Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
School of Biological Sciences, University of East Anglia, Norwich, UK.
Mol Cell. 2020 Apr 16;78(2):317-328.e6. doi: 10.1016/j.molcel.2020.02.020. Epub 2020 Mar 18.
MicroRNAs (miRNAs) are sequentially processed by two RNase III enzymes, Drosha and Dicer. miR-451 is the only known miRNA whose processing bypasses Dicer and instead relies on the slicer activity of Argonaute-2 (Ago2). miR-451 is highly conserved in vertebrates and regulates erythrocyte maturation, where it becomes the most abundant miRNA. However, the basis for the non-canonical biogenesis of miR-451 is unclear. Here, we show that Ago2 is less efficient than Dicer in processing pre-miRNAs, but this deficit is overcome when miR-144 represses Dicer in a negative-feedback loop during erythropoiesis. Loss of miR-144-mediated Dicer repression in zebrafish embryos and human cells leads to increased canonical miRNA production and impaired miR-451 maturation. Overexpression of Ago2 rescues some of the defects of miR-451 processing. Thus, the evolution of Ago2-dependent processing allows miR-451 to circumvent the global repression of canonical miRNAs elicited, in part, by the miR-144 targeting of Dicer during erythropoiesis.
微小 RNA（miRNA）通过两种 RNA 酶 III 酶 Drosha 和 Dicer 进行顺序加工。miR-451 是唯一已知的 miRNA，其加工绕过 Dicer，而是依赖 Argonaute-2（Ago2）的切割活性。miR-451 在脊椎动物中高度保守，调节红细胞成熟，在成熟过程中成为最丰富的 miRNA。然而，miR-451 非典型生物发生的基础尚不清楚。在这里，我们表明 Ago2 比 Dicer 在加工前体 miRNA 时效率更低，但在红细胞生成过程中 miR-144 负反馈抑制 Dicer 时，这种缺陷得到克服。斑马鱼胚胎和人类细胞中 miR-144 介导的 Dicer 抑制丧失导致典型 miRNA 产生增加和 miR-451 成熟受损。Ago2 的过表达可挽救 miR-451 加工的一些缺陷。因此，Ago2 依赖性加工的进化允许 miR-451 绕过 miR-144 靶向 Dicer 在红细胞生成过程中引起的部分典型 miRNA 的全局抑制。
