Abstract 2573: DNA damaging drugs stimulate tRNA cleavage through SLFN11 to inhibit protein synthesis and induce cell death

Abstract

Abstract DNA damaging agents (DDAs) based chemotherapies are the first and still the most widely used anticancer treatments. However, quickly developed drug resistance of cancer cells often impedes their efficacies. Two independent transcriptome analyses in vast collections of cancer cell lines discovered that human SLFN11 is the only gene whose expression significantly sensitizes cancer cells to DNA damaging agents (DDAs) including Top1 and Top2 inhibitors, DNA alkylating agents, and DNA synthesis inhibitors. But the mechanism was unclear. We showed previously that SLFN11 inhibits HIV viral proteins syntheses by modulating tRNAs abundances and exploiting the biased codon usage of the virus. We hereby report that upon DDAs treatment, SLFN11 preferentially inhibits translation of genes involved in DNA damage response and repair, including ATR and ATM, based on their distinct codon usages, while the early DNA damage response signaling remains unaffected. Type II tRNAs, which include all serine and leucine tRNAs, are cleaved in a SLFN11-dependent manner in response to DDAs. The syntheses of proteins encoded by genes with high TTA (Leu) codon usage such as ATR display utmost susceptibility to SLFN11 expression due to the extreme low abundance of cognate tRNA-Leu-TAA. Specific inhibition of tRNA-Leu-TAA expression with special antisense oligonucleotides (Gapmers) suppressed ATR protein expression and restored DDA sensitivity of SLFN11-deficient cancer cells. Our study uncovered a novel mechanism of DNA damage response regulation mediated by SLFN11-dependent tRNA cleavage and codon-specific translational inhibition. Further investigation will elucidate the roles of SLFN11 in DNA damage-related tumorigenesis. More importantly, bioinformatics analysis revealed high frequency of codon TTA (Leu) usage in most genes involved in DNA damage response signaling and repair mechanisms including Homology Directed Repair (HDR), Nonhomologous End-Joining (NHEJ), and Mismatch Mediated Repair (MMR). Instead of targeting single gene product, novel therapies based on the modulation of tRNA-Leu-TAA expression would effect by inhibiting the protein synthesis of a wide spectrum of genes involved in DNA damage response and repair, thus preventing the development of drug resistance by cancer cells. Citation Format: Manqing Li, Elaine Kao, Dane Malone, Xia Gao, Jean Y. Wang, Michael David. DNA damaging drugs stimulate tRNA cleavage through SLFN11 to inhibit protein synthesis and induce cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2573.