The human decapping scavenger enzyme DcpS modulates microRNA turnover.

MicroRNAs (miRNAs) are small non-coding RNAs regulating protein production upon binding 3′UTR of its target mRNA by partial complementary sequence interaction inducing translation inhibition and/or mRNA degradation. The miRNA-mediated gene regulation mechanism is conserved in nearly all eukaryotes including humans. It is predicted that miRNAs could regulate expression of at least 30% of human genome, implicating them in the regulation of almost all biological processes (Reviewed in1). Consequently, miRNA levels alteration observed in human diseases supports their importance in cell homeostasis (reviewed in2,3). It is therefore essential to understand the molecular mechanisms controlling miRNAs biogenesis and stability. MiRNA genes are mostly transcribed by RNA polymerase II to form a miRNA primary transcript (pri-miRNA). In the nucleus, the pri-miRNA is processed to produce the miRNA precursor (pre-miRNA) by a microprocessor complex containing the RNase III-like enzyme Drosha and the RNA binding protein DGCR8 to produce the miRNA precursor (pre-miRNA). After its export to the cytoplasm, the pre-miRNA is cleaved by another RNase III-like enzyme, Dicer, to produce the mature miRNA. Subsequently, the miRNA is bound to an Argonaute protein to form the miRNA Induced Silencing Complex (miRISC). The miRNA serves as guide for the miRISC to target specific mRNA, inducing inhibition of protein production by different ways (Reviewed in4). Over the years, several mechanisms responsible for either activating or blocking the biogenesis of a specific miRNA or a subset of miRNAs in response to different cellular conditions were uncovered (Reviewed in5,6). Nevertheless, the fate of mature miRNAs after binding to mRNAs remains unclear. Recently, the involvement of some ribonucleases in the degradation of specific mature miRNAs has been reported in plants (SDNs), Caenorhabditis elegans (XRN-1 and XRN-2), and human cells (Xrn1, PNPase and RRP4)7. Recently, we have identified DCS-1, the ortholog of the human decapping scavenger enzyme DcpS, as a new modulator of miRNA turnover in Caenorhabditis elegans. DCS-1 interacts with the 5′-3′ exonuclease XRN-1 to promote microRNA degradation independently of its known decapping activity8. To determine if the modulation of miRNAs turnover by DCS-1 is conserved in mammals, we surveyed the implication of human DcpS in miRNA stability. In this study, we report that the cytoplasmic DcpS activates miRNAs degradation in human cells with the contribution of the 5′-3′ exonuclease Xrn2. As observed in nematode, this process is independent of the decapping activity of DcpS. Our findings support a conserved role of DcpS as a modulator of miRNA turnover in animals.