Related Experiment Video

Updated: Jun 1, 2025

Detection and Visualization of DNA Damage-induced Protein Complexes in Suspension Cell Cultures Using the Proximity Ligation Assay
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Detection and Visualization of DNA Damage-induced Protein Complexes in Suspension Cell Cultures Using the Proximity Ligation Assay

Published on: June 9, 2017

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SLFN11-mediated tRNA regulation induces cell death by disrupting proteostasis in response to DNA-damaging agents

Yuki Iimori1,2, Teppei Morita1,2, Takeshi Masuda1,2

  • 1Institute for Advanced Biosciences, Keio University, Tsuruoka, 997-0017, Japan.

Biorxiv : the Preprint Server for Biology
|January 20, 2025
PubMed

Insights

Schlafen 11 (SLFN11) sensitizes cancer cells to DNA-damaging agents (DDAs) by degrading tRNA. This leads to endoplasmic reticulum stress and cell death, offering new therapeutic targets for overcoming cancer drug resistance.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Death Mechanisms

Background:

  • DNA-damaging agents (DDAs) are vital cancer therapeutics, but their precise cell death mechanisms and associated drug resistance are not fully understood.
  • Schlafen 11 (SLFN11) gene expression strongly correlates with DDA sensitivity.
  • SLFN11's role in DDA-induced cell death requires further elucidation to address clinical challenges.

Purpose of the Study:

  • To investigate the detailed mechanism by which SLFN11 induces cell death in response to DDAs.
  • To explore the role of SLFN11 in regulating tRNA and its impact on proteostasis and cell fate.
  • To identify potential therapeutic strategies targeting SLFN11 for improved cancer treatment.

Main Methods:

  • Analysis of SLFN11's effect on tRNALeu(TAA) cleavage and downregulation upon DDA treatment.
  • Investigation of endoplasmic reticulum (ER) stress and cell death pathways involving inositol-requiring enzyme 1 alpha (IRE1α).
  • Proteomic analysis to assess the impact of tRNALeu(TAA) on proteostasis and ubiquitin-dependent proteolysis.

Main Results:

  • SLFN11 cleaves tRNALeu(TAA) upon DDA administration, inducing ER stress and cell death regulated by IRE1α.
  • SLFN11 knockout or tRNALeu(TAA) transfection significantly alleviated DDA-induced responses.
  • Proteomic data indicate tRNALeu(TAA) affects proteostasis proteins, particularly in ubiquitin-dependent proteolysis.
  • Specific tRNALeu(TAA) cleavage sites were identified, and tRNA fragments were found to contribute to ER stress and cell death.

Conclusions:

  • SLFN11 critically regulates proteostasis by controlling tRNA levels, thereby determining cancer cell fate under DDA treatment.
  • The SLFN11-tRNA-ER stress axis represents a key mechanism in DDA-induced cell death.
  • Targeting SLFN11-mediated tRNA regulation offers a promising novel strategy to enhance cancer therapy and overcome drug resistance.

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