Visualizing a protonated RNA state that modulates microRNA-21 maturation
Visualizing a protonated RNA state that modulates microRNA-21 maturation
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可视化调节microRNA-21成熟的质子化RNA状态
DOI：
10.1038/s41589-020-00667-5
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发表时间：
2020-10-26
影响因子：
14.8
通讯作者：
Zhang, Qi
中科院分区：
文献类型：
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作者：
Baisden, Jared T.;Boyer, Joshua A.;Zhang, Qi
microRNA是进化上保守的小的非编码RNA，调节多种生物过程。由于其重要的调控作用，microRNA的生物合成受到严格的调控，其中蛋白质因子通常被发现与特定的初级和前体microRNA相互作用以进行调控。在这里，使用NMR弛豫色散光谱和诱变，我们揭示了致癌microRNA-21的前体作为一个pH依赖性的整体存在，自发地重排整个顶端茎环区域的二级结构，包括Dicer切割位点。我们发现，替代激发构象瞬时螯合凸出的腺嘌呤成非典型质子化的A（+）-G错配，赋予一个实质性的增强在切丁加工超过其地面构象状态。这些结果表明，microRNA的成熟效率可能是编码的内在动力学合奏的初级和前体microRNA，提供了一个潜在的手段，调节microRNA的生物合成响应环境和细胞刺激。
MicroRNAs are evolutionarily conserved small, noncoding RNAs that regulate diverse biological processes. Due to their essential regulatory roles, microRNA biogenesis is tightly regulated, where protein factors are often found to interact with specific primary and precursor microRNAs for regulation. Here, using NMR relaxation dispersion spectroscopy and mutagenesis, we reveal that the precursor of oncogenic microRNA-21 exists as a pH-dependent ensemble that spontaneously reshuffles the secondary structure of the entire apical stem-loop region, including the Dicer cleavage site. We show that the alternative excited conformation transiently sequesters the bulged adenine into a noncanonical protonated A(+)-G mismatch, conferring a substantial enhancement in Dicer processing over its ground conformational state. These results indicate that microRNA maturation efficiency may be encoded in the intrinsic dynamic ensemble of primary and precursor microRNAs, providing a potential means of regulating microRNA biogenesis in response to environmental and cellular stimuli.