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

Towler, Benjamin P, Jones, Christopher I, Viegas, Sandra C, Apura, Patricia, Waldron, Joseph A, Smalley, Sarah K, Arraiano, Cecilia M and Newbury, Sarah F (2015) The 3’-5’ exoribonuclease Dis3 regulates the expression of specific microRNAs in Drosophila wing imaginal discs. RNA Biology, 12 (7). pp. 728-741. ISSN 1547-6286

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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 Drosophila 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 > 2-fold and 6 (5.5%) decreasing in level >2-fold. Of these microRNAs, miR-252-5p is increased 2.1-fold in Dis3-depleted cells compared to controls while the level of the miR-252 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 miR-252-5p for degradation during normal wing development. Another microRNA, miR-982-5p, is expressed at lower levels in Dis3 knockdown cells, while the miR-982 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.

Item Type: Article
Keywords: microRNA, RNA stability, Drosophila development
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
Brighton and Sussex Medical School > Primary Care and Public Health
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics
Depositing User: Sarah Newbury
Date Deposited: 14 Apr 2015 08:30
Last Modified: 28 Sep 2017 14:36

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Project NameSussex Project NumberFunderFunder Ref
UnsetUnsetFCT-PortugalEXPL/BEXBCM/ 1317/2013
UnsetUnsetEuropean CommissionFP7- KBBE-2013-1-289326