Trends in Biochemical Sciences
ReviewMicroRNA turnover: when, how, and why
Section snippets
Degradation facilitates dynamic miRNA expression patterns
MicroRNAs are a large class of small regulatory RNAs, ∼22 nucleotides long. They bind to partially complementary sequences in target mRNAs and silence them translationally or by inducing mRNA degradation [1]. miRNAs are important for gene regulation in numerous cellular and developmental processes [2], therefore it is perhaps of little surprise that miRNAs themselves are subject to extensive regulation. Indeed, a large body of literature connects dysregulation of miRNAs with disease [3],
Cellular conditions affecting miRNA stability
In contrast to the view of miRNAs as generically stable molecules, recent studies have shown that individual miRNAs, or miRNAs in specific environments, are subject to accelerated decay (Table 1), altering miRNA levels and hence activity. This section focuses on discussing cellular conditions and extracellular cues that influence miRNA stability.
miRNA-degrading enzymes
Several miRNA-degrading enzymes have been identified, including both 3′-to-5′ and 5′-to-3′ exoribonucleases, but so far no endoribonucleases (Figure 1). Distinct RNases were found to function in turnover of different sets of miRNAs and/or different organisms, but because these results are only from a small number of studies, substrate specificity and phylogenetic conservation of individual miRNA turnover enzymes remains largely unknown. For convenience, we will refer to miRNA degrading enzymes
Reversing a relation: regulatory functions of target RNAs on miRNAs
At the heart of miRNA-mediated mRNA regulation lies the sequence-specific interaction of the miRNA and the mRNA [54]. The extent of sequence complementarity between miRNA and mRNA determines the mode of mRNA silencing. Extensive complementarity, reminiscent of the siRNA–mRNA interaction, can result in endonucleolytic cleavage of the target mRNA, and constitutes a major means by which miRNAs regulate mRNAs in plants [55]. In metazoans, miRNAs base-pair with mRNAs mainly through partial
Concluding remarks
Although miRNAs were initially considered to be highly stable molecules, rapid and active miRNA degradation has now been demonstrated in many different organisms and experimental systems. Somewhat surprisingly, there appears to be a great diversity of miRNA degrading enzymes and, thus far, little evidence for conserved usage of individual enzymes across phylogeny. However, given that this field is still in its early days, further studies may force us to revise this view by revealing pathways
Note added in proof
Eri1 (3′-to-5′ exoribonuclease 1) has recently been implicated in miRNA turnover in murine immune cells [69]. Previously, C. elegans mutant for eri-1 had been found to accumulate siRNAs derived from exogenously supplied double-stranded RNA [70], although this may be a consequence of enhanced biogenesis rather than, or in addition to, impaired turnover of the siRNAs 71, 72. Thomas et al. now found that loss of Eri1 impaired mouse natural killer cell development, maturation and function. It also
Acknowledgments
We thank Stefan Ameres, Xuemei Chen, Bin Yu, and V. Narry Kim for sharing pre-prints. We are grateful to Nicolas Antih, Witold Filipowicz, Manuel de la Mata, Takashi Miki, and Hannes Richter for comments on the manuscript. S.R. was supported by a Boehringer Ingelheim Fonds PhD Fellowship. Work in the Großhans lab is funded by the Novartis Research Foundation, the Swiss National Science Foundation, and the European Research Council.
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