变表明细胞应对与 DM1 相关的应激的能力发生了改变，而 SGs 和 P-bodies 的结构和动力学的改变表明，细胞结构的生物物理特性的广泛改变是 CUGexp RNA 存在的结果。
