DISE: A Seed-Dependent RNAi Off-Target Effect That Kills Cancer Cells

William Putzbach1, Quan Q Gao1, Monal Patel1

  • 1Department of Medicine, Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

Trends in Cancer
|February 8, 2018
PubMed

Insights

Off-target effects (OTEs) in RNA interference (RNAi) can arise from unintended mRNA targeting. A newly discussed type, death induced by survival gene elimination (DISE), may selectively impact cancer cells.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • RNA interference (RNAi) is a powerful gene silencing tool.
  • Off-target effects (OTEs) are a major limitation of RNAi therapies.
  • siRNA complementarity to unintended mRNAs causes OTEs.

Purpose of the Study:

  • To discuss three types of seed-dependent OTEs (sOTEs).
  • To introduce death induced by survival gene elimination (DISE) as a specific sOTE.
  • To explore the potential of DISE in cancer therapy.

Main Methods:

  • Review of existing literature on RNAi and OTEs.
  • Classification of sOTEs based on siRNA strand and seed activity.
  • Analysis of the mechanism of DISE.

Main Results:

  • Identified three types of sOTEs: guide strand (Type I), passenger strand (Type II), and survival gene targeting (Type III).
  • Type I and II sOTEs lead to unpredictable cellular responses.
  • Type III sOTE, or DISE, results from essential survival gene targeting.

Conclusions:

  • DISE is a distinct consequence of RNAi with potential therapeutic implications.
  • DISE may preferentially affect cancer cells due to their reliance on specific survival pathways.
  • Further research into DISE could lead to more targeted RNAi strategies.

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