Related Experiment Video

Updated: Sep 11, 2025

Detection and Visualization of DNA Damage-induced Protein Complexes in Suspension Cell Cultures Using the Proximity Ligation Assay
13:10

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

Published on: June 9, 2017

10.1K

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

Yuki Iimori1,2, Teppei Morita1,2,3, Takeshi Masuda1,2

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

Nucleic Acids Research
|August 14, 2025
PubMed

Insights

Schlafen 11 (SLFN11) sensitizes cancer cells to DNA-damaging agents (DDAs) by cleaving tRNALeu(TAA), causing ER stress and cell death. Targeting this SLFN11-tRNA pathway offers a new strategy to overcome cancer drug resistance.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Stress Response

Background:

  • DNA-damaging agents (DDAs) are vital cancer therapeutics, but their precise cell death mechanisms and acquired drug resistance are significant clinical hurdles.
  • Schlafen 11 (SLFN11) gene expression strongly correlates with DDA sensitivity, indicating its critical role in treatment response.
  • SLFN11 sensitizes cancer cells to DDAs by reducing tRNALeu(TAA) levels, but the downstream effects remain incompletely understood.

Purpose of the Study:

  • To elucidate the detailed molecular mechanism by which SLFN11 induces cell death upon DDA treatment.
  • To investigate the role of tRNALeu(TAA) cleavage and subsequent cellular events in DDA-induced cytotoxicity.
  • To explore the potential of targeting the SLFN11-tRNA axis for novel cancer therapy strategies.

Main Methods:

  • Administration of DDAs to cancer cells with varying SLFN11 expression levels.
  • Analysis of tRNALeu(TAA) levels, endoplasmic reticulum (ER) stress markers, and protein aggregation.
  • Utilizing SLFN11-knockout and tRNALeu(TAA)-transfected cells to assess functional impact.
  • Proteomic analysis to identify proteins affected by tRNALeu(TAA) levels.
  • Identification of specific tRNA cleavage sites generated by SLFN11.

Main Results:

  • SLFN11-mediated cleavage of tRNALeu(TAA) upon DDA treatment triggers significant ER stress and protein aggregate formation.
  • Inositol-requiring enzyme 1 alpha (IRE1α) pathway is involved in regulating DDA-induced cell death mediated by SLFN11.
  • SLFN11-knockout or tRNALeu(TAA) re-expression substantially alleviated DDA-induced stress and cell death.
  • Proteomic data indicate tRNALeu(TAA) influences proteostasis, particularly ubiquitin-dependent proteolysis.
  • Specific tRNA fragments resulting from SLFN11 cleavage were identified and shown to contribute to ER stress and cell death.

Conclusions:

  • SLFN11 critically regulates proteostasis by controlling tRNALeu(TAA) levels, thereby determining cancer cell fate under DDA stress.
  • The SLFN11-tRNA-ER stress-IRE1α axis represents a key mechanism of DDA-induced cell death.
  • Targeting SLFN11 and its regulation of tRNA offers a promising therapeutic avenue to enhance DDA efficacy and overcome drug resistance in cancer treatment.

More Related Videos

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics06:00

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics

Published on: May 14, 2016

11.1K
Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage10:59

Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage

Published on: August 21, 2021

3.7K

Related Concept Videos

DNA Damage can Stall the Cell Cycle02:37

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.3K
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.6K
Replicative Cell Senescence02:15

Replicative Cell Senescence

Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism's lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere — short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase — an enzyme that adds...
3.7K
Overview of DNA Repair02:25

Overview of DNA Repair

In order to be passed through generations, genomic DNA must be undamaged and error-free. However, every day, DNA in a cell undergoes several thousand to a million damaging events by natural causes and external factors. Ionizing radiation such as UV rays, free radicals produced during cellular respiration, and hydrolytic damage from metabolic reactions can alter the structure of DNA. Damages caused include single-base alteration, base dimerization, chain breaks, and cross-linkage.
Chemically...
31.6K
DNA Damage Can Stall the Cell Cycle02:37

DNA Damage Can Stall the Cell Cycle

2.7K
Translesion DNA Polymerases02:10

Translesion DNA Polymerases

Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
10.1K