Pervasive tertiary structure in the dengue virus RNA genome
Pervasive tertiary structure in the dengue virus RNA genome
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DOI：
10.1073/pnas.1716689115
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发表时间：
2018-11-06
影响因子：
11.1
通讯作者：
Weeks, Kevin M.
中科院分区：
文献类型：
--
作者：
Dethoff, Elizabeth A.;Boerneke, Mark A.;Weeks, Kevin M.
RNA病毒基因组是高效而紧凑的生物信息载体，编码复制所需的信息，包括其初级序列和更高阶的RNA结构。然而，具有高阶折叠的RNA元件的普遍存在--其中螺旋聚集在一起形成复杂的3D结构--以及这些元件对病毒适合性的影响程度在很大程度上是未知的。在这里，我们使用单分子相关化学探针来定义登革2型病毒(DENV2)RNA基因组的二级和三级结构。高阶RNA结构广泛存在，涉及DENV2基因组RNA中超过三分之一的核苷酸。这些3D结构促进了紧凑的整体架构，并有助于病毒式健身。破坏具有高阶结构的RNA区域会导致稳定的、不可逆转的突变，并可能指导基于减毒RNA病毒的疫苗的开发。病毒RNA中存在广泛的具有三级折叠的功能RNA元件区域，可能还有许多其他信使和非编码RNA，这意味着有一些重要的区域具有口袋状表面，可以作为新的RNA导向的药物靶点。
RNA virus genomes are efficient and compact carriers of biological information, encoding information required for replication both in their primary sequences and in higher-order RNA structures. However, the ubiquity of RNA elements with higher-order folds-in which helices pack together to form complex 3D structures-and the extent to which these elements affect viral fitness are largely unknown. Here we used single-molecule correlated chemical probing to define secondary and tertiary structures across the RNA genome of dengue virus serotype 2 (DENV2). Higher-order RNA structures are pervasive and involve more than one-third of nucleotides in the DENV2 genomic RNA. These 3D structures promote a compact overall architecture and contribute to viral fitness. Disrupting RNA regions with higher-order structures leads to stable, nonreverting mutants and could guide the development of vaccines based on attenuated RNA viruses. The existence of extensive regions of functional RNA elements with tertiary folds in viral RNAs, and likely many other messenger and noncoding RNAs, means that there are significant regions with pocket-containing surfaces that may serve as novel RNA-directed drug targets.