Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
Nat Commun. 2022 Mar 2;13(1):1128. doi: 10.1038/s41467-022-28603-2.
SARS-CoV-2 is a betacoronavirus with a single-stranded, positive-sense, 30-kilobase RNA genome responsible for the ongoing COVID-19 pandemic. Although population average structure models of the genome were recently reported, there is little experimental data on native structural ensembles, and most structures lack functional characterization. Here we report secondary structure heterogeneity of the entire SARS-CoV-2 genome in two lines of infected cells at single nucleotide resolution. Our results reveal alternative RNA conformations across the genome and at the critical frameshifting stimulation element (FSE) that are drastically different from prevailing population average models. Importantly, we find that this structural ensemble promotes frameshifting rates much higher than the canonical minimal FSE and similar to ribosome profiling studies. Our results highlight the value of studying RNA in its full length and cellular context. The genomic structures detailed here lay groundwork for coronavirus RNA biology and will guide the design of SARS-CoV-2 RNA-based therapeutics.
SARS-CoV-2 是一种带有单链、正链、30 千碱基 RNA 基因组的β冠状病毒，该基因组负责当前的 COVID-19 大流行。尽管最近有报道称对基因组的群体平均结构模型进行了研究，但关于天然结构组合的实验数据很少，并且大多数结构缺乏功能表征。在这里，我们以单核苷酸分辨率报道了感染细胞中两条线的整个 SARS-CoV-2 基因组的二级结构异质性。我们的结果揭示了整个基因组和关键移码刺激元件（FSE）的替代 RNA 构象，与流行的群体平均模型有很大不同。重要的是，我们发现这种结构组合促进的移码率远高于典型的最小 FSE，与核糖体分析研究相似。我们的结果强调了在全长和细胞环境中研究 RNA 的价值。这里详细介绍的基因组结构为冠状病毒 RNA 生物学奠定了基础，并将指导基于 SARS-CoV-2 RNA 的治疗药物的设计。
