Abstract
A general feature of Argonaute-dependent small RNAs is their base-paired precursor structures, and precursor duplex structures are often required for confident annotation of miRNA genes. However, this rule has been broken by discoveries of functional small RNA species whose precursors lack a predictable double-stranded (ds-) RNA structure, arguing that duplex structures are not prerequisite for small RNA loading to Argonautes. The biological significance of single-stranded (ss-) RNA loading has been recognized particularly in systems where active small RNA amplification mechanisms are involved, because even a small amount of RNA molecules can trigger the production of abundant RNA species leading to profound biological effects. However, even in the absence of small RNA amplification mechanisms, recent studies have demonstrated that potent gene silencing can be achieved using chemically modified synthetic ssRNAs that are resistant to RNases in mice. Therefore, such ssRNA-mediated gene regulation may have broader roles than previously recognized, and the findings have opened the door for further research to optimize the design of ss-siRNAs toward future pharmaceutical and biomedical applications of gene silencing technologies. In this review, we will summarize studies about endogenous ssRNA species that are bound by Argonaute proteins and how ssRNA precursors are recognized by various small RNA pathways.
Highlights
Ever since the Nobel prize-winning discovery of RNA interference (RNAi), gene regulation mediated by double-stranded RNAs has been one of the most active areas of research in molecular biology (Fire et al, 1998)
PERSPECTIVES As described above, single-stranded RNAs (ssRNA) loading pathways were generally revealed as atypical activity of Argonaute proteins in previous studies in eukaryotes
The importance of ssRNA loading pathway in unicellular organisms and the common features of ssRNA loading pathways suggest that the ability of eukaryotic Argonautes to incorporate ssRNAs as guide molecule is a universal activity that was inherited from the primordial ancestral Argonaute protein
Summary
Ever since the Nobel prize-winning discovery of RNA interference (RNAi), gene regulation mediated by double-stranded RNAs (dsRNAs) has been one of the most active areas of research in molecular biology (Fire et al, 1998). They demonstrated that only dsRNAs, not antisense or sense single-stranded RNAs (ssRNA) have the ability to induce strong silencing responses in Caenorhabditis elegans. Together with our recent realization that RNA modifications and cellular nucleases play specific roles in regulation of RNA metabolism (Sun et al, 2013; Liu and Pan, 2014), findings in ssRNA loading mechanisms may add another dimension to Argonaute-mediated gene regulatory pathways
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