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Synthetic design of asymmetric miRNA with engineered 3′-overhang to improve strand selection
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. (Translational Chemical Biology Laboratory)
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. (Translational Chemical Biology Laboratory)ORCID iD: 0000-0002-7256-0758
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. (Translational Chemical Biology Laboratory)
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. (Translational Chemical Biology Laboratory)
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2019 (English)In: Molecular Therapy - Nucleic Acids, ISSN 2162-2531, E-ISSN 2162-2531, Vol. 16, p. 597-604Article in journal (Refereed) Published
Abstract [en]

We have developed a novel miRNA design that significantly improves strand selection within the RISC complex by engineering the 3′-end by adding extra nucleotides. Addition of seven nucleotides at the 3′-ends of the miR or miR* strand resulted in a thermodynamic asymmetry at either of the two-ends, which resulted in selective RISC recruitment as demonstrated by the stem-loop quantitative PCR experiment. Such selective recruitment was also corroborated at the protein level by Western blot analysis. In order to investigate the functional effect due to selective recruitment, we performed apoptosis and metastasis studies using human colon carcinoma cells (HCT116) and human osteosarcoma cells (MG63). These experiments indicated that the recruitment of miR strand is responsible for inducing apoptosis as well as to inhibit invasiveness of cancer cells. Recruitment of miR* strand, on the other hand, showed opposite effect. To the best of our knowledge, our strand engineering strategy is the first report of improved strand selection of desired miRNA strand by RISC without using any chemical modifications or mismatches. We believe such structural modifications of miR34a could mitigate some of the off-target effects of miRNA therapy and would also allow a better understanding of sequence-specific gene regulation. Such a design could also be adapted to other miRNA to enhance their therapeutic potential.

Place, publisher, year, edition, pages
Elsevier, 2019. Vol. 16, p. 597-604
Keywords [en]
RNA interference, miRNA, miR34a, strand selection, anticancer therapy
National Category
Polymer Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-382299DOI: 10.1016/j.omtn.2019.04.012ISI: 000470250900053PubMedID: 31085353OAI: oai:DiVA.org:uu-382299DiVA, id: diva2:1306568
Funder
Swedish Foundation for Strategic Research , SBE13-0028National initiative on Stem Cells for Regenerative Therapy, 2009-1035Available from: 2019-04-24 Created: 2019-04-24 Last updated: 2019-06-26Bibliographically approved

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Kadekar, SandeepNawale, Ganesh N.Podiyan, OommenVarghese, Oommen P.

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