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Inhibition of nucleolar transcription by oxaliplatin involves ATM/ATR kinase signaling

Misha Nechay1, Danyang Wang1, Ralph E Kleiner1

  • 1Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.

Cell Chemical Biology
|July 11, 2023
PubMed

Insights

Oxaliplatin, a platinum drug for colorectal cancer, inhibits rRNA transcription by disrupting the nucleolus via ATM/ATR signaling. This distinct pathway silences transcription without direct DNA damage, revealing a key mechanism of platinum drug toxicity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Platinum (Pt) compounds are crucial anti-cancer drugs.
  • The precise mechanisms of Pt drug action, particularly oxaliplatin, require further elucidation.
  • Understanding oxaliplatin's effects on rRNA transcription and nucleolar function is key to its therapeutic application.

Purpose of the Study:

  • To investigate the mechanism by which oxaliplatin inhibits rRNA transcription.
  • To determine the role of ATM and ATR signaling in oxaliplatin's effects.
  • To clarify the relationship between nucleolar disruption, DNA damage signaling, and transcriptional inhibition by oxaliplatin.

Main Methods:

  • Treatment of cells with oxaliplatin.
  • Analysis of rRNA transcription rates.
  • Assessment of ATM and ATR signaling pathway activation.
  • Investigation of nucleolar protein localization (NBS1, TOPBP1).
  • Evaluation of DNA damage markers in the nucleolus.

Main Results:

  • Oxaliplatin inhibits rRNA transcription through ATM and ATR signaling.
  • The drug causes nucleolar disruption and accumulation of NBS1 and TOPBP1.
  • Transcriptional inhibition is independent of NBS1 and TOPBP1.
  • Oxaliplatin does not induce significant direct DNA damage in the nucleolus.

Conclusions:

  • Oxaliplatin triggers a unique ATM/ATR signaling pathway that suppresses Pol I transcription.
  • This pathway operates independently of direct nucleolar DNA damage.
  • The study highlights a distinct mechanism of nucleolar stress and transcriptional silencing linked to DNA damage signaling, contributing to platinum drug cytotoxicity.
Keywords:
DNA damage responsenucleolus" RNA pol Ioxaliplatin

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