Inosine Substitutions in RNA Activate Latent G-Quadruplexes,Journal of the American Chemical Society

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Inosine Substitutions in RNA Activate Latent G-Quadruplexes
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2021-09-14 , DOI: 10.1021/jacs.1c05214
Timo Hagen ₁ , Artur Laski ₁ , Anneke Brümmer _{2,

3} , Adam Pruška ₁ , Verena Schlösser ₁ , Antoine Cléry _{4,

5} , Frédéric H-T Allain ₄ , Renato Zenobi ₁ , Sven Bergmann _{2,

3,

6} , Jonathan Hall ₁

Affiliation

It is well-accepted that gene expression is heavily influenced by RNA structure. For instance, stem-loops and G-quadruplexes (rG4s) are dynamic motifs in mRNAs that influence gene expression. Adenosine-to-inosine (A-to-I) editing is a common chemical modification of RNA which introduces a nucleobase that is iso-structural with guanine, thereby changing RNA base-pairing properties. Here, we provide biophysical, chemical, and biological evidence that A-to-I exchange can activate latent rG4s by filling incomplete G-quartets with inosine. We demonstrate the formation of inosine-containing rG4s (GI-quadruplexes) in vitro and verify their activity in cells. GI-quadruplexes adopt parallel topologies, stabilized by potassium ions. They exhibit moderately reduced thermal stability compared to conventional G-quadruplexes. To study inosine-induced structural changes in a naturally occurring RNA, we use a synthetic approach that enables site-specific inosine incorporation in long RNAs. In summary, RNA GI-quadruplexes are a previously unrecognized structural motif that may contribute to the regulation of gene expression in vivo.

中文翻译：

RNA中的肌苷取代激活潜在的G-四链体

众所周知，基因表达受 RNA 结构的影响很大。例如，茎环和 G-四链体 (rG4s) 是影响基因表达的 mRNA 中的动态基序。腺苷到肌苷 (A-to-I) 编辑是一种常见的 RNA 化学修饰，它引入与鸟嘌呤同构的核碱基，从而改变 RNA 碱基配对特性。在这里，我们提供了生物物理、化学和生物学证据，证明 A-to-I 交换可以通过用肌苷填充不完整的 G-四重奏来激活潜在的 rG4。我们在体外证明了含肌苷的 rG4（GI-四链体）的形成并验证它们在细胞中的活性。GI-四链体采用平行拓扑结构，由钾离子稳定。与传统的 G-四链体相比，它们表现出适度降低的热稳定性。为了研究天然存在的 RNA 中肌苷诱导的结构变化，我们使用了一种合成方法，该方法能够将位点特异性肌苷掺入长 RNA 中。总之，RNA GI-四链体是一种以前未被认识的结构基序，可能有助于体内基因表达的调节。

更新日期：2021-09-22

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