Precursor miR-886, a novel noncoding RNA repressed in cancer, associates with PKR and modulates its activity

Abstract

Noncoding RNAs have drawn significant attention in biology recently. Whereas the current research is highly inclined to microRNAs, research on other noncoding RNAs has lagged behind. Here, we investigated a novel noncoding RNA that has been known as precursor microRNA miR-886 (pre-miR-886). Pre-miR-886 has been proposed also as a vault RNA, a component of the vault complex implicated in cancer drug resistance. We identified pre-miR-886 as a 102-nucleotide-long, abundant cytoplasmic RNA that is neither a genuine pre-microRNA nor a vault RNA. Pre-miR-886 is physically associated with PKR (Protein Kinase RNA-activated), an interferon-inducible and double-stranded RNA dependent kinase. The suppression of pre-miR-886 activates PKR and its downstream pathways, eIF2a phosphorylation and the NF-kB pathway, leading to impaired cell proliferation. We also found that pre-miR-886 is suppressed in a wide-range of cancer cell lines and in clinical specimens. This study is the first intense characterization of pre-miR-886 as well as the initial report on its function as a PKR regulator, which suggests a critical role in tumorigenesis.

Upregulation of a small vault RNA (svtRNA2-1a) is an early event in Parkinson disease and induces neuronal dysfunction

“…This is especially relevant in the case of vtRNA2-1, for which recent studies show a poor stable association with the vault complex. 44 Our experimental data and evidences from sRNA highthroughput sequencing upon Dicer depletion in MCF7 cells, 24 show that svtRNA2-1a biogenesis is dependent on Dicer, but not on Drosha, unlike canonical miRNAs. Furthermore, our analyses on the alignment of vtRNA2-1 sequencing reads indicate a pattern consistent with a Dicer-dependent biogenesis.…”

“…[45][46] A recent study reported low efficiency for the processing of the stem-loop precursor to the mature svtRNA2-1a and svtRNA2-1a* (miR-886-5p and miR-886-3p) in epithelial cells. 44 However, the mature minor strand (svtRNA2-1a*/hsa-miR-886-3p) is detected by northern blot in HS5 cells, a human stromal cell line. 48 In addition, our results suggest that in PD, svtRNA2-1a processing from vtRNA2-1 is enhanced.…”

“…The post-transcriptional In conclusion, we have shown that svtRNA2-1a biogenesis is largely dependent on Dicer, in agreement with previous studies. 21,44 Its enrichment in Ago immunocomplexes suggests a role for this svtRNA in post-transcriptional gene regulation. Our results further suggest that early deregulation of svtRNA2-1a expression in PD may contribute to the initial perturbations of gene expression networks, underlying cell functional impairment.…”

“…Interestingly, it has been recently shown that pre-miR-886 (vtRNA2-1) has a tumor-suppressing role, through binding to PRKRA (protein kinase, interferon inducible double-stranded RNA-dependent activator). 44 Thus, gene expression deregulation driven by svtRNA2-1a mimic overexpression in differentiated SH-SY5Y cells could reflect both downstream effects of svtRNA precursor (vtRNA2-1) and primary and secondary effects linked to svtRNA2-1a silencing.…”

miR-886-3p Levels Are Elevated in Friedreich Ataxia

“…Since they were discovered in the 1980s, vault RNAs (Kedersha and Rome, 1986) have been implicated in resistance to certain drugs in cancer (Stadler et al, 2009), however, this is the first instance where we report its potentially causal association with a neurodegenerative disease. In April 2011, Lee et al reported the analysis of pre-miR-886 in cancer cells and concluded that this small RNA is neither a miRNA nor vault RNA (since it is not associated with vault particle) but acts as small noncoding regulatory RNA and is capable of physically interacting with ϳ49 proteins which include histone H4 and TNRC6A (Lee et al, 2011) suggesting other possible candidates for the effects of miR-886-3p described here (Fig. 3).…”