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DNA damage-induced cell death relies on SLFN11-dependent cleavage of distinct type II tRNAs
Open accessAbstract
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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“To functionally implicate SLFN11 in response to DNA-damaging chemotherapeutics (topoisomerase inhibitors, an anti-metabolite, and an alkylating agent), Li et al. demonstrated that genetic inhibition of SLFN11 expression caused chemoresistance [28].”
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Metadata
- Authors
- Li, M., Kao, E., Malone, D., Gao, X., Wang, J. Y. J., & David, M.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Li, Manqing
- David, Michael
- Venue
- Nature Structural & Molecular Biology
- Published
- 2018-10-29
- Volume
- 25
- Issue
- 11
- Pages
- 1047-1058
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC6579113
- OpenAlex
- W2895818115
- Cited by
- 136
- References
- 28
- Citations by year
- 2026: 18 · 2025: 27 · 2024: 20 · 2023: 18 · 2022: 12 · 2021: 17 · 2020: 11 · 2019: 13
- FWCI
- 3.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM101982, R01GM128155)
- National Institute of Allergy and Infectious Diseases (R21AI088490, R21AI124199)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- SLFN11, DNA damage response, ATR kinase, ATM kinase, DNA-damaging agents, camptothecin, tumor cell sensitivity
- MeSH terms
- Camptothecin, Codon, DNA Damage, Humans, Nuclear Proteins, RNA, Transfer, RNA, Transfer, Leu, Protein Biosynthesis, Cell Death, RNA, Small Interfering, Cell Line, Tumor, HEK293 Cells, Topoisomerase I Inhibitors, Ataxia Telangiectasia Mutated Proteins
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