Solution Structure of NPSL2, A Regulatory Element in the oncomiR-1 RNA.
Solution Structure of NPSL2, A Regulatory Element in the oncomiR-1 RNA.
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DOI：
10.1016/j.jmb.2022.167688
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发表时间：
2022-09-30
影响因子：
5.6
通讯作者：
Keane, Sarah C.
中科院分区：
文献类型：
--
作者：
Liu, Yaping;Munsayac, Aldrex;Hall, Ian;Keane, Sarah C.
miR-17~ 92 a多顺反子，也称为oncomiR-1，通常在多种癌症中过表达，并具有几种致癌特性。OncomiR-1编码六种组成microRNA（miR），每种以不同的效率酶促加工。然而，调节这种差异处理的结构机制仍不清楚。对oncomiR-1的化学探测揭示了pri-miR-92 a的Drosha切割位点被隔离在四向连接中。NPSL 2是一个独立的茎环元件，位于pri-miR-92 a的上游，并隔离构成pri-miR-92 a的基底螺旋的序列的关键部分。NPSL 2发夹结构的破坏可以促进pri-miR-92 a结构的形成，该结构被Drosha处理。因此，预测NPSL 2作为结构开关起作用，调节pri-miR-92 a加工。在这里，我们使用溶液NMR光谱确定了NPSL 2的溶液结构。这是oncomiR-1元件的第一个高分辨率结构。NPSL 2采用发夹结构，具有大但高度结构化的顶端和内部环。10 bp的顶端环含有pH敏感的A+·C错配。此外，顶端和内环内的几种腺苷具有升高的pKa值。这些腺苷的质子化可以通过静电相互作用稳定NPSL 2结构。我们的研究为调节miR生物发生的重要RNA发夹的二级和三级结构提供了基本见解。
The miR-17~92a polycistron, also known as oncomiR-1, is commonly overexpressed in multiple cancers and has several oncogenic properties. OncomiR-1 encodes six constituent microRNAs (miRs), each enzymatically processed with different efficiencies. However, the structural mechanism that regulates this differential processing remains unclear. Chemical probing of oncomiR-1 revealed that the Drosha cleavage sites of pri-miR-92a are sequestered in a four-way junction. NPSL2, an independent stem loop element, is positioned just upstream of pri-miR-92a and sequesters a crucial part of the sequence that constitutes the basal helix of pri-miR-92a. Disruption of the NPSL2 hairpin structure could promote the formation of a pri-miR-92a structure that is primed for processing by Drosha. Thus, NPSL2 is predicted to function as a structural switch, regulating pri-miR-92a processing. Here, we determined the solution structure of NPSL2 using solution NMR spectroscopy. This is the first high-resolution structure of an oncomiR-1 element. NPSL2 adopts a hairpin structure with a large, but highly structured, apical and internal loops. The 10-bp apical loop contains a pH-sensitive A+·C mismatch. Additionally, several adenosines within the apical and internal loops have elevated pKa values. The protonation of these adenosines can stabilize the NPSL2 structure through electrostatic interactions. Our study provides fundamental insights into the secondary and tertiary structure of an important RNA hairpin proposed to regulate miR biogenesis.
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