Queuosine-modification dependent histidyl tRNA fragment promotes cell-type dependent proliferation [RNA-Seq]

tRNA fragments (tRFs) are natural, small non-coding RNAs produced by endogenous ribonucleolytic cleavage of tRNAs. tRFs play a role in many biological pathways including regulation of cell proliferation. Specific modifications also affect tRF abundance and the abundance of their cognate, full-length tRNA. Queuosine (Q) modification occurs at the wobble anticodon nucleotide of 4 mammalian tRNAs and protects these tRNAs from fragmentation. Here, we investigated cell-type and tRNA Q-modification-dependences on cell proliferation. We found that Q-modified tRNA can either increase, decrease, or make no difference on proliferation. Among the six cell lines tested, proliferation only decreased in MCF7, a breast cancer cell line, when tRNAs were Q-modified, but the proliferation can be restored by the transfection of Q-modification-dependent tRFHis. tRNA-seq showed that in MCF7 cells, tRNA Q-modification reduced m1A58 and m3C32 modification levels, consistent with reduced translation. Additionally, polysome profiling showed a Q-modification associated codon usage pattern that corresponded with altered translation efficiency of ribosomal proteins required for faster proliferation. Protein pull-down using tRFHis identified Musashi RNA binding protein 2 (Msi2) as a tRFHis binding protein. Msi2 is known to enhance mitochondrial activities, and Msi2 knockdown reduced the tRFHis dependent cell proliferation effect. Our results illustrate a highly cell-type dependent proliferation effect of tRNA Q-modification, suggesting multi-faceted mechanisms in studying this ubiquitous tRNA modification.