Transfer-RNA-derived small RNAs (tsRNAs; also called tRNA-derived fragments) are an abundant class of small non-coding RNAs whose biological roles are not well understood. Here we show that inhibition of a specific tsRNA, LeuCAG3′tsRNA, induces apoptosis in rapidly dividing cells in vitro and in a patient-derived orthotopic hepatocellular carcinoma model in mice. This tsRNA binds at least two ribosomal protein mRNAs (RPS28 and RPS15) to enhance their translation. A decrease in translation of RPS28 mRNA blocks pre-18S ribosomal RNA processing, resulting in a reduction in the number of 40S ribosomal subunits. These data establish a post-transcriptional mechanism that can fine-tune gene expression during different physiological states and provide a potential new target for treating cancer.
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Gene Expression Omnibus
We thank J. Sage for HCC tissues from conditional TKO (Rblox/lox; p130lox/lox; p107−/−) adult mice and liver tissues from p107−/− mice. This work was supported by grants to M.A.K. from the National Institutes of Health (R01AI071068 and R01DK114483). M.A.K. received support from the Stanford Cancer Institute, and S.S. from the CJ Huang Foundation and the TS Kwok Liver Cancer Foundation.
Extended data figures
This file contains gel source data.
This file contains the DNA sequences of the CUG (original) and CUC/CUU (modified) Renilla genes from the psiCHECK-2 plasmid from Fig. 1c.Red colored nucleotides show the LeuCUG codon and blue colored nucleotides are LeuCUU or LeuCUC codons. There are thirteen LeuCUG, four LeuCUU, and five LeuCUC codons in original Renilla gene. Thirteen LeuCUG codons were replaced by CUU or CUC codons in the modified Renilla gene.
This file contains samples that were sequenced in Extended Data Fig. 3d. 50bp paired-end reads were generated on an Illumina HiSeq 2000 machine yielding a total of 10 to 40 million paired-end reads. Sequences were mapped to the human hg19 genome.
This file contains quantification of each ribosomal RNA in Fig. 3d. Each pre-rRNA was normalized by each mature 28S rRNA. Normalized pre-rRNA from Anti-Leu3′ts LNA was again normalized to that of control (con). Normalized pre-rRNA from siRPS6, 10, 13, and 29 were normalized to the siRNA control (sicontrol).
This file contains the list of antisense Locked nucleic acid (LNA), synthetic RNA, and northern probe oligonucleotides. LNA bases are upper-case letters and DNA bases are lower –case letters.
This file contains DNA oligonucleotides used for the target sequences of tsRNAs and microRNAs in the luciferase vector in Extended Data Fig. 3a.
This file contains PCR primers for the generation of the Northern probes.
This file contains Biotin labelled oligonuclotides used for the ChIRP studies in Extended Data Fig. 8a.
This file contains modified nucleotide sequences of the ribosomal protein mutants. Upper characters are altered sequences and the numbers next to each sequence indicate the sequence position in the each ribosomal protein gene.
This file contains primers for site-directed mutageneis.
This file contains icSHAPE scores for the full-length studied mRNAs. Each number represents the scores for each nucleotide. The icSHAPE data are scaled from 0 (no reactivity; double-strandedness) to 1 (maximum reactivity; single-strandedness).