MicroRNA assassins: factors that regulate the disappearance of miRNAs

Abstract

MicroRNAs (miRNAs) control essential gene regulatory pathways in plants and animals. Serving as guides in silencing complexes, miRNAs direct Argonaute proteins to specific target messenger RNAs to repress protein expression. The mature, 22-nucleotide (nt) miRNA is the product of multiple processing steps, and recent studies have uncovered factors that directly control the stability of the functional RNA form. Although alteration of miRNA levels has been linked to numerous disease states, the mechanisms responsible for stabilized or reduced miRNA expression have been largely elusive. The discovery of specific cis-acting modifications and trans-acting proteins that affect miRNA half-life reveals new elements that contribute to the homeostasis of these vital regulatory molecules.

Figure 1

A general model of miRNA biogenesis and function^–. After synthesis by RNA polymerase II, miRNA primary transcripts are recognized by Pasha/DGCR8 and Drosha, which excises the hairpin precursor. Exportin 5 delivers the miRNA precursor to Dicer and its RNA binding partner, TRBP/Loqs, for final processing to the mature 22-nt miRNAs. One strand is selected for stable association with Argonaute, where it serves as a guide to target and regulate specific mRNAs.

Figure 2

Proteins that regulate miRNA stability. Incorporation into Argonaute stabilizes mature miRNAs and release from this complex leaves miRNAs vulnerable to decay by XRN-2 or SDN exonucleases^–,,. In C. elegans, XRN-2 also facilitates release of miRNAs from Argonaute proteins that are not associated with targets.

Figure 3

Outstanding questions regarding factors that regulate miRNA stability. First, some modifications appear general, such as methylation of plant miRNAs, whereas others may be targeted to specific miRNAs, such as adenylation of miR-122 (refs. 18,29). In several cases the modifying enzyme and effect of the modification on miRNA stability are not yet known. Second, evidence is mounting that Argonaute is a limiting factor for miRNA function and stability^–. Target availability has been shown to influence the association of a miRNA with Argonaute and its protection from degradation in vitro, but whether this parameter influences miRNA accumulation in vivo is not yet established. Third, the extent of targeted degradation of specific miRNAs as a means to transform the cellular miRNA population is unclear. Decay of select miRNAs could contribute to the dynamic changes in miRNA levels that often accompany differentiation.