Related Experiment Video

Updated: Jun 3, 2025

Chemotherapy-induced Vascular Toxicity - Real-time In vivo Imaging of Vessel Impairment
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Chemotherapy-induced Vascular Toxicity - Real-time In vivo Imaging of Vessel Impairment

Published on: January 7, 2015

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METTL3-Mediated m6A Modification of ISG15 mRNA Regulates Doxorubicin-Induced Endothelial Cell Apoptosis

Dongdong Jian1,2, Han Li3,4, Chenqiu Wang3

  • 1Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.

Journal of Cellular and Molecular Medicine
|January 9, 2025
PubMed

Insights

Methyltransferase-like 3 (METTL3) protects against doxorubicin-induced vascular injury by methylating interferon-stimulated gene 15 (ISG15) RNA. This m6A modification reduces ISG15 levels, preventing endothelial cell apoptosis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • N6-adenosine methylation (m6A) regulates diverse biological processes and diseases.
  • The role of m6A in chemotherapy-induced vascular endothelial injury remains unclear.

Purpose of the Study:

  • To investigate the role of methyltransferase-like 3 (METTL3) in doxorubicin (DOX)-induced vascular endothelial injury.
  • To elucidate the molecular mechanism by which METTL3 affects endothelial cell apoptosis.

Main Methods:

  • In vivo and in vitro models of DOX-induced vascular endothelial injury.
  • Transcriptome and proteome sequencing.
  • Methylated RNA immunoprecipitation (meRIP)-qPCR and mRNA stability assays.
  • Gene silencing techniques (METTL3 and ISG15).

Main Results:

  • METTL3 expression decreased in DOX-treated vascular endothelial cells, exacerbating apoptosis.
  • METTL3 silencing led to increased interferon-stimulated gene 15 (ISG15) mRNA and protein levels.
  • METTL3 directly methylated ISG15 RNA at site 1,014,147, reducing ISG15 mRNA stability.
  • ISG15 knockdown attenuated DOX-induced endothelial cell apoptosis and dysfunction.

Conclusions:

  • METTL3-mediated m6A modification of ISG15 mRNA is a key mechanism in DOX-induced endothelial cell apoptosis.
  • METTL3-ISG15 pathway represents a potential therapeutic target for chemotherapy-associated vascular injury.
Keywords:
ISG15METTL3apoptosisdoxorubicinendothelial cell

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