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Mechanism mediated by a noncoding RNA, nc886, in the cytotoxicity of a DNA-reactive compound

Nawapol Kunkeaw1,2, Yeon-Su Lee3, Wonkyun Ronny Im4

  • 1Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-1072.

Proceedings of the National Academy of Sciences of the United States of America
|April 6, 2019
PubMed

Insights

Doxorubicin triggers apoptosis in cancer cells via a novel pathway involving nc886 noncoding RNA and protein kinase R (PKR). This mechanism explains how DNA-damaging chemotherapy drugs harm normal cells, preceding DNA damage responses.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • DNA-reactive compounds are key in cancer chemotherapy, primarily through genotoxicity.
  • Their cytotoxicity is thought to target rapidly dividing cancer cells, but they also affect normal cells.
  • This suggests additional cytotoxic mechanisms beyond DNA damage.

Purpose of the Study:

  • To uncover alternative cytotoxic mechanisms of DNA-reactive chemotherapy agents.
  • To investigate the role of noncoding RNA (ncRNA) and protein kinase R (PKR) in doxorubicin-induced cytotoxicity.
  • To explain the toxicity of DNA-damaging drugs in normal quiescent cells.

Main Methods:

  • Utilized doxorubicin as a model DNA-reactive compound.
  • Investigated the interaction between nc886 ncRNA, PKR, and RNA polymerase III (Pol III).
  • Examined cellular responses in 3D and monolayer culture systems following short-pulse doxorubicin treatment.

Main Results:

  • Doxorubicin disrupts Pol III binding to DNA, inhibiting nc886 transcription.
  • This leads to rapid nc886 depletion, activating PKR and inducing apoptosis.
  • This ncRNA/PKR pathway activation precedes DNA damage response, explaining cytotoxicity in quiescent cells.

Conclusions:

  • Identified a novel doxorubicin-induced cytotoxic pathway mediated by nc886 ncRNA and PKR.
  • nc886 acts as a molecular sensor for doxorubicin, triggering apoptosis via PKR.
  • This pathway provides a mechanism for DNA-damaging drug toxicity in normal quiescent cells.
Keywords:
RNA polymerase IIIcytotoxicitydoxorubicinnc886protein kinase R

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