Nuclease-resistant 63-bp trimeric siRNAs simultaneously silence three different genes in tumor cells

FEBS Lett. 2018 Jan;592(1):122-129. doi: 10.1002/1873-3468.12927. Epub 2017 Dec 29.

Abstract

We designed a multimeric nuclease-resistant 63-bp trimeric small-interfering RNA (tsiRNA) comprising in one duplex the sequence of siRNAs targeting mRNAs of MDR1, LMP2, and LMP7 genes. We show that such tsiRNA is able to suppress the expression of all the target genes independently and with high efficiency, acting via a Dicer-dependent mechanism. tsiRNA is diced into 42- and 21-bp duplexes inside the cell. tsiRNA-induced gene silencing is characterized by kinetics similar to that of canonical siRNA, while the silencing efficiency is significantly higher than that of canonical siRNA with the same sequence.

Keywords: LMP2; LMP7; MDR1; 2′-O-methyl modifications; Dicer-substrate RNAs; siRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Base Sequence
  • Cell Line, Tumor
  • Cysteine Endopeptidases / genetics
  • DEAD-box RNA Helicases / metabolism
  • Drug Design
  • Gene Silencing*
  • Humans
  • Kinetics
  • Proteasome Endopeptidase Complex / genetics
  • RNA Processing, Post-Transcriptional
  • RNA Stability
  • RNA, Small Interfering / chemical synthesis
  • RNA, Small Interfering / genetics*
  • RNA, Small Interfering / therapeutic use*
  • Ribonuclease III / metabolism
  • Ribonucleases / metabolism

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • RNA, Small Interfering
  • LMP-2 protein
  • Ribonucleases
  • DICER1 protein, human
  • Ribonuclease III
  • Cysteine Endopeptidases
  • LMP7 protein
  • Proteasome Endopeptidase Complex
  • DEAD-box RNA Helicases