Abstract
Transcriptome analysis reveals a strong positive correlation between human Schlafen family member 11 (SLFN11) expression and the sensitivity of tumor cells to DNA-damaging agents (DDAs). Here, we show that SLFN11 preferentially inhibits translation of the serine/threonine kinases ATR and ATM upon DDA treatment based on distinct codon usage without disrupting early DNA damage response signaling. Type II transfer RNAs (tRNAs), which include all serine and leucine tRNAs, are cleaved in a SLFN11-dependent manner in response to DDAs. Messenger RNAs encoded by genes with high TTA (Leu) codon usage, such as ATR, display utmost susceptibility to translational suppression by SLFN11. Specific attenuation of tRNA-Leu-TAA sufficed to ablate ATR protein expression and restore the DDA sensitivity of SLFN11-deficient cells. Our study uncovered a novel mechanism of codon-specific translational inhibition via SLFN11-dependent tRNA cleavage in the DNA damage response and supports the notion that SLFN11-deficient tumor cells can be resensitized to DDAs by targeting ATR or tRNA-Leu-TAA.
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Acknowledgements
The authors wish to thank R. Lardelli and M. Arribas-Layton for assistance with northern blot and polysome profile analyses. This work was supported by grants R01-GM101982 and R21-AI124199 to M.D.
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M.L., J.Y.W. and M.D. conceived the experiments. E.K. and X.G. performed the cell viability studies, ATR experiments and polysome analysis. M.L., X.G. and D.M. are responsible for all tRNA data and codon usage studies. M.L. and X.G. designed and performed all gapmer related studies. M.L., E.K. and D.M. generated the figures. M.L. and M.D. wrote the manuscript.
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Supplementary Tables 1–6
Supplementary Dataset 1
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Supplementary Dataset 2
Source data for Fig. 6a
Supplementary Dataset 3
Source data for Fig. 6b
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Li, M., Kao, E., Malone, D. et al. DNA damage-induced cell death relies on SLFN11-dependent cleavage of distinct type II tRNAs. Nat Struct Mol Biol 25, 1047–1058 (2018). https://doi.org/10.1038/s41594-018-0142-5
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DOI: https://doi.org/10.1038/s41594-018-0142-5
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