Differences in silencing of mismatched targets by sliced versus diced siRNAs

Guihua Sun, Jinghan Wang, Yasheng Huang, Christine Wan Yin Yuan, Keqiang Zhang, Shuya Hu, Linling Chen, Ren Jang Lin, Yun Yen, Arthur D. Riggs

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

It has been reported that the two major types of RNA interference triggers, the classical Dicer-generated small RNAs (siRNAs), which function with all members of the Argonaute (Ago) protein family in mammals, and the Ago2-sliced small RNAs (sli-siRNAs), which function solely through Ago2, have similar potency in target cleavage and repression. Here, we show that sli-siRNAs are generally more potent than siRNAs in silencing mismatched targets. This phenomenon is usually more apparent in targets that have mismatched nucleotides in the 3 supplementary region than in targets with mismatches in the seed region. We demonstrate that Ago2 slicer activity is a major factor contributing to the greater silencing efficiency of sli-siRNA against mismatched targets and that participation of non-slicing Agos in silencing mismatched siRNA targets may dilute the slicing ability of Ago2. The difference in length of the mature guide RNA used in sli-RISCs and si-RISCs may also contribute to the observed difference in knockdown efficiency. Our data suggest that a sli-siRNA guide strand is likely to have substantially stronger off-target effects than a guide strand with the same sequence in a classical siRNA and that Dicer and non-slicing Agos may play pivotal roles in controlling siRNA target specificity.

Original languageEnglish
Pages (from-to)6806-6822
Number of pages17
JournalNucleic Acids Research
Volume46
Issue number13
DOIs
Publication statusPublished - Jan 1 2018

ASJC Scopus subject areas

  • Genetics

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  • Cite this

    Sun, G., Wang, J., Huang, Y., Yuan, C. W. Y., Zhang, K., Hu, S., Chen, L., Lin, R. J., Yen, Y., & Riggs, A. D. (2018). Differences in silencing of mismatched targets by sliced versus diced siRNAs. Nucleic Acids Research, 46(13), 6806-6822. https://doi.org/10.1093/nar/gky287