Queuosine-modification dependent histidyl tRNA fragment promotes cell-type dependent proliferation

Abstract

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 tRNA modifications affect tRF biogenesis. 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 dependencies on mammalian cell proliferation. We found that Q-modified tRNA can either increase, decrease, or make no difference in proliferation. Proliferation decreased in MCF7, a breast cancer cell line, when tRNAs were Q-modified and dependent on the modification enzyme complex, QTRT1/2. MCF7 proliferation increases upon the transfection of Q-modification-dependent tRFHis or decreases upon knockdown of endogenous tRFHis. Consistent with Q-dependent proliferation reduction, polysome profiling showed decreased translation efficiency of ribosomal proteins. Finally, protein pull-down of MCF7 lysates using tRFHis identified Musashi RNA-binding protein 2 (Msi2) as a tRFHis-binding protein. Msi2 knockdown reduced the Q-modification-dependent or 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.