双链 RNA 的双链结构提供相对于单链 RNA 的水解稳定性,Environmental Science & Technology

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双链 RNA 的双链结构提供相对于单链 RNA 的水解稳定性
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2021-05-25 , DOI: 10.1021/acs.est.1c01255
Ke Zhang ₁ , Joseph Hodge ₁ , Anamika Chatterjee ₁ , Tae Seok Moon ₁ , Kimberly M Parker ₁

Affiliation

已知双链 (ds) RNA 和单链 (ss) RNA 骨架中的磷酸二酯键会发生碱性水解。因此，用于新兴 RNA 干扰 (RNAi) 产品的 dsRNA 试剂被认为在溶液中表现出低化学持久性。然而，尚未评估 dsRNA 双链结构对碱性水解的影响。在这项研究中，我们证明了 dsRNA 的碱性水解比 ssRNA 慢几个数量级。此外，我们观察到 dsRNA 在中性 pH 下保持完整数月，挑战了 dsRNA 化学不稳定的假设。在能够对 dsRNA 进行酶促降解和碱性水解的系统中，我们发现，增加 pH 可以有效地减弱酶促降解，而不会引起 ssRNA 所观察到的碱性水解。总体而言，我们的研究结果首次表明，dsRNA 的关键降解途径与 ssRNA 的关键降解途径显着不同。考虑到 dsRNA 的独特特性，可以在新兴 RNAi 技术应用过程中更好地控制 dsRNA 稳定性，更准确地评估其在环境和生物系统中的命运，并提供对更广泛应用领域的见解，包括 dsRNA 分离、检测和灭活dsRNA 病毒和益生元分子进化。

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Duplex Structure of Double-Stranded RNA Provides Stability against Hydrolysis Relative to Single-Stranded RNA

Phosphodiester bonds in the backbones of double-stranded (ds)RNA and single-stranded (ss)RNA are known to undergo alkaline hydrolysis. Consequently, dsRNA agents used in emerging RNA interference (RNAi) products have been assumed to exhibit low chemical persistence in solutions. However, the impact of the duplex structure of dsRNA on alkaline hydrolysis has not yet been evaluated. In this study, we demonstrated that dsRNA undergoes orders-of-magnitude slower alkaline hydrolysis than ssRNA. Furthermore, we observed that dsRNA remains intact for multiple months at neutral pH, challenging the assumption that dsRNA is chemically unstable. In systems enabling both enzymatic degradation and alkaline hydrolysis of dsRNA, we found that increasing pH effectively attenuated enzymatic degradation without inducing alkaline hydrolysis that was observed for ssRNA. Overall, our findings demonstrated, for the first time, that key degradation pathways of dsRNA significantly differ from those of ssRNA. Consideration of the unique properties of dsRNA will enable greater control of dsRNA stability during the application of emerging RNAi technology and more accurate assessment of its fate in environmental and biological systems, as well as provide insights into broader application areas including dsRNA isolation, detection and inactivation of dsRNA viruses, and prebiotic molecular evolution.

更新日期：2021-06-15

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