MicroRNA turnover: a tale of tailing, trimming, and targets

Degradation of Argonaute (AGO) proteins by the ubiquitin-proteasome system and modification of miRNA 3′ ends by tailing and trimming are mechanisms that can promote global or miRNA-specific turnover. The consequences of tailing and trimming of small RNAs vary depending on the class of small RNA, the identity of the nucleotides that are added to the small RNA 3′ end, and the species in which the modifications occur. Tailing and trimming appears to regulate the stability of plant miRNAs, animal siRNAs, and animal piRNAs, but usually not animal miRNAs. Target-directed miRNA degradation (TDMD), which is triggered by extensive base-pairing of both the miRNA 5′ and 3′ end with a target, appears to be the major mechanism of regulated turnover of animal miRNAs. The ZSWIM8 ubiquitin ligase mediates TDMD by promoting the destruction of AGO:miRNA complexes engaged with highly complementary targets. MicroRNAs (miRNAs) post-transcriptionally repress gene expression by guiding Argonaute (AGO) proteins to target mRNAs. While much is known about the regulation of miRNA biogenesis, miRNA degradation pathways are comparatively poorly understood. Although miRNAs generally exhibit slow turnover, they can be rapidly degraded through regulated mechanisms that act in a context- or sequence-specific manner. Recent work has revealed a particularly important role for specialized target interactions in controlling rates of miRNA degradation. Engagement of these targets is associated with the addition and removal of nucleotides from the 3′ ends of miRNAs, a process known as tailing and trimming. Here we review these mechanisms of miRNA modification and turnover, highlighting the contexts in which they impact miRNA stability and discussing important questions that remain unanswered. MicroRNAs (miRNAs) post-transcriptionally repress gene expression by guiding Argonaute (AGO) proteins to target mRNAs. While much is known about the regulation of miRNA biogenesis, miRNA degradation pathways are comparatively poorly understood. Although miRNAs generally exhibit slow turnover, they can be rapidly degraded through regulated mechanisms that act in a context- or sequence-specific manner. Recent work has revealed a particularly important role for specialized target interactions in controlling rates of miRNA degradation. Engagement of these targets is associated with the addition and removal of nucleotides from the 3′ ends of miRNAs, a process known as tailing and trimming. Here we review these mechanisms of miRNA modification and turnover, highlighting the contexts in which they impact miRNA stability and discussing important questions that remain unanswered. the region of an mRNA downstream of the translation termination codon where cis-acting regulatory elements, such as miRNA-binding sites, are often located. a family of proteins that associate with various classes of small RNAs, including miRNAs and siRNAs. Small RNAs guide AGO proteins to target transcripts for gene silencing. an enzyme that adds a 2′-O-methyl group at the 3′ end of specific classes of small RNAs, such as plant miRNAs and animal siRNAs and piRNAs. This modification prevents tailing and trimming when these classes of small RNAs engage highly complementary targets. a family of proteins related to AGO proteins that are loaded with a specialized class of small RNAs known as piRNAs. In many species, PIWI proteins and their associated piRNAs play an important role in transposon suppression in the germline. addition of non-templated nucleotides to the 3′ end of a small RNA. a miRNA degradation pathway that is triggered by the interaction of miRNAs with specialized target transcripts that exhibit extensive 5′ and 3′ complementarity to the miRNA. removal of nucleotides from the 3′ end of a small RNA. a substrate adapter for a cullin-RING E3 ubiquitin ligase complex that mediates TDMD by recognizing AGO:miRNA complexes engaged with highly complementary targets and triggering their degradation by the proteasome; known as Dora in Drosophila melanogaster and EBAX-1 in Caenorhabditis elegans.