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DNA damage-induced cell death relies on SLFN11-dependent cleavage of distinct type II tRNAs

Manqing Li1, Elaine Kao2, Dane Malone2

  • 1Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA. m5li@ucsd.edu.

Nature Structural & Molecular Biology
|October 31, 2018
PubMed

Insights

Schlafen family member 11 (SLFN11) inhibits tumor cell DNA-damaging agent sensitivity by suppressing ATR and ATM translation via tRNA cleavage. Restoring ATR or tRNA-Leu-TAA can re-sensitize SLFN11-deficient cells to DNA-damaging agents.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Schlafen family member 11 (SLFN11) expression correlates with tumor cell sensitivity to DNA-damaging agents (DDAs).
  • The precise mechanism linking SLFN11 to DDA sensitivity remains incompletely understood.
  • Understanding SLFN11's role is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To elucidate the mechanism by which SLFN11 influences tumor cell response to DDAs.
  • To investigate the role of codon usage and tRNA cleavage in SLFN11-mediated translational inhibition.
  • To identify potential therapeutic strategies for resensitizing SLFN11-deficient tumors.

Main Methods:

  • Transcriptome analysis to identify correlations between SLFN11 and DDA sensitivity.
  • Investigating the impact of SLFN11 on the translation of specific kinases (ATR, ATM) upon DDA treatment.
  • Analyzing SLFN11-dependent cleavage of Type II tRNAs (serine and leucine tRNAs) in response to DDAs.
  • Assessing the effect of tRNA-Leu-TAA attenuation on ATR expression and DDA sensitivity.

Main Results:

  • SLFN11 preferentially inhibits ATR and ATM translation through codon usage bias upon DDA treatment.
  • SLFN11 induces cleavage of Type II tRNAs, including tRNA-Leu-TAA, in response to DDAs.
  • Messenger RNAs with high TTA (Leu) codon usage, like ATR, are highly susceptible to SLFN11-mediated translational suppression.
  • Reducing tRNA-Leu-TAA levels effectively blocks ATR protein expression and restores DDA sensitivity in SLFN11-deficient cells.

Conclusions:

  • SLFN11 employs a novel mechanism of codon-specific translational inhibition via tRNA cleavage during the DNA damage response.
  • SLFN11-deficient tumors can potentially be resensitized to DDAs by targeting ATR or tRNA-Leu-TAA.
  • This study provides a mechanistic basis for SLFN11's role in DDA sensitivity and suggests new therapeutic avenues.

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