A new molecular mechanism of RNA circularization and the microRNA sponge formation
A new molecular mechanism of RNA circularization and the microRNA sponge formation
复制标题
DOI：
10.1080/07391102.2020.1844802
复制
发表时间：
2020-11-16
影响因子：
4.4
通讯作者：
Barciszewski, Jan
中科院分区：
文献类型：
--
作者：
Belter, Agnieszka;Popenda, Mariusz;Barciszewski, Jan
描述了一种由miRNAs特异性结合驱动的RNA环化新机制。我们鉴定了71个CUUCC五核苷酸基序，它们规则地分布在CDR1as RNA的整个分子中，通过它们的种子序列GGAAG与71个miRNAs结合。MiR-7 RNA(71个分子)的顺序结合使CDR1as RNA(1个分子)的两端结合在一起，并分别在5‘端和3’端刺激核苷酸C-1和A(1299)之间的磷酸二酯键的形成。MiRNAs与CDR1as RNA结合形成独特的复合体，表现出三个特定的结构域：(I)两个带内环的短螺旋，(Ii)铰链和(Iii)三螺旋。所提出的机制解释了特定的RNA环化及其作为miRNAs海绵的功能。此外，现有关于CDR1as RNA与miR-7相互作用的湿实验数据充分支持我们的观察。虽然miR-671与miR-7显示相同的种子序列，但它与CDR1as RNA形成几乎完美的双螺旋，并诱导CDR1as的切割，但不刺激环化。为了检查所提出的机制在环状RNA中有多常见，我们分析了最新的CircAtlas数据库，统计了近110万个序列。结果发现，有大量的CircRNAs，这表明miRNAs种子结合序列分布在整个CircRNA序列中，证明线性转录本的环化是依赖于miRNA的。
A new mechanism of RNA circularization driven by specific binding of miRNAs is described. We identified the 71 CUUCC pentanucleotide motifs distributed regularly throughout the entire molecule of CDR1as RNA that bind to 71 miRNAs through their seed sequence GGAAG. The sequential binding of miR-7 RNAs (71 molecules) brings both ends of CDR1as RNA (1 molecule) together and stimulate phosphodiester bond formation between nucleotides C-1 and A(1299) at the 5' and 3' end, respectively. The binding of miRNAs to CDR1as RNA results in the unique complex formation, which shows three specific structural domains: (i) two short helixes with an internal loop, (ii) the hinge, and (iii) the triple-helix. The proposed mechanism explains specific RNA circularization and its function as a miRNAs sponge. Furthermore, the existing wet experimental data on the interaction of CDR1as RNA with miR-7 fully supports our observation. Although miR-671 shows the same seed sequence as miR-7, it forms an almost perfect double helix with CDR1as RNA and induces the cleavage of CDR1as, but does not stimulate circularization. To check how common is the proposed mechanism among circular RNAs, we analyzed the most recent circAtlas database counting almost 1.1 million sequences. It turned out that there are a huge number of circRNAs, which showed miRNAs seed binding sequences distributed through the whole circRNA sequences and prove that circularization of linear transcript is miRNA dependent.Communicated by Ramaswamy H. Sarma