LAUSR

Breaking down miRNAs Although much work has examined microRNA (miRNA) biogenesis, relatively little is known about miRNA decay. Elbarbary et al. now identify Tudor-SN, an endonuclease that interacts with the RNA-induced silencing complex. Tudor-SN targets miRNAs at CA and UA dinucleotides located more than five nucleotides from miRNA ends. Tudor-SN-mediated miRNA decay removes miRNAs that silence genes encoding proteins that are critical for the G1-to-S phase transition in the cell cycle. Science, this issue p. 859 An endonuclease initiates decay of microRNAs that regulate the cell cycle. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression. The pathways that mediate mature miRNA decay are less well understood than those that mediate miRNA biogenesis. We found that functional miRNAs are degraded in human cells by the endonuclease Tudor-SN (TSN). In vitro, recombinant TSN initiated the decay of both protein-free and Argonaute 2–loaded miRNAs via endonucleolytic cleavage at CA and UA dinucleotides, preferentially at scissile bonds located more than five nucleotides away from miRNA ends. Cellular targets of TSN-mediated decay defined using microRNA sequencing followed this rule. Inhibiting TSN-mediated miRNA decay by CRISPR-Cas9 knockout of TSN inhibited cell cycle progression by up-regulating a cohort of miRNAs that down-regulates mRNAs that encode proteins critical for the G1-to-S phase transition. Our study indicates that targeting TSN nuclease activity could inhibit pathological cell proliferation.