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

Transcriptome analysis revealed a strong positive correlation between human SLFN11 expression and the sensitivity of tumor cells to DNA damaging agents (DDAs). We show here that SLFN11 preferentially inhibits translation of ATR or ATM upon DDAs treatment based on distinct codon usage without disrupting early DNA damage response signaling. Type II tRNAs, which include all serine and leucine tRNAs, are cleaved in a SLFN11-dependent manner in response to DDAs. mRNAs 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 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.