The 3’-5’ exoribonuclease Dis3 regulates the expression of specific microRNAs in <i>Drosophila</i> wing imaginal discs

Dis3 is a highly conserved exoribonuclease which degrades RNAs in the 3'-5' direction. Mutations in Dis3 are associated with a number of human cancers including multiple myeloma and acute myeloid leukaemia. In this work, we have assessed the effect of a Dis3 knockdown on <i>Drosophila</i> imaginal disc development and on expression of mature microRNAs. We find that Dis3 knockdown severely disrupts the development of wing imaginal discs in that the flies have a “no wing” phenotype. Use of RNA-seq to quantify the effect of Dis3 knockdown on microRNA expression shows that Dis3 normally regulates a small subset of microRNAs, with only 11 (10.1%) increasing in level &gt; 2-fold and 6 (5.5%) decreasing in level &gt;2-fold. Of these microRNAs, <i>miR–252–5p</i> is increased 2.1-fold in Dis3-depleted cells compared to controls while the level of the <i>miR–252</i> precursor is unchanged, suggesting that Dis3 can act in the cytoplasm to specifically degrade this mature miRNA. Furthermore, our experiments suggest that Dis3 normally interacts with the exosomal subunit Rrp40 in the cytoplasm to target <i>miR–252–5p</i> for degradation during normal wing development. Another microRNA, <i>miR–982–5p</i>, is expressed at lower levels in Dis3 knockdown cells, while the <i>miR–982</i> precursor remains unchanged, indicating that Dis3 is involved in its processing. Our study therefore reveals an unexpected specificity for this ribonuclease towards microRNA regulation, which is likely to be conserved in other eukaryotes and may be relevant to understanding its role in human disease.